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WO2012025925A1 - Procédés d'amélioration de la transplantation en utilisant des sdf-1alpha - Google Patents

Procédés d'amélioration de la transplantation en utilisant des sdf-1alpha Download PDF

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Publication number
WO2012025925A1
WO2012025925A1 PCT/IL2011/000683 IL2011000683W WO2012025925A1 WO 2012025925 A1 WO2012025925 A1 WO 2012025925A1 IL 2011000683 W IL2011000683 W IL 2011000683W WO 2012025925 A1 WO2012025925 A1 WO 2012025925A1
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WO
WIPO (PCT)
Prior art keywords
tissue
cell
fat
subject
sdf
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PCT/IL2011/000683
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English (en)
Inventor
Saher Hamed
Yehuda Ullmann
Benjamin Brenner
Ariel Roguin
Original Assignee
Rappaport Family Institute For Research In The Medical Sciences
Fund For Medical Research Development Of Infrastructure And Health Services - At Rambam Medical Center
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Publication of WO2012025925A1 publication Critical patent/WO2012025925A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/195—Chemokines, e.g. RANTES
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution

Definitions

  • the present invention in some embodiments thereof, relates to the use of SDF- la for improving transplantation of cells, tissues or organ grafts including fat grafts.
  • EPCs endothelial progenitor cells
  • BM-MNCs BM mononuclear cells
  • VEGF vascular endothelial cell growth factor
  • the stromal cell-derived factor- la (SDF-la, GenBank Accession Nos.
  • NM_000609 and NM_199168 also referred to as CXCL12
  • CXCL12 is produced by many cell types, including bone marrow stromal cells, astrocytes and endothelial cells.
  • SDF-la typically binds CXCR4, also known as fusin or LESTR, which has a wide cellular distribution, with expression on most immature and mature hematopoietic cell types, vascular endothelial cells and neuronal/nerve cells.
  • the SDF- la/CXCR4 pathway is critical for hematopoiesis, and for vascular and cardiac development.
  • SDF-la is essential for EPC homing, mobilization, and differentiation [Lapidot et al. Blood. (2005) 106(6):1901-10]. It induces the expression of VEGF, and stimulates angiogenesis in vivo [Salcedo R et al., Am J Pathol. (1999) 154(4):1125-35]. Recent reports demonstrated that local delivery of the SDF-la protein [Yamaguchi J. et al. Circulation.
  • U.S. Patent Application No. 2010/0166717 discloses methods of treating ischemic disorders and tissue injuries by administering SDF-1 to ischemic tissues of the subject in an amount effective for inhibiting cell apoptosis.
  • PCT Publication No. 2008/019434 discloses use of agents to enhance adipogenesis and to promote fat graft survival.
  • growth factors e.g. platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and/or fibroblast growth factor (FGF)
  • PDGF platelet-derived growth factor
  • VEGF vascular endothelial growth factor
  • FGF fibroblast growth factor
  • a method of enhancing transplantation of a cell, a tissue or an organ graft in a subject in need thereof comprising administering to a subject who has undergone transplantation of a cell, a tissue or an organ graft a therapeutically effective amount of SDF-lalpha, thereby enhancing transplantation of the cell, the tissue or the organ graft in the subject.
  • a method of enhancing survival of a cell, a tissue or an organ graft in a subject in need thereof comprising: (a) implanting a cell, a tissue or an organ graft into the subject; and (b) administering to the subject a therapeutically effective amount of SDF-lalpha, thereby enhancing survival of the cell, the tissue or the organ graft in the subject.
  • a method of enhancing survival of a cell, a tissue or an organ graft in a subject in need thereof comprising: (a) contacting a cell, a tissue or an organ graft with SDF-lalpha; and (b) implanting the cell, the tissue or the organ graft into the subject, thereby enhancing survival the cell, the tissue or the organ graft in the subject.
  • SDF-lalpha for enhancing survival of a cell, a tissue or an organ graft in a subject in need thereof.
  • a pharmaceutical composition comprising a cell, a tissue or an organ graft, SDF-lalpha and a pharmaceutically acceptable carrier or diluent.
  • a method of enhancing survival of a fat cell or fat tissue in a subject in need thereof comprising: (a) implanting a fat cell or fat tissue into the subject; and (b) administering to the subject a therapeutically effective amount of SDF-lalpha, thereby enhancing survival of the fat cell or fat tissue.
  • the cell or the tissue is a fat cell or fat tissue.
  • the cell or the tissue is a beta cell graft.
  • the subject has diabetes.
  • the fat cell or fat tissue is for treating a soft tissue defect.
  • the soft tissue defect is selected from the group consisting of a skin condition, a skin malady, a wound, a burn, a cancer, a surgery, a reconstruction surgery, a skin depression, a congenital malformation and an acquired disease.
  • the method further comprises contacting the cell, the tissue or the organ graft with SDF-lalpha prior to the implanting.
  • the subject is treated with a therapeutically effective amount of SDF-lalpha prior to the implanting of the cell, the tissue or the organ graft.
  • the method further comprises administering a therapeutically effective amount of SDF-lalpha to the subject following the implanting.
  • the administering is effected by direct injection of the SDF-lalpha into the cell, the tissue or the organ graft.
  • the dose of the SDF-lalpha is about 1 pg/1,000,000 cells to about 1 mg/1,000,000 cells per injection.
  • the administering the SDF- lalpha is effected by a systemic route.
  • the dose of the SDF-lalpha is about 1 pg/kg to about 1 mg/kg body weight.
  • the therapeutically effective amount is for promoting angiogenesis and reducing apoptosis of the cell, the tissue or the organ graft.
  • the subject is diabetic.
  • the subject is a human subject.
  • the cell, the tissue or the organ graft is selected from the group consisting of a cardiac, a retina, a liver, a kidney, a lung, a splenic, a bone, a cartilage and a lymph cell, tissue or organ.
  • the tissue or the organ graft is a solid tissue or a solid organ.
  • the cell, the tissue or the organ graft is from an autologous origin.
  • the method further comprises administering to the subject endothelial precursor cells (EPCs).
  • EPCs endothelial precursor cells
  • the method further comprises administering to the subject at least one factor selected from the group consisting of an extracellular matrix component, a growth factor, a hormone, an angiogenic factor, a coagulation factor, a cytokine, a chemokine, an enzyme, a neurotransmitter, a vitamin, a carbohydrate, an ion, an iron chelator, a fatty acid, an antibiotic and an amino acid.
  • at least one factor selected from the group consisting of an extracellular matrix component, a growth factor, a hormone, an angiogenic factor, a coagulation factor, a cytokine, a chemokine, an enzyme, a neurotransmitter, a vitamin, a carbohydrate, an ion, an iron chelator, a fatty acid, an antibiotic and an amino acid.
  • the pharmaceutical composition further comprises at least one factor selected from the group consisting of an extracellular matrix component, a growth factor, a hormone, an angiogenic factor, a coagulation factor, a cytokine, a chemokine, an enzyme, a neurotransmitter, a vitamin, a carbohydrate, an ion, an iron chelator, a fatty acid, an antibiotic, and an amino acid.
  • at least one factor selected from the group consisting of an extracellular matrix component, a growth factor, a hormone, an angiogenic factor, a coagulation factor, a cytokine, a chemokine, an enzyme, a neurotransmitter, a vitamin, a carbohydrate, an ion, an iron chelator, a fatty acid, an antibiotic, and an amino acid.
  • the dose of the SDF-lalpha in the pharmaceutical composition is about 1 pg/kg to about 1 mg/kg body weight.
  • the method further comprises contacting fat cell or fat tissue with SDF-lalpha prior to the implanting.
  • the administering is effected systemically.
  • the administering is effected locally.
  • the fat cell or fat tissue is for treating a soft tissue defect.
  • all technical and/or scientific terms used herein have- the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.
  • methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control.
  • the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
  • FIGs. 1A-T are photographs depicting mice 15 weeks after fat transplantation.
  • Figure 1A is a photograph of a representative mouse at day 1 post fat transplantation
  • Figures 1B-D are photographs of a representative mouse undergoing a fat graft dissection 15 weeks post fat transplantation
  • Figures 1E-L are photographs of representative non-homogenous lumps in the scalps of mice from the different treatment groups at week 15 (as indicated in the photographs)
  • Figures 1M-T are photographs of representative fat grafts after dissection from the different treatment groups (as indicated in the photographs).
  • FIGs. 2A-D are graphs depicting fat weight and volume.
  • Figure 2A-B are graphs of mean weights of fat grafts from non-diabetic mice (Figure 2A) and from diabetic mice ( Figure 2B); and
  • Figure 2C-D are graphs of mean volumes of fat grafts from non- diabetic mice ( Figure 2C), and from diabetic mice ( Figure 2D).
