Methods and compositions for modulating angiogenesis and vasculogenesis

Abstract

Disclosed herein are methods and compositions for stimulating angiogenesis, using cells descended from marrow adherent stromal cells that have been transfected with sequences encoding a Notch intracellular domain. Applications of these methods and compositions include treatment of ischemic disorders such as stroke.

1 . A method for the repair of ischemic damage in a subject, the method comprising administering to the subject a population of SB623 cells; wherein the SB623 cells are obtained by:
 (a) providing a culture of mesenchymal stem cells,   (b) contacting the cell culture of step (a) with a polynucleotide comprising sequences encoding a Notch intracellular domain (NICD) wherein said polynucleotide does not encode a full-length Notch protein,   (c) selecting cells that comprise the polynucleotide of step (b), and   (d) further culturing the selected cells of step (c) in the absence of selection.   
     
     
         2 . The method of  claim 1 , wherein the repair of ischemic damage is selected from the group consisting of augmentation of angiogenesis, prevention of endothelial cell death, enhancement of endothelial cell survival, stimulation of endothelial cell proliferation, enhancement of blood vessel branching, and provision of one or more angiogenic factors. 
     
     
         3 . The method of  claim 2 , wherein the angiogenic factor is selected from the group consisting of one or more of angiogenin, angiopoietin-2, epidermal growth factor, basic fibroblast growth factor, leptin, platelet-derived growth factor-BB, and placental growth factor. 
     
     
         4 . The method of  claim 1 , wherein the ischemic damage occurs in the central nervous system of the subject. 
     
     
         5 . The method of  claim 4 , wherein the ischemic damage occurs in the brain of the subject. 
     
     
         6 . A composition for use in the treatment of ischemic damage in a subject, the composition comprising:
 (1) a population of SB623 cells; wherein the SB623 cells are obtained by:
 (a) providing a culture of mesenchymal stem cells, 
 (b) contacting the cell culture of step (a) with a polynucleotide comprising sequences encoding a Notch intracellular domain (NICD) wherein said polynucleotide does not encode a full-length Notch protein, 
 (c) selecting cells that comprise the polynucleotide of step (b), and 
 (d) further culturing the selected cells of step (c) in the absence of selection; and 
   (2) a pro-angiogenic agent.   
     
     
         7 . The composition of  claim 6 , wherein the pro-angiogenic agent is a polypeptide. 
     
     
         8 . The composition of  claim 6 , wherein the pro-angiogenic agent is a nucleic acid. 
     
     
         9 . The composition of  claim 7 , wherein the polypeptide is a transcription factor that activates expression of a pro-angiogenic protein. 
     
     
         10 . The composition of  claim 9 , wherein the pro-angiogenic protein is vascular endothelial growth factor (VEGF). 
     
     
         11 . The composition of  claim 10 , wherein the transcription factor is a non-naturally-occurring zinc finger protein that activates transcription of the VEGF gene. 
     
     
         12 . A method for the repair of ischemic damage in a subject, the method comprising administering to the subject an effective amount of the composition of  claim 6 . 
     
     
         13 . The method of  claim 12 , wherein the repair of ischemic damage is selected from the group consisting of augmentation of angiogenesis, prevention of endothelial cell death, enhancement of endothelial cell survival, stimulation of endothelial cell proliferation, enhancement of blood vessel branching, and provision of one or more angiogenic factors. 
     
     
         14 . The method of  claim 13 , wherein the angiogenic factor is selected from the group consisting of one or more of angiogenin, angiopoietin-2, epidermal growth factor, basic fibroblast growth factor, leptin, platelet-derived growth factor-BB, and placental growth factor. 
     
     
         15 . The method of  claim 12 , wherein the ischemic damage occurs in the central nervous system of the subject. 
     
     
         16 . The method of  claim 15 , wherein the ischemic damage occurs in the brain of the subject. 
     
     
         17 . The method of  claim 16 , wherein the ischemic damage results from stroke.