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The invention provides compositions comprising stem and/or progenitor cells that have been treated to enhance the therapeutic properties of the cells for treating ischemia. In particular, the present invention relates to the use of stem and/or progenitor cells having enhanced therapeutic properties

The invention provides compositions comprising stem and/or progenitor cells that have been treated to enhance the therapeutic properties of the cells for treating ischemia. In particular, the present invention relates to the use of stem and/or progenitor cells having enhanced therapeutic properties to treat an ischemic tissue, a tissue damaged by ischemia, or at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia.

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1. A method of increasing stem or progenitor cell homing to an ischemic tissue or a tissue damaged by ischemia, comprising: (a) treating stem or progenitor cells ex vivo with a prostaglandin pathway agonist and a glucocorticoid; and(b) administering a composition comprising the treated stem or proge

1. A method of increasing stem or progenitor cell homing to an ischemic tissue or a tissue damaged by ischemia, comprising: (a) treating stem or progenitor cells ex vivo with a prostaglandin pathway agonist and a glucocorticoid; and(b) administering a composition comprising the treated stem or progenitor cells to a subject having an ischemic tissue or a tissue damaged by ischemia. 2. A method of treating a subject having an ischemic tissue or a tissue damaged by ischemia comprising: administering a therapeutically effective amount of a composition comprising stem or progenitor cells treated ex vivo with a prostaglandin pathway agonist and a glucocorticoid. 3. A method of ameliorating at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia in a subject comprising: administering a therapeutically effective amount of a composition comprising stem or progenitor cells treated ex vivo with a prostaglandin pathway agonist and a glucocorticoid. 4. The method according to any one of claims 1 to 3, wherein the treatment of the stem or progenitor cells is sufficient to increase the percent (%) migration in an SDF-1 transwell migration assay at least two fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells. 5. The method of any one of claims 1 to 3, wherein: a) the stem or progenitor cells have been treated at a temperature of about 22° C. to about 37° C. for a period of time of less than about 24 hours;b) the stem or progenitor cells have been treated at a temperature of about 22° C. to about 37° C. for a time of about one to about four hours; orc) the stem or progenitor cells have been treated at a temperature of about 37° C. for a time of about 4 hours. 6. The method of any one of claims 1 to 3, wherein: a) the stem or progenitor cells are embryonic stem cells;b) the stem or progenitor cells are adult stem cells;c) the stem or progenitor cells are selected from the group consisting of: endothelial stem or progenitor cells, mesodermal stem or progenitor cells, and ectodermal stem or progenitor cells;d) the stem or progenitor cells are selected from the group consisting of: mesenchymal stem or progenitor cells, hematopoietic stem or progenitor cells, placental stem or progenitor cells, umbilical cord stem or progenitor cells, bone marrow stem cells, and Wharton's jelly stem or progenitor cells;e) the stem or progenitor cells are hematopoietic stem or progenitor cells;f) the stem or progenitor cells are isolated from peripheral blood, bone marrow, umbilical cord blood, Wharton's jelly, placenta, or fetal blood;g) the stem or progenitor cells are CD34+ cells;h) the stem or progenitor cells are, or have been, expanded ex vivo prior to the treatment of the cells;i) the stem or progenitor cells are allogeneic or autologous;j) the stem or progenitor cells are allogeneic and have a complete or partial HLA-match with the patient;k) the stem or progenitor cells are not matched with the patient;l) the stem or progenitor cells are xenogeneic; orm) the stem or progenitor cells are washed to substantially remove the prostaglandin pathway agonist or glucocorticoid in the composition, prior to administration of the composition to the subject. 7. The method of any one of claims 1 to 3, wherein: a) the prostaglandin pathway agonist is selected from the group consisting of: a prostaglandin, a prostaglandin EP2 receptor agonist, a prostaglandin EP4 receptor agonist and an agent having 16,16-dimethyl PGE2 (dmPGE2) activity;b) the prostaglandin pathway agonist is selected from the group consisting of: prostaglandin E2 (PGE2), and dmPGE2;c) the glucocorticoid is selected from the group consisting of: alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, cloprednol, cortisol, cortisone, cortivazol, deflazacort, desonide, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fluclorolone, fluclorolone acetonide, fludroxycortide, flumethasone, flumethasone pivalate, flunisolide, flunisolide hemihydrate, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, meprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide and ulobetasol;d) the glucocorticoid is selected from the group consisting of: medrysone, hydrocortisone, alclometasone, dexamethasone, methylprednisolone, triamcinolone or Cortisol; ore) the prostaglandin pathway agonist is PGE2 or dmPGE2 or an analogue thereof, and the glucocorticoid is medrysone or dexamethasone. 8. The method of any one of claims 1 to 3, wherein: a) expression of one or more genes associated with increased homing of the stem or progenitor cells to the ischemic tissue or tissue damaged by ischemia, is increased at least two fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells, wherein the one or more genes is selected from the group consisting of: CXCR4, hyaluronan synthase 1 (HAS1), GTP-binding protein GEM (GEM), dual specificity protein phosphatase 4 (DUSP4), amphiregulin (AREG), Nuclear receptor related 1 protein (NR4A2), renin (REN), cAMP-responsive element modulator (CREM), collagen, type I, alpha 1 (COL1A1), and Fos-related antigen 2 (FOSL2);b) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about five fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;c) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about ten fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;d) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about twenty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;e) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about fifty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;f) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about sixty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;g) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about seventy fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;h) the gene expression of at least one of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about eighty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;i) the gene expression of at least two of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about two fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;j) the gene expression of at least two of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about five fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;k) the gene expression of at least two of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about ten fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;l) the gene expression of at least two of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about twenty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;m) the gene expression of at least three of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about two fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;n) the gene expression of at least three of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about five fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;o) the gene expression of at least three of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about ten fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;p) the gene expression of at least three of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about twenty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;q) the gene expression of at least five of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about two fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;r) the gene expression of at least five of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about five fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;s) the gene expression of at least five of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about ten fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells; ort) the gene expression of at least five of HAS1, GEM, DUSP4, AREG, NR4A2, REN, CREM, COL1A1, FOSL2, and CXCR4 is increased by at least about twenty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells. 9. The method of claim 4, wherein: a) the % migration of the treated cells in an SDF-1 transwell migration assay is increased at least three fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;b) the % migration of the treated cells in an SDF-1 transwell migration assay is increased at least three fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;c) the % migration of the treated cells in an SDF-1 transwell migration assay is increased at least four fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cellsd) the % migration of the treated cells in an SDF-1 transwell migration assay is increased at least five fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells;e) the % migration of the treated cells in an SDF-1 transwell migration assay is increased at least ten fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells; orf) the % migration of the treated cells in an SDF-1 transwell migration assay is increased at least twenty fold in the treated stem or progenitor cells compared to non-treated stem or progenitor cells. 10. The method of any one of claims 1 to 3, wherein: a) the ischemia is associated with acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defect, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, bone fracture, brain edema, brain hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarct, cerebral ischemia, cerebral stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue damage, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wound, delayed ulcer healing, delayed wound-healing, diabetes (type I and type II), diabetic neuropathy, diabetes induced ischemia, disseminated intravascular coagulation (DIC), embolic brain ischemia, frostbite, graft-versus-host disease, hereditary hemorrhagic telengiectasiaischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendons, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic-reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower extremity ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral artery disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcers, solid organ transplantation, spinal cord injury, stroke, subchondral-bone cyst, thrombosis, thrombotic brain ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, vascular inflammatory conditions, von Hippel-Lindau syndrome, or wounds to tissues or organs;b) the subject has cerebrovascular ischemia, myocardial ischemia, limb ischemia (CLI), myocardial ischemia (especially chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, intestinal ischemia;c) the subject has had surgery, chemotherapy, radiation therapy, or a cell, tissue, or organ transplant;d) the ischemic tissue or tissue damaged by ischemia is selected from the group consisting of: skin tissue, skeletal muscle tissue, cardiac muscle tissue, smooth muscle tissue, cartilage tissue, tendon tissue, brain tissue, spinal cord tissue, retinal tissue, corneal tissue, lung tissue, liver tissue, kidney tissue, pancreatic tissue, ovary tissue, testes tissue, intestinal tissue, stomach tissue, and bladder tissue;e) the ischemic tissue or tissue damaged by ischemia has decreased blood flow, hypoxia, anoxia, hypoglycemia, decreased metabolism, increased necrosis, or increased apoptosis compared to non-ischemic tissue; orf) the one or more symptoms associated with the ischemic tissue or tissue damaged by ischemia is selected from the group consisting of: cramping, claudication, numbness, tingling, weakness, pain, reduced wound healing, inflammation, skin discoloration, and gangrene. 11. The method of any one of claims 1 to 3, wherein: a) the composition comprises hematopoietic stem or progenitor cells, the prostaglandin pathway agonist is 16,16-dmPGE2 or PGE2, the gene expression of CXCR4 is increased by at least five fold in the treated cells compared to non-treated cells, and the hematopoietic stem or progenitor cells have been contacted with 16,16-dmPGE2 at a temperature of about 37° C. for a time of about two hours; orb) the composition comprises hematopoietic stem or progenitor cells, the prostaglandin pathway agonist is 16,16-dmPGE2 or PGE2, the glucocorticoid is selected from the group consisting of medrysone, hydrocortisone, alclometasone, dexamethasone, methylprednisolone, triamcinolone or Cortisol, the gene expression of CXCR4 is increased by at least five fold in the treated cells compared to non-treated cells, and wherein the hematopoietic stem or progenitor cells have been contacted with 16,16-dmPGE2 at a temperature of about 37° C. for a time of about two hours. 12. The method of any one of claims 1 to 3 wherein the prostaglandin pathway agonist is 16,16-dmPGE2 or PGE2 and the glucocorticoid is dexamethasone.