  • FIGs. 3A-D are graphs depicting EPC number in bone marrow mononuclear cells
  • FIGS. 3A-B are graphs of mean EPC number from BM ( Figure 3A) and from PB ( Figure 3B) calculated by double staining with acLDL and BS-1 lectin;
  • Figures 3C-D are graphs of mean EPC number from BM ( Figure 3C) and from PB ( Figure 3D) calculated by FACS using Sca-1 and Flk-1 double staining. *P ⁇ 0.05, **P ⁇ 0.001, ⁇ P ⁇ 0.001.
  • FIGs. 4A-Q are photographs depicting morphology and characterization of EPCs.
  • Endothelial progenitor cells EPCs
  • Figures 4A-C are photographs of uptake of acetylated LDL by spindle-shaped adherent EPCs, FITC-conjugated lectin BS-1 binding on the EPC cell surface, and the merged image, respectively
  • Figures 4D-F are photographs of immunofluorescence detection of CD31 (red, Figure 4D) and CD34 (green, Figure 4E) on the EPC surface, and the merged image (Figure 4F)
  • Figures 4G-I are photographs of immunofluorescence detection of Sca-1 (red, Figure 4G), Flk-1 (green, Figure 4H) and merged image ( Figure 41).
  • EPC nuclei are blue because the cells were counterstained with the fluorescent DNA dye DRAQ5TM. Scale bar: 20 ⁇ ;
  • Figures 4J- Q are photographs of double staining with acLDL and lectin BS-1 binding on the EPC cell surface, isolated from PB-MNCs of mice treated as indicated.
  • FIGs. 5A-B are graphs depicting the effect of SDFla on MVD in fat grafts following fat transplantation. Each bar represents the mean MVD ⁇ SD from five fields of the pooled data in fat grafts of non-diabetic mice ( Figure 5A) and diabetic mice ( Figure 5B). *P ⁇ 0.05, **P ⁇ 0.001, ⁇ P ⁇ 0.001.
  • Figures 6A-H are representative micrographs as follows: from a PBS-treated fat graft in a non-diabetic mouse ( Figure 6A), from a SDFlotreated fat qjaft in a non-diabetic mouse ( Figure 6B), from an EPC-treated fat graft in a diabetic mouse ( Figure 6C) and from a SDF la-treated fat graft in a diabetic mouse ( Figure 6D);
  • Figures 6E-H are representative micrograph of CD31 -stained sections as follows: a PBS- treated fat graft of a non-diabetic mouse ( Figure 6E), a SDF la-treated fat graft in a non- diabetic mouse ( Figure 6F), an EPC-treated fat graft in a diabetic mouse ( Figure 6G) and a SDF la-treated fat graft in a diabetic mouse ( Figure 6H). Scale bar: 200 ⁇ .
  • FIGs. 7A-B are graphs depicting the effect of SDFla on angiogenic and apoptotic factors in the fat grafts.
  • Figure 7A is a graph depicting western blot analysis of protein expression of the angiogenic factors VEGF, CXCR4, AKT and eNOS in the fat grafts in diabetic mice; and
  • Figure 7B is a graph depicting western blot analysis of protein expression of the apoptotic factors caspase 3 and cytochrome c in the fat grafts in diabetic mice.
  • Each bar represents the mean protein expression of each factor ⁇ SD in the fat grafts.
  • FIGs. 8A-B are graphs depicting the effect of SDFla on in-vivo EPC migration and in-vitro EPC tube formation in matrigel.
  • Figure 8A the feeder trays were coated with 100 ⁇ of EBM-2 containing 200 ng/ml of SDFla. EPC migration was allowed for 12 hours after plating them on a Boyden membrane chamber. Extent of migration was assessed by the intensity of the fluorescence signal as measured by a fluorescence spectrophotometer, and the results were expressed as the average of relative fluorescence units (RFU). Each bar represents the mean RFU percentage of non-diabetic control ⁇ SD in the Boyden chamber for each group.
  • Figure 8B depicts EPC tube formation on matrigel in vitro with the different treatments. Each bar represents the mean percentage of tube formation score of non-treated control EPCs ⁇ SD for each treatment. **P ⁇ 0.001
  • the present invention in some embodiments thereof, relates to the use of SDFla for improving transplantation of cells, tissues or organ grafts including fat grafts.
  • the present inventors have utilized a nude mouse model (diabetic and non-diabetic mice) and injected subcutaneously thereto human fat tissue.
  • the fat grafts were treated with either EPCs (in diabetic mice) or with SDF-la (in diabetic and nori-diabetic mice) and the results were compared to PBS-treated fat grafts of non-diabetic and diabetic mice.
  • a method of enhancing survival of a cell, a tissue or an organ graft in a subject in need thereof comprising: (a) implanting a cell, a tissue or an organ graft into the subject; and prior to, concomitantly with, or following (b) administering to the subject a therapeutically effective amount of SDF-la.
  • SDF-la is administrated following transplantation of a cell, tissue or organ graft.
  • a cell, a tissue or an organ graft refers to a cell, group of cells, bodily tissue or organ which may be transplanted in full or in part, including solid tissues and soft tissues.
  • Exemplary cells, tissues or organs which may be transplanted according to the present teachings include, but are not limited to, liver, pancreas, spleen, kidney, heart, lung, skin, intestine, retina, bone, cartilage, fat and lymphoid/hematopoietic (e.g. lymph node, Peyer's patches thymus or bone marrow) cells, tissues or organs-
  • the cell or tissue is a fat cell or fat tissue.
  • a method of enhancing survival of a fat cell or fat tissue in a subject in need thereof comprising: (a) implanting a fat cell or fat tissue into the subject; and (b) administering to the subject a therapeutically effective amount of SDF-1 alpha.
  • fat cell or “fat tissue” as used herein refer to any cell or group of cells composed in a fat tissue, including for example, lipocytes, adipocytes, adipocyte precursors including pre-adipocytes and mesenchymal stem cells. It will be appreciated that according to the present teachings, the fat cells may be dispersed or may be comprised in a tissue.
  • the cell or tissue is a beta cell graft.
  • beta cell graft refers to the pancreatic islet endocrine cells capable of producing and secreting insulin (e.g. in response to physiological signals such as elevated glucose concentrations) and expressing typical beta cell markers including, but not limited to, insulin, pdx, ⁇ , PCl/3, Beta2, Nkx2.2, GLUT2 and
  • the cell, tissue or organ graft may be naive i.e., not subject to treatment or culturing prior to implantation, or a treated cell, tissue or organ graft which has been subject to culturing or genetic modification.
  • the graft can be of fully differentiated cells (i.e., fetal or adult somatic tissue) or can be partially or terminally differentiated.
  • the tissue or organ comprises a solid tissue or organ.
  • the cells comprise isolated cells.
  • the isolated cells may be of homogeneous or heterogeneous nature.
  • the number of cells may vary over a wide range and one of ordinary skill in the art will recognize that this number will vary depending upon the type and size of the area to be treated, the relative degree of vascularization of the area to be treated, the age of the subject to be treated and the relative viability of the cells available for transplantation. It will be appreciated that the number of cells transplanted may be adjusted according to the procedure used, the site of injection and the relative vascularization of the site to be injected. One of ordinary skill in the art will recognize that certain conditions may necessitate the adjustment of the cell numbers outside of the below described ranges.
  • the number of fat cells for transplantation range from about 100 to about 1000 cells per 1 ml, 100 to about 10,000 cells per 1 ml, 100 to about 100,000 cells per 1 ml, 100 to about 1,000,000 cells per 1 ml, about 1,000 to about 100,000 cells per 1 ml, about 1,000 to about 1,000,000 cells per 1 ml, about 10,000 to about 1,000,000 cells per 1 ml, about 10,000 to about 10,000,000 cells per 1 ml, about 10,000 to about 100,000,000 cells per 1 ml, about 100,000 to about 10,000,000 cells per 1 ml, or about 1,000,000 to about 10,000,000 cells per 1 ml.
  • the subject may be administered a single transplantation or several transplantations along a period of time (e.g. about 2, 5, 10, 20, 50, 100 or more transplantation procedures), as described in further detail hereinbelow.
  • a period of time e.g. about 2, 5, 10, 20, 50, 100 or more transplantation procedures
  • the phrase "survival” as used herein refers to the ability of the cell, tissue or organ graft to remain viable and intact following engraftment thereof. Preferably, the cell, tissue or organ graft survives for a period of a few days, a few weeks, a few months or a few years following engraftment thereof.
