EFFICIENT INDUCTION OF PLURIPOTENT STEM CELLS USING SMALL MOLECULE COMPOUNDS

• US 20120021519A1
• Filed: 09/21/2009
• Published: 01/26/2012
• Est. Priority Date: 09/19/2008
• Status: Abandoned Application

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Rubin, Lee, Eggan, Kevin, Lam, Kelvin, Ichida, Justin, Blanchard, Joel
• Application Number:
  US13/119,848
• Publication Number:
  US 20120021519A1
• Time in Patent Office: Days
• US Class Current: 435/377
• CPC Class Codes: C12N 2501/065 Modulators of histone acetylation
• CPC Class Codes: C12N 2501/15 Transforming growth factor beta (TGF-β)
• CPC Class Codes: C12N 2501/603 Oct-3/4
• CPC Class Codes: C12N 2501/604 Klf-4
• CPC Class Codes: C12N 2501/606 c-Myc
• CPC Class Codes: C12N 2501/727 Kinases (EC 2.7.)
• CPC Class Codes: C12N 2501/999 Small molecules not provided for elsewhere
• CPC Class Codes: C12N 5/0696 Artificially induced pluripotent stem cells, e.g. iPS

Abstract

The disclosure features a method of producing a reprogrammed cell (e.g. an induced pluripotent stem cell or an undifferentiated cell) from a differentiated (e.g. somatic) cell. In some embodiments, the methods includes contacting a differentiated (e.g. somatic cell) with a TGFBR1 inhibitor or anti-TGF-β-antibody to produce a reprogrammed cell (e.g. pluripotent stem cell or undifferentiated cell). Embodiments of the present invention relate to a reprogrammed cell and methods and compositions for producing a chemically produced reprogrammed cell or populations thereof.

Claims

1-135. -135. (canceled)

136. A method of reprogramming a differentiated cell in the absence of exogenous Sox2 transcription factor, comprising contacting an isolated differentiated cell with the compound of any of Formula I, II, or III to thereby produce a reprogrammed cell, wherein the compound of Formula I is:

137. The method of claim 136, wherein the compound of formula (I) comprises the structure:

138. The method of claim 136, wherein the compound of formula (I) comprises the structure:

139. The method of claim 136, wherein an isolated differentiated cell is contacted with the compound of Formula I(a) or Formula I(b) to thereby produce a reprogrammed cell, wherein the compound of Formula I(a) is:

140. The method of claim 136, wherein the compound of formula (II) comprises the structure:

141. The method of claim 136, wherein the compound of formula (III) comprises the structure

142. The method of claim 136, wherein an isolated differentiated cell is contacted with the compound of Formula III(a) or Formula III(b) to thereby produce a reprogrammed cell, wherein the compound of Formula III(a) is:

144. The method of claim 136 wherein the isolated differentiated cell is contacted with one or more exogenous transcription factors selected from the group consisting of a nucleic acid encoding at least one transcription factor selected from the group consisting of Oct-4, Klf-4, c-Myc, lin-28 and Nanog or a biologically active polypeptide of at least one transcription factor selected from the group consisting of Oct-4, Klf-4, c-Myc, lin-28 and Nanog.

143. A method of reprogramming a differentiated cell in the absence of exogenous Sox2 transcription factor comprising contacting an isolated differentiated cell with a compound of any of Formula IV-VII to thereby produce a reprogrammed cell, wherein the compound of Formula IV is Formula IV(a) or Formula IV(b), wherein the compound of Formula IV(a) is:

145. A method of reprogramming a differentiated cell in the absence of exogenous Klf4, comprising contacting an isolated differentiated cell with any compound of Formula VIII or IX to produce a reprogrammed cell, wherein a compound of Formula VIII is:

146. The method of claim 145, wherein an isolated differentiated cell is contacted with a compound of Formula VIII comprising the structure:

147. The method of claim 145, wherein an isolated differentiated cell is contacted with a compound of Formula IX(a) to produce a reprogrammed cell, wherein the Formula IX(a) is:

148. The method of claim 146, wherein an isolated differentiated cell is contacted with a compound comprising the structure: