Lithium stimulation of cord blood stem cell proliferation and growth factor production

Abstract

The present invention provides methods for expanding human umbilical cord blood stem cells and methods for stimulating growth factor production by cord blood stem cells using an in vitro cell culture system comprising a lithium salt. The present invention also provides in vivo methods for enhancing the survival and growth of transplanted cord blood stem cells by treating the cells with a lithium salt prior to transplantation. In vivo methods for reducing rejection of transplanted cord blood stem cells by administering a lithium salt after transplantation are also provided.

What is claimed is: 
     
         1 . A method for stimulating growth factor production by human umbilical cord blood cells, said method comprising:
 culturing said cells in a medium comprising a lithium salt.   
     
     
         2 . The method of  claim 1 , wherein said growth factor is selected from the group consisting of a cell survival factor, an anti-differentiation factor, and combinations thereof. 
     
     
         3 . The method of  claim 2 , wherein said growth factor is a cell survival factor selected from the group consisting of a neurotrophin, a cytokine, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), and combinations thereof. 
     
     
         4 . The method of  claim 3 , wherein said cell survival factor is a neurotrophin selected from the group consisting of neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and combinations thereof. 
     
     
         5 . The method of  claim 2 , wherein said growth factor is an anti-differentiation factor, wherein said anti-differentiation factor is leukemia inhibitory factor (LIF). 
     
     
         6 . The method of  claim 1 , wherein said lithium salt is selected from the group consisting of lithium chloride, lithium carbonate, and lithium sulfate. 
     
     
         7 . The method of  claim 1 , wherein said lithium salt is lithium chloride. 
     
     
         8 . The method of  claim 1 , wherein said lithium salt is present in said medium at a concentration of from about 0.5 to about 5 mM. 
     
     
         9 . The method of  claim 1 , wherein said lithium salt is present in said medium at a concentration of about 3 mM. 
     
     
         10 . An in vitro method for expanding human umbilical cord blood cells, said method comprising:
 culturing said cells in a medium comprising a lithium salt.   
     
     
         11 . The method of  claim 10 , wherein said lithium salt is selected from the group consisting of lithium chloride, lithium carbonate, and lithium sulfate. 
     
     
         12 . The method of  claim 10 , wherein said lithium salt is lithium chloride. 
     
     
         13 . The method of  claim 10 , wherein said lithium salt is present in said medium at a concentration of from about 0.5 to about 5 mM. 
     
     
         14 . The method of  claim 10 , wherein said lithium salt is present in said medium at a concentration of about 3 mM. 
     
     
         15 . A method for enhancing survival and growth of transplanted human umbilical cord blood cells in a subject, said method comprising:
 (a) culturing said cells in a medium comprising a lithium salt; and   (b) administering the cells of step (a) to said subject.   
     
     
         16 . The method of  claim 15 , wherein said lithium salt is selected from the group consisting of lithium chloride, lithium carbonate, and lithium sulfate. 
     
     
         17 . The method of  claim 15 , wherein said lithium salt is lithium chloride. 
     
     
         18 . The method of  claim 15 , wherein said lithium salt is present in said medium at a concentration of from about 0.5 to about 5 mM. 
     
     
         19 . The method of  claim 15 , wherein said lithium salt is present in said medium at a concentration of about 3 mM. 
     
     
         20 . The method of  claim 15 , wherein said subject is a human. 
     
     
         21 . The method of  claim 15 , wherein said subject has been diagnosed with a spinal cord injury. 
     
     
         22 . The method of  claim 15 , wherein said cells are administered intraspinally. 
     
     
         23 . The method of  claim 15 , further comprising: (c) administering a lithium salt to said subject. 
     
     
         24 . The method of  claim 23 , wherein said subject is a human. 
     
     
         25 . The method of  claim 23 , wherein said lithium salt is lithium chloride. 
     
     
         26 . The method of  claim 23 , wherein said lithium salt is administered by a route selected from the group consisting of oral, intrathecal, intraventricular, subcutaneous, intraperitoneal, intravenous, and intramuscular. 
     
     
         27 . The method of  claim 23 , wherein said lithium salt is administered at a dose of from about 1 mg/kg to about 150 mg/kg. 
     
     
         28 . The method of  claim 23 , wherein said lithium salt is administered at a dose of about 10 mg/kg. 
     
     
         29 . A method for reducing rejection of transplanted human umbilical cord blood cells in a subject, said method comprising:
 administering a lithium salt to said subject after cell transplantation.   
     
     
         30 . The method of  claim 29 , wherein said subject is a human. 
     
     
         31 . The method of  claim 29 , wherein said subject has been diagnosed with a spinal cord injury. 
     
     
         32 . The method of  claim 29 , wherein said lithium salt is selected from the group consisting of lithium chloride, lithium carbonate, and lithium sulfate. 
     
     
         33 . The method of  claim 29 , wherein said lithium salt is lithium chloride. 
     
     
         34 . The method of  claim 29 , wherein said lithium salt is administered by a route selected from the group consisting of oral, intrathecal, intraventricular, subcutaneous, intraperitoneal, intravenous, and intramuscular. 
     
     
         35 . The method of  claim 29 , wherein said lithium salt is administered at a dose of from about 1 mg/kg to about 150 mg/kg. 
     
     
         36 . The method of  claim 29 , wherein said lithium salt is administered at a dose of about 10 mg/kg.