  • the term "enhancing" in respect to survival of the cell, tissue or organ graft refers to a process of increasing the life span of cells in the graft and/or decreasing the number of cells which undergo resorption, apoptosis or cell death within the graft.
  • enhancing refers to at least about 10 %, 20 %, 50 %, 80 , 90 % increase in viable cells and/or at least about 10 %, 20 %, 50 %, 80 %, 90 % arrest in cell death.
  • Those of skill in the art will understand that various in vitro and in vivo methodologies and assays can be used to assess cell viability, and similarly, various methodologies and assays may be used to assess cell death or cell apoptosis.
  • assessment may be carried out in a cell or tissue sample of the transplanted subject in vitro by FACS analysis, terminal deoxyuridine triphosphate nick end labeling (TUNEL) assay and/or cell viability assays e.g. MultiTox Assays.
  • assessment of graft survival may be carried out in vivo by invasive or non-invasive mechanisms, as for example, using magnetic resonance (MR) for detection of labeled cells (e.g. iron-labeled cells) transplanted into a subject (e.g. using a clinical 3.0-T magnetic resonance scanner).
  • MR magnetic resonance
  • Enhancing survival of the cell, tissue or organ graft according to the present teachings is achieved by administering to the subject SDF-la.
  • SDF-la stromal cell-derived factor-1 alpha
  • a mammalian (e.g., human) C-X-C chemokine polypeptide also designated CXCL12
  • the SDF-la of the present invention is capable of increasing the frequency of circulating endothelial progenitor cells (EPCs) in the subject being transplanted and increasing the microvascular density (MVD) and reducing apoptosis of the graft as further described hereinbelow.
  • EPCs circulating endothelial progenitor cells
  • MVD microvascular density
  • the SDF- la of the present invention is also capable of increasing integration and decreasing inflammation of the graft (see Example 1 of the Examples section which follows).
  • Exemplary SDF-la of the present invention are set forth in GenBank Accession Nos. NP_954637.1, NP_000600.1, NP_001029058.1, NP 001171605.1.
  • any SDF-la known in the art can be used in accordance with the teachings of the present invention.
  • the SDF-la used in accordance with the present invention may be recombinant SDF-la or purified SDF-la.
  • exemplary SDF-la which may be used in accordance with the present invention include, but are not limited to, recombinant human SDF-lcc (CXCL12) available from Sigma Aldrich (MO, USA), from ProSpec-Tany TechnoGene Ltd, or from Cell Sciences.
  • the phrase "subject in need thereof refers to a mammal, preferably a human being, male or female at any age that is in need of a cell, tissue or organ transplantation.
  • the subject is in need of a cell, tissue or organ transplantation (also referred to herein as recipient) due to a disorder or a pathological or undesired condition, state, or syndrome, or a physical, morphological or physiological abnormality which is amenable to treatment via a cell, tissue or organ transplantation. Examples of such disorders or conditions are provided below.
  • the subject has diabetes.
  • diabetes refers to a disease resulting either from an absolute deficiency of insulin (type 1 diabetes) due to a defect in the biosynthesis or production of insulin, or a relative deficiency of insulin in the presence of insulin resistance (type 2 diabetes), i.e., impaired insulin action, in an organism.
  • the diabetic patient thus has absolute or relative insulin deficiency, and displays, among other symptoms and signs, elevated blood glucose concentration, presence of glucose in the urine and excessive discharge of urine. Diabetes is typically associated with massive loss of pancreatic beta cells.
  • diabetic subjects often have diabetic eye disease (e.g. diabetic retinopathy, cataract or glaucoma) as well as peripheral vascular disease and reduced collateral formation leading to conditions such as delayed wound healing and organ transplant rejection.
  • diabetes subject may require transplantation of beta cells (e.g. to replace those destroyed by the disease), of retinal cells (e.g. for treatment of diabetic eye disease as detailed above), of blood vessels (e.g. in peripheral arterial disease), of hair (e.g. for restoration of bald or balding areas, eyelashes, eyebrows, beard hair, chest hair or pubic hair or to fill in scars caused by accidents or surgery such as face-lifts and previous hair transplants) and/or of fat cells or tissues (e.g. for treatment of uncured wounds, for filling of lost tissue, etc. as detailed in further detail below).
  • beta cells e.g. to replace those destroyed by the disease
  • retinal cells e.g. for treatment of diabetic eye disease as detailed above
  • blood vessels e.g. in peripheral arterial disease
  • hair e.g. for restoration of bald or balding areas, eyelashes, eyebrows, beard hair, chest hair or pubic hair or to fill in scars caused by accidents or surgery such as face-lifts and previous hair transplant
  • any transplant including a fat cell or tissue graft, a beta cell graft, a retinal cell graft or a blood vessel graft may be administered to a diabetes subject along with SDF- ⁇ essentially as taught herein, in order to enhance engraftment thereof.
  • the subject has a soft tissue defect.
  • fat transplantation may be used to treat any soft tissue defect, to fill any soft tissue deficit and for augmentation of external and internal surfaces and structures of the body which are missing due to surgery, as a result of aging of a tissue, or due to disease, trauma or an injury. Examples include, but are not limited to, urological surgeries, tumor removal surgeries, reconstructive surgeries and skin surgeries. Likewise, fat transplantation may be used as an alternative to silicone or collagen fillers. Fat transplantation may be used to fill depressions (i.e.
  • Fat transplantation may also be used in numerous other applications, including urological procedures involving the buildup of weak or damaged structural tissue, in treatment of wrinkles, burns, skin conditions, skin maladies and wounds and to augment areas of the body, such as the buttocks, biceps, triceps muscles, calf muscles, breasts, hands and penis. Furthermore, fat transplantation may be used to treat congenital malformations such as Hemifacial microsomia and acquired diseases such as Romberg's lipodystrophy and Acquired immune deficiency syndrome (AIDS).
  • AIDS Acquired immune deficiency syndrome
  • fat cell or tissue transplantation is carried out in a diabetic subject.
  • Transplanting the cell, tissue or organ may be effected in numerous ways, depending on various parameters, such as, for example, the graft type; the type, stage or severity of the disease or condition; the recipient's organ failure; the physical or physiological parameters specific to the subject; and/or the desired therapeutic outcome.
  • transplanting the cell, tissue or organ may be effected using a cell, tissue or organ originating from any of various mammalian species; by implanting the cell, tissue or organ into various anatomical locations of the subject; using cells, or using a whole or partial organ or tissue; and/or by using a transplant consisting of various numbers of discrete organs, tissues, and/or portions thereof.
  • the method may be effected using a cell, tissue or organ which is asyngeneic or non-syngeneic with the subject.
  • a cell, tissue or organ which is "syngeneic" with the subject refers to a cell, tissue or organ which is derived from an individual who is essentially genetically identical with the subject.
  • essentially fully inbred mammals, mammalian clones, or homozygotic twin mammals are syngeneic.
  • syngeneic cells, tissues or organs include cells, tissues or organs derived from the subject (also referred to in the art as "autologous"), a clone of the subject, or a homozygotic twin of the subject.
  • the autologous fat cells are typically taken from a subject to fill in depressions or soft tissue deficits in the body of the same subject in an area of the body other than that site from which the fat cells were removed.
  • a cell, tissue or organ which is "non-syngeneic" (or non- autologous) with the subject refers to a cell, tissue or organ which is derived from an individual who is allogeneic or xenogeneic with the subject's lymphocytes.
  • a cell, tissue or organ which is "allogeneic" with the subject refers to a cell, tissue or organ which is derived from a donor who is of the same species as the subject, but which is substantially non-clonal with the subject. Typically, outbred, non-zygotic twin mammals of the same species are allogeneic with each other.
  • a cell, tissue or organ which is "xenogeneic" with the subject refers to a cell, tissue or organ which substantially expresses antigens of a different species relative to the species of a substantial proportion of the lymphocytes of the subject.
  • outbred mammals of different species are xenogeneic with each other.
  • xenogeneic cells, tissues or organs are obtained from a mammal, such as e.g. of a porcine origin.
  • the fat cells may be obtained from a subject of the same species as the recipient subject (i.e. allogeneic fat cells as for example from a human donor to a human recipient) or from a different species (i.e. xenogeneic fat cells as for example from a porcine donor to a human recipient).
  • a subject of the same species as the recipient subject i.e. allogeneic fat cells as for example from a human donor to a human recipient
  • xenogeneic fat cells as for example from a porcine donor to a human recipient
  • tissue or organ graft it is preferably obtained from a source which is known to be substantially pathogen-free.
  • the cell, tissue or organ may be obtained from a prenatal organism, postnatal organism, an adult or a cadaver donor.
