Methods and compositions for provision of angiogenic factors

Abstract

Disclosed herein are methods and compositions for the use of marrow adherent stem cells and their descendents; e.g., bone marrow-derived neural regenerating cells; for provision of angiogenic factors to cells. In certain embodiments, provision of angiogenic factors to sites of neural degeneration stimulates growth and/or survival of host neurons.

We claim: 
     
         1 . A method for stimulating the growth of endothelial cells in a subject in need of endothelial cell growth, the method comprising:
 (a) obtaining a subject having an injury whose treatment requires growth of endothelial cells; and   (b) transplanting a cell to the subject in need of endothelial cell growth, wherein the cell is obtained by a process consisting of:
 (i) contacting a culture of marrow adherent stromal cells with a polynucleotide comprising sequences encoding a Notch intracellular domain; 
 (ii) selecting cells that comprise the polynucleotide; and 
 (iii) further culturing the cells of step (ii) in the absence of selection. 
   
     
     
         2 . The method of  claim 1 , wherein the Notch intracellular domain comprises amino acids 1703-2504 of the Notch-1 protein. 
     
     
         3 . The method of  claim 1 , wherein the cell of step (b) provides two or more angiogenic factors to the subject, selected from the group consisting of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), bone morphogenetic protein 4 (BMP-4), Dickkopf-1 (Dkk-1), fibroblast growth factor-7 (FGF-7), heparin-binding epidermal growth factor-like growth factor (HB-EGF), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-1 (MMP-1), monocyte chemoattractant protein-1 (MCP-1), platelet-derived growth factor AA (PDGF-AA), and transforming growth factor alpha (TGF-α). 
     
     
         4 . A method for stimulating the growth of blood vessels in a subject in need of blood vessel growth, the method comprising:
 (a) obtaining a subject having an injury whose treatment requires growth of blood vessels; and   (b) transplanting a cell to the subject in need of blood vessel growth, wherein the cell is obtained by a process consisting of:
 (i) contacting a culture of marrow adherent stromal cells with a polynucleotide comprising sequences encoding a Notch intracellular domain; 
 (ii) selecting cells that comprise the polynucleotide; and 
 (iii) further culturing the cells of step (ii) in the absence of selection. 
   
     
     
         5 . The method of  claim 4 , wherein the Notch intracellular domain comprises amino acids 1703-2504 of the Notch-1 protein. 
     
     
         6 . The method of  claim 4 , wherein the cell of step (b) provides two or more angiogenic factors to the subject, selected from the group consisting of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), bone morphogenetic protein 4 (BMP-4), Dickkopf-1 (Dkk-1), fibroblast growth factor-7 (FGF-7), heparin-binding epidermal growth factor-like growth factor (HB-EGF), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-1 (MMP-1), monocyte chemoattractant protein-1 (MCP-1), platelet-derived growth factor AA (PDGF-AA), and transforming growth factor alpha (TGF-α). 
     
     
         7 . A method for providing a plurality of trophic factors to a subject, the method comprising:
 (a) obtaining a subject having an injury whose treatment requires an angiogenic factor; and   (b) transplanting a cell to the subject in need of said angiogenic factor, wherein the cell is obtained by a process comprising the steps of:
 (i) contacting a culture of marrow adherent stromal cells with a polynucleotide comprising sequences encoding a Notch intracellular domain; 
 (ii) selecting cells that comprise the polynucleotide; and 
 (iii) further culturing the cells of step (ii) in the absence of selection; 
   wherein the plurality of trophic factors comprises vascular endothelial growth factor (VEGF), bone morphogenetic protein 4 (BMP-4), Dickkopf-1 (Dkk-1), fibroblast growth factor-7 (FGF-7), heparin-binding epidermal growth factor-like growth factor (HB-EGF), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-1 (MMP-1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor AA (PDGF-AA).   
     
     
         8 . The method of  claim 7 , wherein the Notch intracellular domain comprises amino acids 1703-2504 of the Notch-1 protein. 
     
     
         9 . The method of  claim 7 , wherein provision of the trophic factors stimulates the growth of endothelial cells. 
     
     
         10 . The method of  claim 7 , wherein provision of the trophic factors stimulates the growth of blood vessels. 
     
     
         11 . A method for providing a plurality of trophic factors to a subject, the method comprising:
 (a) obtaining a subject having an injury whose treatment requires an angiogenic factor; and   (b) transplanting a cell to the subject, wherein the cell is obtained by a process comprising the steps of:
 (i) contacting a culture of marrow adherent stromal cells with a polynucleotide comprising sequences encoding a Notch intracellular domain; 
 (ii) selecting cells that comprise the polynucleotide; and 
 (iii) further culturing the cells of step (ii) in the absence of selection; 
   wherein the plurality of trophic factors comprises brain-derived neurotrophic factor (BDNF), bone morphogenetic protein 7 (BMP-7), nerve growth factor (b-NGF), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF).   
     
     
         12 . The method of  claim 11 , wherein the Notch intracellular domain comprises amino acids 1703-2504 of the Notch-1 protein. 
     
     
         13 . The method of  claim 11 , wherein provision of the trophic factors stimulates the growth of endothelial cells. 
     
     
         14 . The method of  claim 11 , wherein provision of the trophic factors stimulates the growth of blood vessels.