Methods and compositions for inducing brown adipogenesis

Abstract

Methods and compositions for treating obesity and related disorders. The methods include the use of stem cells treated with BMP-2, -4, -5, -6 and/or -7.

1 . A population of pluripotent mesenchymal stem cells, wherein the cells:
 (i) are genetically engineered to express one or both of a BMP-6 or -7 polypeptide;   (ii) have been treated with one or both of a bone morphogenetic protein 6 (BMP 6) polypeptide or nucleic acid, or a bone morphogenetic protein 7 (BMP 7) polypeptide or nucleic acid; or   (iii) have an increased level of one or both of bone morphogenetic protein 6 (BMP 6) polypeptide or nucleic acid, or bone morphogenetic protein 7 (BMP 7) polypeptide or nucleic acid.   
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The population of BMP-activated pluripotent mesenchymal stem cells of  claim 1 , wherein the cells have been contacted with another compound selected from the group consisting of BMP-1, BMP-3, peroxisome proliferator-activated receptor gamma (PPARγ), Retinoid X receptor, alpha (RxRα), insulin, T3, a thiazolidinedione (TZD), vitamin A, retinoic acid, insulin, glucocorticoid or agonist thereof; Wingless-type (Wnt), Insulin-like Growth Factor-1 (TGF-1), Epidermal growth factor (EGF), Fibroblast growth factor (FGF), Transforming growth factor (TGF)-α, TGF-β, Tumor necrosis factor alpha (TNFα), Macrophage colony stimulating factor (MCSF), Vascular endothelial growth factor (VEGF) and/or Platelet-derived growth factor (PDGF). 
     
     
         5 . The population of BMP-activated pluripotent mesenchymal stem cells of  claim 1 , wherein the cells are secondary cells. 
     
     
         6 . The population of BMP-activated pluripotent mesenchymal stem cells of  claim 1 , wherein the cells are primary cells. 
     
     
         7 . A therapeutic composition comprising the population of BMP-activated pluripotent mesenchymal stem cells of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         8 . A method of promoting brown adipogenesis in a subject, the method comprising administering to the subject a population of BMP-activated pluripotent mesenchymal stem cells of  claim 1 . 
     
     
         9 . A method of preparing a population of BMP-activated pluripotent mesenchymal stem cells, the method comprising contacting a population of pluripotent mesenchymal stem cells with one or both of bone morphogenetic protein 6 (BMP-6) polypeptide or nucleic acid or bone morphogenetic protein 7 (BMP-7) polypeptide or nucleic acid. 
     
     
         10 . The method of  claim 9 , further comprising obtaining a sample comprising a population of pluripotent mesenchymal stem cells from a subject. 
     
     
         11 . The method of  claim 10 , further comprising enriching the sample to obtain a purified population of pluripotent mesenchymal stem cells. 
     
     
         12 . The method of  claim 11 , wherein the purified population of pluripotent mesenchymal stem cells comprises at least 60% pluripotent mesenchymal stem cells. 
     
     
         13 . A delivery system configured to allow the introduction of cells into a subject, wherein the delivery system comprises a reservoir containing a population of BMP-activated pluripotent mesenchymal stem cells of  claim 1 . 
     
     
         14 . The delivery system of  claim 13 , further comprising a needle in fluid communication with the reservoir. 
     
     
         15 . The delivery system of  claim 13 , wherein the population of BMP-activated pluripotent mesenchymal stem cells is in a pharmaceutically acceptable carrier. 
     
     
         16 . A method of promoting brown adipogenesis in a subject, the method comprising administering to the subject a population of BMP-activated pluripotent mesenchymal stem cells that have been treated with one or both of a bone morphogenetic protein (BMP)-6 or BMP-7 polypeptide or nucleic acid, wherein said population of BMP-activated pluripotent mesenchymal stem cells, or their progeny, undergo brown adipogenesis. 
     
     
         17 . The method of  claim 16 , wherein the cells are administered to decrease fat stores or weight in the subject. 
     
     
         18 . The method of  claim 16 , wherein the cells are administered to enhance insulin sensitivity in the subject. 
     
     
         19 . The methods of  claim 16 , wherein the BMP-activated population of pluripotent mesenchymal stem cells comprises a number of cells sufficient to promote brown adipogenesis in the subject. 
     
     
         20 . The method of  claim 16 , wherein the BMP-activated pluripotent mesenchymal stem cells have been treated with a BMP-7 polypeptide. 
     
     
         21 . The method of  claim 16 , wherein the BMP-activated pluripotent mesenchymal stem cells have been treated with a BMP-7 nucleic acid. 
     
     
         22 . The method of  claim 16 , wherein the BMP-activated pluripotent mesenchymal stem cells have been treated with a BMP-6 polypeptide. 
     
     
         23 . The method of  claim 16 , wherein the BMP-activated pluripotent mesenchymal stem cells have been treated with a BMP-6 nucleic acid. 
     
     
         24 . The method of  claim 16 , wherein the cells have been contacted with another compound selected from the group consisting of BMP-1, BMP-3, peroxisome proliferator-activated receptor gamma (PPARγ), Retinoid X receptor, alpha (RxRα), insulin, T3, a thiazolidinedione (TZD), vitamin A, retinoic acid, insulin, glucocorticoid or agonist thereof, Wingless-type (Wnt), Insulin-like Growth Factor-1 (IGF-1), Epidermal growth factor (EGF), Fibroblast growth factor (FGF), Transforming growth factor (TGF)-α, TGF-β, Tumor necrosis factor alpha (TNFα), Macrophage colony stimulating factor (MCSF), Vascular endothelial growth factor (VEGF) and/or Platelet-derived growth factor (PDGF). 
     
     
         25 . The method of  claim 16 , wherein the pluripotent mesenchymal stem cells are secondary cells. 
     
     
         26 . The method of  claim 16 , wherein the pluripotent mesenchymal stem cells are primary cells. 
     
     
         27 . The method of  claim 26 , wherein the primary cells are from the subject. 
     
     
         28 . The method of  claim 16 , wherein the subject is an obese human subject. 
     
     
         29 . The method of  claim 16 , wherein the subject is a food animal.