  • a cell, tissue or organ derived from a prenatal organism may be obtained from a fetus at any gestational stage of pregnancy. It will be understood by one skilled in the art that a period of gestation corresponds to a time-period elapsed since fertilization of a developing embryo or fetus. Thus, the stage of differentiation of a developing organ corresponds to the developmental stage of the embryo or fetus from which it is derived. The ordinarily skilled artisan will possess the necessary expertise for suitably obtaining a cell, tissue or organ at a specific gestational stage so as to enable the practicing of the present invention.
  • the cell, tissue or organ according to the present invention may also be obtained from a postnatal organism.
  • the cell, tissue or organ may be obtained from an organism during the period beginning immediately after birth and extending for about six weeks.
  • the cell, tissue or organ may be obtained from an adult, either a living or cadaver donor. If the cell, tissue or organ is obtained from a cadaver donor, it is best to obtain the organ within 36-50 hours of death as to enable optimal chances of engraftment and functionality. In order to minimize rejection of transplanted cells, tissues or organs, it will be appreciated that factors such as blood type and tissue type should be considered prior to transplantation.
  • fat cells are generally obtained by removing same (e.g. by suctioning) from subcutaneous fat layers in the area of the stomach, legs or other areas where significant fat cells may be found.
  • the fat cells of the present invention are substantially free of unrelated cells such as erythrocytes, other blood cells, fibroblasts and other cells which may contaminate the fat cells.
  • these cells are kept in a sterile environment until used for transplantation.
  • the fat cells may be further separated from other components which may be found in the aspirated fat, such as, for example, triglycerides, lysozomes, other cellular fragments, blood components, blood cells and large connective tissue fragments, among other less desirable components, before use. Any methods known in the art may be used to separate the fat cells from these other components, but preferably, at least one centrifugation step is employed.
  • Transplanting a cell, tissue or organ of the present invention may be effected by transplanting the cell, tissue or organ into any one of various anatomical locations, depending on the application.
  • the cell, tissue or organ may be transplanted into a homotopic anatomical location (a normal anatomical location for the transplant), or into an ectopic anatomical location (an abnormal anatomical location for the transplant).
  • the graft may be advantageously implanted under the renal capsule, or into the kidney, the testicular fat, the sub cutis, the omentum, the portal vein, the liver, the spleen, the heart cavity, the heart, the chest cavity, the lung, the pancreas and/or the intra abdominal space.
  • an organ of the present invention when transplanting an organ of the present invention into a subject having a defective organ, it may be advantageous to first at least partially remove the failed organ from the subject so as to enable optimal development of the transplant, and structural/functional integration thereof with the anatomy/physiology of the subject.
  • implanting fat cells may be carried out by any method known in the art, such as for example, by injection thereof into the desired location, by microsurgery and by surgery in cases were a large amount of fat cells or fat tissue is being transplanted.
  • the fat cells are immediately implanted into a subject.
  • the fat cells are implanted within 30 minutes, within an hour, within two hours, within three hours, within four hours or within one day of collection (see e.g. Example 1, of the examples section which follows).
  • the fat cells of the present invention may be preserved for longer periods of time prior to translation in, for example, by freezing in liquid nitrogen.
  • monitoring the size and integration of the fat graft may be monitored via computerized tomography, by magnetic resonance (e.g. MRI), by ultrasound imaging, by assessment of a physician (e.g. surgeon) or by any other acceptable method.
  • the subject following implantation of the cell, tissue or organ graft, the subject is administered SDF-la.
  • SDF-la may be administered via a systemic administration or via a local administration.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration of SDF-la of the present invention.
  • the phrase "local administering” refers to applying the SDF-la of the present invention directly to the area of the implanted graft or in close proximity to the implanted graft.
  • the SDF-la of the present invention is directly administered to the transplanted cell, tissue or organ graft via injection.
  • the contemplated dose of SDF-la applied for local administration may range between about 1 pg kg to about 1 mg/kg, between about 0.01 ng/kg to about 1 mg/kg, between about 0.1 ng/kg to about 1 mg/kg, between about 1 pg/kg to about 0.1 mg/kg, between about 1 pg/kg to about 0.01 mg/kg, between about 1 pg/kg to about 0.001 mg/kg, between about 0.001 ng/kg to about 1000 ng/kg, between about 0.01 ng/kg to about 100 ng/kg, or between about 0.1 ng kg to about 100 ng/kg of SDF-la per kg body weight.
  • the contemplated dose of SDF-la may range between about 1 pg 1,000,000 cells to about 1 mg/1,000,000 cells, between about 0.01 ng/1,000,000 cells to about 1 mg/1,000,000 cells, between about 0.1 ng/1,000,000 cells to about 1 mg/1,000,000 cells, between about 1 pg/1,000,000 cells to about 0.1 mg/1,000,000 cells, between about 1 pg/1,000,000 cells to about 0.01 mg/1,000,000 cells, between about 1 pg 1,000,000 cells to about 0.001 mg/1,000,000 cells, between about 0.001 ng/1,000,000 cells to about 1000 ng/1,000,000 cells, between about 0.01 ng/1,000,000 cells to about 100 ng/1,000,000 cells, or between about 0.1 ng/1,000,000 cells to about 100 ng/1,000,000 cells of SDF- ⁇ per administration.
  • the dose of SDF- ⁇ for systemic administration may range between about 1 pg/kg to about 1 mg/kg, between about 0.01 ng/kg to about 1 mg/kg, between about 0.1 ng/kg to about 1 mg/kg, between about 1 pg/kg to about 0.1 mg/kg, between about 1 pg/kg to about 0.01 mg/kg, between about 1 pg/kg to about 0.001 mg/kg, between about 0.001 ng/kg to about 1000 ng/kg, between about 0.01 ng/kg to about 100 ng/kg, or between about 0.1 ng/kg to about 100 ng/kg of SDF- ⁇ per kg body weight.
  • the contemplated dose of SDF- ⁇ may range between about 1 pg/1,000,000 cells to about 1 mg/1,000,000 cells, between about 0.01 ng/1,000,000 cells to about 1 mg/1,000,000 cells, between about 0.1 ng/1,000,000 cells to about 1 mg/1,000,000 cells, between about 1 pg/1,000,000 cells to about 0.1 mg/1,000,000 cells, between about 1 pg/1,000,000 cells to about 0.01 mg/1,000,000 cells, between about 1 pg/1,000,000 cells to about 0.001 mg/1,000,000 cells, between about 0.001 ng/1,000,000 cells to about 1000 ng/1,000,000 cells, between about 0.01 ng/1,000,000 cells to about 100 ng/1,000,000 cells, or between about 0.1 ng/1,000,000 cells to about 100 ng/1,000,000 cells of SDF- ⁇ per administration.
  • the dose of SDF- ⁇ for systemic or local administration may range between about 1 pg/ml to about 1 mg/ml, between about 0.01 ng/ml to about 1 mg/ml, between about 0.1 ng/ml to about 1 mg/ml, between about 1 pg/ml to about 0.1 mg/ml, between about 1 pg/ml to about 0.01 mg/ml, between about 1 pg/ml to about 0.001 mg/ml, between about 0.001 ng/ml to about 1000 ng/ml, between about 0.01 ng/ml to about 100 ng/ml, or between about 0.1 ng/ml to about 100 ng/ml of SDF- ⁇ per ml fat per administration.
  • the dose of SDF- ⁇ selected for treatment depends on the type of graft, on the subject being treated, on the location of the graft, and when transplanting cells, on the number and concentration of the cells. It will be appreciated that when mimetics compositions are used the dosages of SDF-la should be calibrated such as according to the molar value. Such a calibration is a routine calculation for those of ordinary skill in the art.
  • SDF-la is administered to the subject within a few minutes or within a few hours of implantation.
  • SDF-la is administered to the subject starting from the first day of transplantation and is continuously administered until the graft has been integrated and vascularized in the subject (e.g. for at least about 1-10 days, 5-20 days, 10-40 days, 5-50 days or 1-90 days).
  • SDF-la can be provided to the subject by daily injection or injections every 2 days.
  • SDF-la can also be also administered in slow release devices (e.g. scaffold or beads that slowly release SDF-la).
  • the release of SDF- la is typically continued until optimal or acceptable results are reached (e.g. vascularization and integration of the graft). This can range from 1 day (i.e. a single administration), 1 month (about 10 administrations) or slow released for up to 1 month according to an acceptable dose.
  • SDF-la is administered to the subject for about 1 day, about 3 days, about 5 days, about 1 week, about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years or about 3 years or more.
  • the present invention contemplates treating the cell, tissue or organ graft with SDF-la prior to implantation thereof. This may be in addition to administration of SDF-la following implantation or instead of administration of SDF-la following implantation.
