Producing astrocytes using small molecules

Abstract

Disclosed herein are methods of reprograming autologous tissues or cells into astrocytes or astroglial progenitor cells using one or more small molecule compounds only without any transgenes. Also disclosed are methods of preventing or treating neurodegenerative diseases or neurological disorders associated with dysfunction of astrocytes, such as Alzheimer's Disease, by transplanting the astrocytes or astroglial progenitor cells produced by the methods disclosed herein into the brain of a subject suffering from the neurodegenerative disease or neurological disorder.

1 . A method of preventing or treating a neurodegenerative disease associated with astrocyte dysfunction in a subject, comprising:
 reprogramming or converting somatic tissue or cells into astrocytes or astroglial progenitor cells by contacting the somatic tissue or cells with one or more small molecules, wherein the one or more small molecules include at least one TGF-β inhibitor; and   transplanting the astrocytes or astroglial progenitor cells into the brain of the subject.   
     
     
         2 . The method of  claim 1 , further comprising isolating the somatic tissue or cells from the subject before reprogramming. 
     
     
         3 . The method of  claim 1 , wherein the subject is human. 
     
     
         4 . The method of  claim 1 , wherein the somatic tissue or cells are fibroblasts, urinary cells, blood cells, adipocytes, keratinocytes, or dental pulp cells. 
     
     
         5 . The method of  claim 1 , wherein a single small molecule is used and the small molecule is a TGF-β inhibitor. 
     
     
         6 . The method of  claim 5 , wherein the TGF-β inhibitor is an inhibitor of TGF-βR1 (ALK5). 
     
     
         7 . The method of  claim 5 , wherein the TGF-β inhibitor is 616452, SB-431542, A-83-01, SD-208, LY 2109761, GW 788388, LDN-212854, A 77-01, LY2157299, K02288, ML347, or SB-505124 hydrochloride. 
     
     
         8 . The method of  claim 1 , wherein the one or more small molecules further include at least one of a histone deacetylase inhibitor, a GSK3β inhibitor, a lysine specific histone demethylase 1 (LSD1) inhibitor, and an Oct4-activating compound. 
     
     
         9 . The method of  claim 8 , wherein the one or more small molecules are a combination of VPA (V), CHIR99021 (C), 616452 (6), tranylcypromine (T), and OAC1 (O), a combination of VPA (V), CHIR99021 (C), A-83-01 (A), tranylcypromine (T), and OAC1 (O), or a combination of VPA (V), CHIR99021 (C), SB-431542 (S), tranylcypromine (T), and OAC1 (O). 
     
     
         10 . A combination of small molecules comprising a TGF-β inhibitor, wherein the combination induces or promotes reprogramming or converting somatic tissue or cells into astrocytes or astroglial progenitor cells. 
     
     
         11 . The combination of  claim 10 , further comprising at least one of a histone deacetylase inhibitor, a GSK3β inhibitor, a lysine specific histone demethylase 1 (LSD1) inhibitor, and an Oct4-activating compound. 
     
     
         12 . The combination of  claim 10 , wherein the combination is a combination of VPA (V), CHIR99021 (C), 616452 (6), tranylcypromine (T), and OAC1 (O), a combination of VPA (V), CHIR99021 (C), A-83-01 (A), tranylcypromine (T), and OAC1 (O), or a combination of VPA (V), CHIR99021 (C), SB-431542 (S), tranylcypromine (T), and OAC1 (O). 
     
     
         13 . A composition comprising a combination of small molecules, wherein the combination induces or promotes reprogramming or converting somatic tissue or cells into astrocytes or astroglial progenitor cells, and wherein the combination comprises a TGF-β inhibitor. 
     
     
         14 . The composition of  claim 13 , wherein the combination further comprises at least one of a histone deacetylase inhibitor, a GSK3β inhibitor, a lysine specific histone demethylase 1 (LSD1) inhibitor, and an Oct4-activating compound. 
     
     
         15 . The composition of  claim 13 , wherein the combination is a combination of VPA (V), CHIR99021 (C), 616452 (6), tranylcypromine (T), and OAC1 (O), a combination of VPA (V), CHIR99021 (C), A-83-01 (A), tranylcypromine (T), and OAC1 (O), or a combination of VPA (V), CHIR99021 (C), SB-431542 (S), tranylcypromine (T), and OAC1 (O).