  • Treatment of the cell, tissue or organ may be carried out by any method known to one of ordinary skill in the art as for example by ex vivo contacting the cell or tissue graft with SDF-la in a tissue culture plate or by injection of SDF-la directly into the tissue or organ graft.
  • the cell, tissue or organ graft may be exposed to SDF-la prior to removal from the donor.
  • Contemplated concentrations of SDF-la for treating a cell, tissue or organ graft prior to transplantation include a dose between about 1 pg/1,000,000 cells to about 1 mg/1,000,000 cells, between about 0.01 ng/1,000,000 cells to about 1 mg/1,000,000 cells, between about 0.1 ng/1,000,000 cells to about 1 mg/1,000,000 cells, between about 1 pg/1,000,000 cells to about 0.1 mg/1,000,000 cells, between about 1 pg/1,000,000 cells to about 0.01 mg/1,000,000 cells, between about 1 pg/1,000,000 cells to about 0.001 mg/1,000,000 cells, between about 0.001 ng/1,000,000 cells to about 1000 ng/1,000,000 cells, between about 0.01 ng/1,000,000 cells to about 100 ng/1,000,000 cells, or between about 0.1 ng/1,000,000 cells to about 100 ng/1,000,000 cells of SDF- ⁇ per cells.
  • contemplated concentrations of SDF-lct for treating a cell, tissue or organ graft prior to transplantation include a dose between about 1 pg/kg to about 1 mg/kg, between about 0.01 ng/kg to about 1 mg/kg, between about 0.1 ng/kg to about 1 mg/kg, between about 1 pg/kg to about 0.1 mg/kg, between about 1 pg/kg to about 0.01 mg/kg, between about 1 pg/kg to about 0.001 mg/kg, between about 0.001 ng/kg to about 1000 ng/kg, between about 0.01 ng/kg to about 100 ng/kg, or between about 0.1 ng/kg to about 100 ng/kg of SDF- ⁇ per kg body weight.
  • the contemplated concentrations of SDF- ⁇ for treating a cell, tissue or organ graft prior to transplantation include a dose between about 1 pg/ml to about 1 mg/ml, between about 0.01 ng/ml to about 1 mg/ml, between about 0.1 ng/ml to about 1 mg/ml, between about 1 pg/ml to about 0.1 mg/ml, between about 1 pg/ml to about 0.01 mg/ml, between about 1 pg/ml to about 0.001 mg/ml, between about 0.001 ng/ml to about 1000 ng/ml, between about 0.01 ng/ml to about 100 ng/ml, or between about 0.1 ng/ml to about 100 ng/ml of SDF- ⁇ per ml fat.
  • the subject may be treated with SDF- ⁇ prior to implantation of the cell, tissue or organ graft. Such a subject may continue to receive SDF- ⁇ following implantation of the graft as depicted in detail hereinabove.
  • SDF- ⁇ may be administered to a subject who has previously received a cell, tissue or organ graft as to assist vascularization and/or integration thereof in the subject.
  • the subject may have undergone transplantation a few hours, a few days, a few weeks, a few months or a few years prior to administration of SDF- ⁇ as detailed above.
  • endothelial precursor cells are also administered to the subject.
  • EPCs refers to the stem cells capable of forming blood vessels (also known as endothelial progenitor cells).
  • EPCs may be obtained by mobilization of same from the bone marrow using any mobilization factor known in the art (e.g. placental growth factor, G-CSF, GM-CSF and VEGF) and may be identified and selected by their cell surface expression of CD34+CD133+VEGFR2+[KDR+].
  • about 10,000 to about 10,000,000 cells/ml, about 10,000 to about 1,000,000 cells/ml, about 10,000 to about 100,000 cells/ml, about 1000 to about 10,000,000 cells/ml, about 100 to about 10,000,000 cells/ml, about 1000 to about 10,000 cells/ml or about 100 to about 1000 cells/ml of EPCs are typically administered to a subject.
  • EPCs according to the present methods may be autologous or non-autologous with respect to the subject as described in further detail hereinabove. Furthermore, EPCs may be co-administered with the cell, tissue or organ graft. Alternatively, EPCs may be administered independently from the graft, thus, EPCs may be administered to the subject prior to, concomitantly with or following transplantation of a cell, tissue or organ graft.
  • SDF- ⁇ can be administered to the subject per se or as a pharmaceutical composition.
  • the cell, tissue or organ graft of the present invention can be administered per se or as part of a pharmaceutical composition.
  • a "pharmaceutical composition” refers to a preparation of the active ingredients described herein with other chemical components such as physiologically suitable carriers and excipients.
  • the purpose of the composition is to facilitate administration of the active ingredients (e.g., SDF- ⁇ ) to the subject.
  • active ingredient refers to the agent accountable for the biological effect.
  • physiologically acceptable carrier and “pharmaceutically acceptable carrier” which may be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to the subject and does not abrogate the biological activity and properties of the administered active ingredients.
  • An adjuvant is included under these phrases.
  • excipient refers to an inert substance added to the composition (pharmaceutical composition) to further facilitate administration of an active ingredient of the present invention.
  • suitable routes of administration of SDF- ⁇ may, for example, include a systemic manner including oral, rectal, transmucosal, especially transnasal, intestinal Or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, inrtaperitoneal, intramuscular, intranasal, or intraocular injections.
  • Suitable routes of administration of the compositions may, for example, include topical (e.g., to a keratinous tissue, such as the skin, scalp) and mucosal (e.g., oral, vaginal, eye) administrations.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional m;,'iner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the active ingredients of the pharmaceutical composition may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the pharmaceutical composition can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, siich as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions described herein may be formulated for parenteral administration, e.g., by bolus injection or continues infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water based solution, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water based solution
  • compositions of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of active ingredients (e.g. SDF-la) effective in enhancing a cell, tissue or organ graft survival or enhancing transplantation thereof. According to an embodiment, a therapeutically effective amount is for promoting angiogenesis and reducing apoptosis of the cell, tissue or organ graft.
  • active ingredients e.g. SDF-la
  • the therapeutically effective amount or dose can be estimated initially from in vitro and cell culture assays.
  • a dose can be formulated in animal models to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans.
  • Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals.
  • the data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.l).
  • Dosage amount and interval may be adjusted individually to levels of the active ingredient which are sufficient to induce or suppress the biological effect (minimal effective concentration, MEC).
  • MEC minimum effective concentration
  • the MEC will vary for each preparation, but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. Detection assays can be used to determine plasma concentrations.
  • An animal model which can be used according to the present teachings to assess the biological effect of the compositions described herein includes diabetic nude mice (as described in detail in Example 1 of the Examples section which follows).
  • dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or months or until cure is effected or until the cell, tissue or organ graft has been acceptably integrated in the subject.
  • SDF- ⁇ compositions are administered once, administered twice, administered three times, administered four times, administered five times, administered six times, administered seven times, administered eight times, administered nine times or administered ten times to the subject in order to enhance survival of the cell, tissue or organ graft. It will be appreciated that if multiple transplantations are carried out (e.g.
  • the number of administrations of SDF- ⁇ may be vast and may be prolonged for as long as needed (as determined by one of ordinary skill in the art).
  • the compositions of the present invention are administered at least once a day. It will be appreciated that the number of administrations can be determined by one of ordinary skill in the art.
  • compositions to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • Determination of efficacy of treatment may be determined by measuring the number and viability of the engrafted cells (e.g. by ultrasound), measuring the number of apoptotic cells within the graft (e.g. by PCR), and evaluating the vascularization of the transplanted cells, tissues or organs (e.g. by ultrasound).
  • compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration.
  • Such notice for example, may include labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • compositions comprising a preparation of the invention formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition, as further detailed above.
  • SDF- ⁇ and the cell, tissue or organ graft e.g. fat cells
  • the SDF- ⁇ and the cell, tissue or organ graft may be formulated in a single pack or alternatively may be placed in separate packs.
  • compositions of the present invention are utilized in vivo, the compositions are preferably of high purity and substantially free of potentially harmful contaminants, e.g., at least National Food (NF) grade, generally at least analytical grade, and preferably at least pharmaceutical grade.
  • NF National Food
  • synthesis or subsequent purification shall preferably result in a product that is substantially free of any potentially contaminating toxic agents that may have been used during the synthesis or purification procedures.
  • compositions of the present invention may be incorporated into the compositions of the present invention (i.e., SDF- ⁇ described hereinabove) to enhance survival of the cell, tissue or organ graft or to enhance transplantation thereof.
  • extracellular matrix components e.g. vitronectin, laminin, collagen, elastin
  • growth factors e.g. FGF 1, FGF 2, IGF 1, IGF 2, PDGF, EGF, KGF, HGF, VEGF, GM-CSF, CSF, G-CSF, TGF alpha, TGF beta, NGF and ECGF
  • hypoxia inducible factors e.g.
  • HIF-1 alpha and beta and HIF-2 hormones
  • hormones e.g., erythropoietin, insulin, growth hormone (GH), CRH, Leptin, Prolactin and TSH
  • angiogenic factors e.g., angiogenin and angiopoietin
  • coagulation and anticoagulation factors e.g., Factor I, Factor XIII, tissue factor, calcium, vWF, protein C, protein S, protein Z, fibronectin, antithrombin, heparin, plasminogen, low molecular weight heparin (Clixan), high molecular weight kininogen (HMWK), prekallikrein, plasminogen activator inhibitor-1 (PAI1), plasminogen activator inhibitor-2 (PAI2), urokinase, thrombomoduline, tissue plasminogen activator (tPA), alpha 2-antiplasmin and Protein Z-related protease inhibitor (ZPI)], cyto
  • endoglycosidases exoglycosidases, endonucleases, exonucleases, peptidases, lipases, oxidases, decarboxylases, hydrases, chondroitinase, chondroitinase ABC, chondroitinase AC, hyaluronidase, keratanase, heparanases, heparanase splice variance, collagenase, trypsin, catalases), neurotransmitters (e.g., acetylcholine and monoamines), neuropeptides (e.g.
  • substance P substance P
  • vitamins e.g., D-biotin, Choline Chloride, Folic acid, Myo-inositol, Niacinamide, D- Pantothenic acid, Calcium salts, Pyridoxal.HCl, Pyrodixine.HCl, Riboflavin, Thiamine.HCl, Vitamin B12, vitamin E, vitamin C, vitamin D, vitamin Bl-6, vitamin K, vitamin A and vitamin PP
  • carbohydrates e.g. Mono/Di/Polysacharides including glucose, mannose, maltose and fructose
  • ions e.g.
  • Fe chelators Fe chelators, Ca chelators
  • antioxidants e.g., Vitamin E, Quarcetin, superoxide scavengers, Superoxide dismutase
  • H202 scavengers free radicals scavengers, Fe scavengers
  • fatty acids e.g., Triglycerides, Phospholipids, Cholesterols, free fatty acids and non free fatty acids, fatty alcohol, Linoleic acid, oleic acid and lipoic acid
  • antibiotics e.g., Penicillins, Cephalosporins and Tetracyclines
  • analgesics anesthetics, antibacterial agents, anti- yeast agents, anti-fungal agents, antiviral agents, pro-biotic agents, anti-protozal agents, anti-pruritic agents, anti-dermatitis agents, anti-emetics, anti-inflammatory agents, anti- hyperkeratolyic agents, antiperspirants, anti-psoriatic agents
  • Calcium Sulfate calcium Sulfate
  • steroids e.g., androgens, estrogens, progestagens, glucocorticoids and mineralocorticoids
  • catecholamines e.g., Epinephrine and Norepinephrine
  • Nucleosides and Nucleotides e.g., Purins and Pyrimidines
  • Prostaglandins e.g. Prostaglandin E2
  • Leucotriens Proteoglycans
  • Proteoglycans e.g. Heparan sulfate, keratan sulfate
  • Hydroxyapatites e.g.
  • Hydroxyapatite (Cajo(P0 4 ) 6 (OH) 2 )], Haptoglobins (Hpl-1, Hp2-2 and Hpl-2), Superoxide dismutases (e.g. SOD 1/2/3), Nitric Oxides, Nitric Oxide donors (e.g. nitroprusside, Sigma Aldrich, St. Louis, MO, USA, Glutathione peroxidases, Hydrating compounds (e.g. vasopressin), cells (e.g. Platelets), cell medium (e.g. M199, DMEM/F12, RPMI, Iscovs), serum (e.g.
  • human serum fetal calf serum, , fetal bovine serum
  • buffers e.g., HEPES, Sodium Bicarbonate
  • detergents e.g., Tween
  • disinfectants herbs, fruit extracts, vegetable extracts (e.g. cabbage, cucumber), flower extracts, plant extracts, flavinoids (e.g. pomegranate juice), spices, leafs (e.g. Green tea, Chamomile), Polyphenols (e.g. Red Wine), honey, lectins, microparticles, nanoparticles (lyposomes), micelles, calcium carbonate (CaC03, e.g.
  • the present composition may also contain ingredients, substances, elements and materials containing, hydrogen, alkyl groups, aryl groups, halo groups, hydroxy groups, alkoxy groups, alkylamino groups, dialkylamino groups, acyl groups, carboxyl groups, carboamido groups, sulfonamide groups, aminoacyl groups, amide groups, amine groups, nitro groups, organo selenium compounds, hydrocarbons, and cyclic hydrocarbons.
  • the present composition may be combined with substances such as benzol peroxide, vasoconstrictors, vasodilatators, salicylic acid, retinoic acid, azelaic acid, lactic acid, glycolic acid, pyreuric acid, tannins, benzlidenecamphor and derivatives thereof, alpha hydroxyis, surfactants.
  • substances such as benzol peroxide, vasoconstrictors, vasodilatators, salicylic acid, retinoic acid, azelaic acid, lactic acid, glycolic acid, pyreuric acid, tannins, benzlidenecamphor and derivatives thereof, alpha hydroxyis, surfactants.
  • compositions of some embodiments of the present invention may be bioconjugated to polyethylenglycol (e.g. PEG, SE-PEG) which preserves the stability (e.g., against protease activities) and/or solubility (e.g., within a biological fluid such as blood, digestive fluid) of the active ingredients (e.g. SDF-la) while preserving their biological activity and prolonging its half-life.
  • polyethylenglycol e.g. PEG, SE-PEG
  • solubility e.g., within a biological fluid such as blood, digestive fluid
  • active ingredients e.g. SDF-la
  • compositions of the present invention can be used in combination with other currently practiced therapies for cell, tissue or organ transplantation as, without being limited to, treatment of the subject with growth factors, transplantation of the cells or tissues on scaffolds or transplantation of the cells on polyester beads.
  • the cell, tissue or organ graft of the present invention can be derived from either autologous sources or from non-autologous sources (e.g. allogeneic or xenogeneic). Since non-autologous cells, tissues or organs are likely to induce an immune reaction when administered to the body several approaches have been developed to reduce the likelihood of rejection of non-autologous grafts. These include either suppressing the recipient immune system or encapsulating the non-autologous grafts (e.g. cells or tissues) in immunoisolating, semipermeable membranes before transplantation.
  • non-autologous grafts e.g. cells or tissues
  • Encapsulation techniques are generally classified as microencapsulation, involving small spherical vehicles and macroencapsulation, involving larger flat-sheet and hollow-fiber membranes (Uludag, H. et al. Technology of mammalian cell encapsulation. Adv Drug Deliv Rev. 2000; 42: 29-64).
  • Methods of preparing microcapsules are known in the arts and include for example those disclosed by Lu MZ, et al., Cell encapsulation with alginate and alpha- phenoxycinnamylidene-acetylated poly(allylamine). Biotechnol Bioeng. 2000, 70: 479- 83, Chang TM and Prakash S.
  • microcapsules are prepared by complexing modified collagen with a ter-polymer shell of 2-hydroxyethyl methylacrylate (HEMA), methacrylic acid (MAA) and methyl methacrylate (MMA), resulting in a capsule thickness of 2-5 ⁇ .
  • HEMA 2-hydroxyethyl methylacrylate
  • MAA methacrylic acid
  • MMA methyl methacrylate
  • Such microcapsules can be further encapsulated with additional 2-5 ⁇ ter-polymer shells in order to impart a negatively charged smooth surface and to minimize plasma protein absorption (Chia, S.M. et al. Multi-layered microcapsules for cell encapsulation Biomaterials. 2002 23: 849-56).
  • microcapsules are based on alginate, a marine polysaccharide (Sambanis,
  • microcapsules can be prepared by the polyelectrolyte complexation between the polyanions sodium alginate and sodium cellulose sulphate with the polycation poly(methylene-co-guanidine) hydrochloride in the presence of calcium chloride.
  • the method of the present invention may further advantageously comprise conditioning the subject with an immunosuppressive regimen prior to, concomitantly with, or following transplantation of the cell, tissue or organ graft.
  • the methods of the present invention require a reduced immunosuppressive regimen as compared to a subject not treated with SDF-lcL
  • immunosuppressive regimens include administration of immunosuppressive drugs and/or immunosuppressive irradiation.
  • the immunosuppressive regimen consists of administering at least one immunosuppressant agent to the subject.
  • immunosuppressive agents include, but are not limited to, methotrexate, cyclophosphamide, cyclosporine, cyclosporin A, chloroquine, hydroxychloroquine, sulfasalazine (sulphasalazopyrine), gold salts, D-penicillamine, leflunomide, azathioprine, anakinra, infliximab (REMICADE), etanercept, TNF.alpha. blockers, a biological agent that targets an inflammatory cytokine, and Non-Steroidal Anti-Inflammatory Drug (NSAIDs).
  • methotrexate cyclophosphamide
  • cyclosporine cyclosporin A
  • chloroquine hydroxychloroquine
  • sulfasalazine sulphasalazopyrine
  • gold salts gold salts
  • D-penicillamine leflunomide
  • azathioprine anakin
  • NSAIDs include, but are not limited to acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors and tramadol. These agents may be administered individually or in combination.
  • the methods of the present invention require a reduced anti-inflammatory treatment [e.g. anti-inflammatory drugs such as steroids, non- steroidal anti-inflammatory drugs or immune selective anti-inflammatory derivatives (ImSAIDs)] as compared to a subject not treated with SDF-la.
  • a reduced anti-inflammatory treatment e.g. anti-inflammatory drugs such as steroids, non- steroidal anti-inflammatory drugs or immune selective anti-inflammatory derivatives (ImSAIDs)
  • transplantation of a graft e.g. fat graft
  • SDF-la treatment leads to a suppressed graft rejection and/or graft versus host disease (GVHD) as illustrated by a higher weight and volume of the transplanted graft as compared to a graft transplanted without SDF-la treatment.
  • a graft e.g. fat graft
  • GVHD graft versus host disease
  • a method of preventing graft rejection or graft versus host disease of a cell, tissue or organ graft in a subject in need thereof comprising (a) implanting a cell, a tissue or an organ graft into the subject; and prior to, concomitantly with, or following (b) administering to the subject a therapeutically effective amount of SDF-la.
  • Methods of assessing graft rejection include, for example, monitoring the subject for symptoms such as less urine output (e.g. for kidney transplants), yellow skin color and easy bleeding (e.g. for liver transplants) and shortness of breath and less tolerance to exertion (e.g. for heart transplants). Additional methods include e.g. biopsy of the transplanted organ, lab tests of e.g. kidney or liver function, ultrasound of the transplanted graft, arteriography (e.g. kidney), CT scan, heart echocardiography, chest x-ray and MRI.
  • methods of assessing GVHD include, for example, monitoring the subject for symptoms such as abdominal pain or cramps, diarrhea, fever, jaundice, skin rash, vomiting and weight loss. Additional methods include e.g. immunohistochemical and FISH analyses.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.
  • the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
  • Fat was harvested from the thigh of a 40-year-old woman by suction-assisted lipectomy under general anesthesia. Before the beginning of the procedure, a local anesthesia solution containing lidocaine (0.5 %) and adrenaline (1:1,000,000) was injected to the areas designated for aspiration in order to decrease bleeding during the procedure and to relieve pain after it.
  • the fat was aspirated using a 14-gauge blunt cannula with three holes near its tip that was attached to a sterile 10 cc syringe.
  • the aspirated fat was then processed and prepared under sterile conditions for subsequent grafting into nude mice within two hours of its collection according to previously published protocols [Ullmann Y et al., Dermatol Surg (2005) 31:1304-7]. The procedure was reviewed and approved by the Institutional Review Board of the Rambam Health Care Campus, and the donor gave her written informed consent.
  • BM-MNCs BM mononuclear cells
  • EBM-2 Endothelial cell basal medium-2
  • the EPCs were identified as adherent cells that stained double positive for acetylated LDL (acLDL) and lectin under a fluorescent microscope (Vasa M. 2001).
  • adherent cells from the EPC cultures were first incubated with l,l'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled acLDL (Dil-acLDL; Biomedical Technologies), fixed in 2 % paraformaldehyde, and then counterstained with fluorescein isothiocyanate-labeled lectin from Bandeiraea Simplicifolia (BS-1) (Sigma Aldrich, MO, USA).
  • BS-1 Bandeiraea Simplicifolia
  • the putative EPCs were immunostained for (a) CD34, (b) stem cell antigen-1 (Sca-1) (c) fetal liver kinase-1 (Flk-l), and (d) CD31 using monoclonal antibodies all of which were purchased from Santa Cruz, CA, USA.
  • the study comprised eighty adult eight-week-old female CD-I nude mice (Harlan, Jerusalem, Israel). The mice were acclimated for one week prior to the study in a room with an artificial 12 h light/dark cycle, and were fed a standard laboratory chow and water ad libitum. Diabetes was then induced in sixty mice by six intraperitoneal injections of 10 mg kg/injection of streptozotocin (STZ) (Sigma Aldrich, MO, USA) repeated every other two days for each mouse. The blood glucose level in a drop of tail blood from each STZ-injected mouse was measured by a glucometer (FreeStyle, Alameda, CA, USA), and mice were considered diabetic when their blood glucose levels were greater than 300 mg/dl. Twenty apparently healthy mice were used for the non- diabetic groups.
  • STZ streptozotocin
  • mice received a transplant of 1 ml aspirated human fat.
  • the fat was injected subcutaneously into the scalp using a 14 G needle while the animals were manually restrained.
  • the diabetic mice were randomly divided into six groups according to treatment of the transplanted human fat subsequent to its injection into the scalps of mice.
  • PBS PBS-
  • SDFla, AMD3100, L-NAME and anti-SDFla antibody were all purchased from Sigma. No post-procedural treatment of the non-diabetic or diabetic mice was performed. Post-operative analgesics and antibiotics were not administered to the mice.
  • the duration of the study period was 15 weeks after fat transplantation, and during the study period, each mouse was weighed 3 times; on the first day, on day 18 and on the last day of the experiment.
  • the mice were maintained under the same conditions as described in the "study design" section above. After 15 weeks, all mice were sacrificed humanely by an overdose of ketamine. After death, the fat grafts were carefully dissected from the scalps of the mice and then weighed. The volume of each of the fat grafts was measured by the liquid overflow method [Ayhan M. et al., Aesthetic Plast Surg (2001) 25: 338-342].
  • the fat graft was placed in a 15-ml sterile measuring cylinder that contained 10 cc sterile PBS.
  • the volume of the fat graft was considered to be 1 ml when the level of the solution rose to the 11 cc mark.
  • each fat graft was divided into two portions from the middle. One portion was stored at -80 °C until required for determining the expression levels of VEGF receptor-2 (VEGF-R2), CXCR4, eNOS and AKT and the apoptotic protein levels of caspase-3 and cytochrome c by western blot (see further detail hereinbelow). The second portion was placed in 4 % formalin for histological examination and determining microvascular density (MVD).
  • PB-MNCs and BM-MNCs obtained before fat transplantation and on day 18 and week 15 after fat transplantation were isolated and cultured with EBM-2 at 37 °C.
  • EPC populations in BM-MNCs and PB-MNCs were further analyzed using fluorescence-activated cell sorting (FACS) with phycoerythrin (PE)-conjugated antibody against Sca-1 and fluorescein isothiocyanate (FITC)-conjugated antibody against Flk-1 antigens (eBioscience, San Diego, CA, USA) as previously described [Goldstein LJ et al., Stem Cells (2006) 24(10):2309-18]. Isotype-matched IgGs were used as negative controls. Immunofluorescence-labeled cells were analyzed by the Macintosh Cell-Quest Software program counting 100,000 events per sample (Becton Dickinson, NJ, USA).
  • Plasma SDFla and VEGF levels were determined using a commercial enzyme- linked immunosorbent assay (ELISA) Quantikine IVD ® SDFla Kit and Quantikine IVD ® VEGF Kit both from (R&D Systems, MN, USA) in accordance with the manufacturer's instructions, and were expressed as picograms per ml.
  • ELISA enzyme- linked immunosorbent assay
  • Histological slides of the formalin-maintained samples were prepared from fat grafts of sacrificed mice at week 15, and then stained with hematoxylin and eosin using standard procedures. To this end, the formalin-maintained samples were washed in tap water, dehydrated using an ascending alcohol series, and then embedded in paraffin blocks. Sections (5 ⁇ thick) were cut, mounted on glass slides, and then hydrated using distilled water.
  • the slides were examined under a light microscope for (a) the extent of integration, as evidenced by the extent of organization of intact and nucleated fat cells, (b) the extent of fibrosis, as evidenced by the amount of collagen and elastic fibrils, (c) the presence of cysts and vacuoles, and (d) the intensity of the inflammatory response, as evidenced by the extent of lymphocyte and macrophage infiltration.
  • microvascular density Assessment of microvascular density (MVD)
  • the paraffin-embedded fat graft sections were incubated with a monoclonal antibody against tissue CD31 (R&D Systems, Minneapolis MN, USA) overnight at room temperature. Upon completion of the incubation, the specimens were counterstained with hematoxylin. Mouse IgG was used as a negative control. The microvascular density (MVD) was determined in five regions of interest where the CD31 antibody signal was the most intense. The number of blood vessels in each region was counted under a light microscope at 40 x magnification by investigators who were blind to the treatment of the mice.
  • VEGF-R2, CXCR4, eNOS and AKT The expression levels of VEGF-R2, CXCR4, eNOS and AKT, and the apoptotic proteins caspase 3 and cytochrome c were determined by western blotting in homogenates of the harvested fat grafts on day 18. Homogenates of samples of the fat grafts were lysed in RIPA buffer (R&D Systems, MN, USA). A 40 ⁇ g aliquot of each lysate was loaded onto SDS-PAGE, and then transferred to nitrocellulose membranes.
  • EPCs that were obtained from PB-MNCs of non-diabetic and diabetic mice was assessed at day 18 and week 15, after 4 days in culture.
  • inventors used a Boyden chamber-based cell migration assay chamber using the CytoSelect ® 96-well Cell Migration Assay (Cell Biolabs, CA, USA) in accordance with the manufacturer's protocol.
  • the feeder trays were coated with 100 ⁇ of EBM-2 that contained 200 ng/ml) of recombinant human SDFla (Sigma Aldrich, MO, USA).
  • EPCs 100,000 cells
  • 100 ⁇ serum-free EBM-2 100 ⁇ serum-free EBM-2
  • the migratory EPCs were detached from the membrane by cell detachment solution, and then lysed with a fluorescent dye-containing lysis buffer. The extent of migration was assessed by the intensity of the fluorescence signal which was measured in a fluorescence spectrophotometer. The results were expressed as the average percentage of relative fluorescence units (RFU) of cultured non-treated, non-diabetic EPCs in duplicates, or cultured control EPCs from four independent experiments.
  • ROU relative fluorescence units
  • EPCs that were obtained from PB-MNCs of non-treated, non-diabetic mice were incubated in high glucose concentrations (25 mmol/1) for 4 days. After 4 days, glucose-stressed EPCs or non-stressed EPCs (control) were detached using trypsin EDTA (0.5 %) and then cultured onto matrigel coated 96-well tissue culture plates supplemented with SDFla. To this end, frozen matrigel (Sigma Aldrich, St Louis MO, USA) was thawed, supplemented with 200 ng/ml SDFla and spread onto 96-well plates (50 ⁇ /well) at room temperature for 30 minutes to allow solidification.
  • EPCs 5 x 10 4 cells/ ⁇ EBM-2/well
  • EBM-2 The detached EPCs (5 x 10 4 cells/ ⁇ EBM-2/well) were placed on the matrigel surface, and then incubated at 37 °C for 24 hours in EBM-2.
  • EPCs were treated either with anti-SDFla antibody (10 ng/ml), AMD3100 (2 ⁇ g/ml) or L-NAME (100 ⁇ g/ml). After 24 hours, the non-integrated cells were removed by washing, and tube formation on matrigel was assessed under a light microscope at xlO magnification.
  • mice completed the 15-week study period.
  • Five diabetic mice died: one mouse each from the PBS-treated, EPC-treated, SDFla/L-NAME- treated, SDF la-treated and SDFla/anti-SDFla antibody-treated fat graft groups.
  • the red blood cell, leukocyte and platelet counts, and the plasma hemoglobin and SDFla concentrations in the PBS-treated non-diabetic and diabetic groups, and the EPC-treated diabetic group did not change over the 15 week study period.
  • SDF la-treated fat grafts in the non-diabetic group and SDF la-treated fat grafts in the diabetic group only the leukocyte counts significantly increased (Table 1, below).
  • mice Values are presented as mean ⁇ SD. (N) Number of mice. Statistical significance is set at P ⁇ 0.05. *P ⁇ 0.05, **P ⁇ 0.001 indicate difference from non diabetic mice whose fat graft was treated with phosphate buffered saline (PBS, control); RBC, red blood cells; SDFla, stromal derived factor-1 alpha.
  • PBS phosphate buffered saline
  • RBC red blood cells
  • SDFla stromal derived factor-1 alpha.
  • the fats grafts were successful in the PBS- and SDF la-treated grafts of non-diabetic mice, and in the EPC- and SDF la- treated fat grafts in the diabetic mice, as evidenced by well-defined subcutaneous lumps on the animal's scalps ( Figures 1A-L), and subsequently from measuring the isolated fat grafts ( Figures 1M-T).
  • the weight and volume of the SDF la-treated fat grafts in the non-diabetic mice were significantly higher than those in the PBS-treated non-diabetic mice ( Figures 2 A and 2C).
  • the weight and volume of the EPC-treated fat grafts in the diabetic mice were not different from those in the PBS-treated non-diabetic mice.
  • the weight and volume of the SDF la- treated fat grafts in the diabetic mice were significantly higher than the EPC-treated fat grafts in these mice ( Figures 2B and 2D).
  • the weight and volume of both SDFla/AMD3100-treated fat grafts and SDFla/L- NAME-treated fat grafts in diabetic mice were very small and significantly lower than the weight and volume of fat grafts found in the other groups ( Figures 2B and 2D).
  • PB- and bone marrow (BM)-MNCs by double staining for Dil-acLDL incorporation and BS-1 lectin binding.
  • Representative images of cultured EPCs from PB-MNCs are shown in Figures 4A-Q.
  • the number of EPCs increased at day 18 in the SDFla- and SDFla/AMD3100-treated diabetic mice and decreased in the SDFla/L-NAME-treated diabetic mice compared to P T/IL2011/
  • FIGS. 6A-D are photographs showing representative micrographs of fat integration
  • Figures 6E-H are photographs showing representative microvascular density (MVD) micrographs.
  • the MVD in the SDF la-treated fat grafts in the non-diabetic mice was significantly greater than that found in the PBS-treated fat grafts in non-diabetic mice (P ⁇ 0.001; Figure 5 A).
  • the MVD in the EPC-treated fat grafts in the diabetic mice was not significantly different than that found in the PBS-treated fat grafts in the non-diabetic mice (P-NS).
  • the MVD in the SDF la-treated fat grafts in the diabetic mice was significantly greater than that found in the EPC-treated fat grafts in the diabetic mice (P ⁇ 0.05; Figure 5B) and significantly greater than that found in the SDFla/AMD3100- or SDFla/L- NAME-treated fat grafts in diabetic mice (P ⁇ 0.001 for both; Figure 5B).
  • Treatment of the fat grafts with SDFla decreased caspase 3 and cytochrome c protein expression by 6.8-fold and 15.3-fold, respectively (P ⁇ 0.001 for both).
  • EPC migration in diabetic mice was significantly lower than that found in the non-diabetic mice (P ⁇ 0,001).
  • Intraperitoneal injection of AMD3100, L-NAME or anti- SDFla neutralizing antibody significantly suppressed SDF la-induced elevated EPC migration in the diabetic mice. Treatment of the fat grafts with EPCs had no effect on EPC migration in the diabetic mice.
  • the present inventors have shown that diabetes results in full fat resorption after fat transplantation, however, treatment of fat grafts with SDFla maintains fat weight and volume in diabetic mice and results in higher fat weight and volume compared to those in non-diabetic mice.
  • possible mechanisms that underlie fat weight and volume maintenance by SDFla in diabetic mice might be due to BM-EPC recruitment to the fat grafts that induce neovascularization and reduced fat cell apoptosis.
  • SDFla treatment of fat grafts promotes vasculogenesis and improves fat cell survival.

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Abstract

La présente invention concerne un procédé d'amélioration de la transplantation d'une cellule ou d'un tissu ou d'une greffe d'organe chez un sujet le nécessitant. Le procédé comprend l'administration à un sujet qui a subi une transplantation de cellule ou de tissu ou une greffe d'organe d'une quantité thérapeutiquement efficace de SDF-1alpha, améliorant ainsi la transplantation de la cellule ou du tissu ou la greffe d'organe chez le sujet.
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WO2019070538A1 (fr) * 2017-10-03 2019-04-11 Wallkill BioPharma, Inc. Traitement du diabète avec des cellules bêta génétiquement modifiées
US10639351B2 (en) 2013-10-22 2020-05-05 Helixmith Co., Ltd. Method for treating amyotrophic lateral sclerosis with a polynucleotide encoding two or more isoforms of hepatocyte growth factor
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