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US 2013/0280809 A1Published application
Reprogramming of cells to a new fate
AssigneeThe Scripps Research Institute
InventorsJem A. Efe, Janghwan Kim, Saiyong Zhu, Simon Hilcove, Sheng Ding
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Abstract
Methods and compositions for transdifferentiation of an animal cell from (i) a first pluripotent cell fate to a second nonpluripotent cell fate or (ii) from a non-pluripotent mesodermal, endodermal, or ectodermal cell fate to a different non-pluripotent mesodermal, endodermal, or ectodermal cell fate.
Claims48
A method of converting an animal cell from a first non-pluripotent cell fate to a second non-pluripotent cell fate, the method comprising:
- increasing the quantity of at least one reprogramming transcription factor in an animal cell having the first cell fate to generate a cell that differentiates in response to lineage-specific differentiating factors to a second cell fate different from the first cell fate;
- and
- submitting the cell that differentiates in response to lineage-specific differentiating factors to conditions that induce differentiation of the cell to generate a cell having the second non-pluripotent cell fate.
A method of differentiating an animal cell into a cardiomyocyte, the method comprising:
- contacting the animal cell with a GSK-3 inhibitor and/or a BMP protein under conditions to generate a cardiomyocyte.
A method of transdifferentiating an animal cell into a cardiomyocyte, comprising:
- introducing into a non-pluripotent animal cell having a first non-pluripotent cell fate one or more polynucleotides encoding one or more polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- or contacting a non-pluripotent animal cell having a first non-pluripotent cell fate with one or polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- and
- contacting the non-pluripotent animal cell with a GSK-3 inhibitor, a calcium channel agonist, a Gαs activating agent, a cAMP analog, and/or a BMP protein under conditions to generate the cardiomyocyte;
- thereby differentiating the non-pluripotent animal cell into the cardiomyocyte.
2 more elements
A method of transdifferentiating an animal cell into a neural progenitor cell, the method comprising:
- introducing into a non-pluripotent animal cell having a first non-pluripotent cell fate one or more polynucleotides encoding one or more polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- or contacting a non-pluripotent animal cell having a first non-pluripotent cell fate with one or polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- and
- contacting the non-pluripotent animal cell with FGF2, FGF4, and EGF under conditions to generate the neural progenitor cell;
- thereby differentiating the non-pluripotent animal cell into the neural progenitor cell.
2 more elements
A method of transdifferentiating an animal cell into a retinal pigmented epithelium cell, the method comprising:
- introducing into a non-pluripotent animal cell having a first non-pluripotent cell fate one or more polynucleotides encoding one or more polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- or contacting a non-pluripotent animal cell having a first non-pluripotent cell fate with one or polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- contacting the non-pluripotent animal cell with FGF2, FGF4, and EGF under conditions to generate a neural progenitor cell;
- and
- contacting the neural progenitor cell with a TGFβ inhibitor and a GSK-3 inhibitor to generate the retinal pigmented epithelium cell;
- thereby differentiating the non-pluripotent animal cell into the retinal pigmented epithelium cell.
3 more elements
A method of transdifferentiating an animal cell into a tyrosine hydroxylase (TH)-positive neuronal cell, the method comprising:
- introducing into a non-pluripotent animal cell having a first non-pluripotent cell fate one or more polynucleotides encoding one or more polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- or contacting a non-pluripotent animal cell having a first non-pluripotent cell fate with one or polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- and
- contacting the non-pluripotent animal cell with FGF8 and SHH under conditions to generate the TH-positive neuronal cell;
- thereby differentiating the non-pluripotent animal cell into the TH-positive neuronal cell.
2 more elements
A method of transdifferentiating an animal cell into a pancreatic lineage cell, the method comprising:
- (1) introducing into a non-pluripotent animal cell having a first non-pluripotent cell fate one or more polynucleotides encoding one or more polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- or contacting a non-pluripotent animal cell having a first non-pluripotent cell fate with one or polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- and
- (2) under conditions to generate the pancreatic lineage cell,
- (a) contacting the non-pluripotent animal cell with a TGFβ/Activin/Nodal family member and a JAK inhibitor;
- (b) contacting the cell of step (2)(a) with a TGFβ/ALK5 receptor inhibitor, BMP4, bFGF, and RA;
- and
- (c) contacting the cell of step (2)(b) with nicotinamide;
- thereby differentiating the non-pluripotent animal cell into the pancreatic lineage cell.
6 more elements
A method of transdifferentiating an animal cell into an induced definitive endoderm (iDE) cell, the method comprising:
- introducing into a non-pluripotent animal cell having a first non-pluripotent cell fate one or more polynucleotides encoding one or more polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- or contacting a non-pluripotent animal cell having a first non-pluripotent cell fate with one or polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- and
- contacting the non-pluripotent animal cell with a GSK-3 inhibitor, an HDAC inhibitor, and a TGFβ/Activin/Nodal family member under conditions to generate the iDE cell;
- thereby differentiating the non-pluripotent animal cell into the iDE cell.
2 more elements
A method of transdifferentiating an animal cell into a pancreatic beta cell, the method comprising:
- (1) introducing into a non-pluripotent animal cell having a first non-pluripotent cell fate one or more polynucleotides encoding one or more polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- or contacting a non-pluripotent animal cell having a first non-pluripotent cell fate with one or polypeptides selected from the group consisting of an Oct polypeptide, a Klf polypeptide, a Sox2 polypeptide and a Myc polypeptide;
- (2) contacting the non-pluripotent animal cell with a GSK-3 inhibitor, an HDAC inhibitor, and a TGFβ/Activin/Nodal family member under conditions to generate an iDE cell;
- and
- (3) under conditions to generate the pancreatic beta cell,
- (a) contacting the iDE cell with FGF7, RA, a Hedgehog pathway inhibitor, a BMP inhibitor, and a TGFβ/ALK5 receptor inhibitor;
- (b) contacting the cell of step (3)(a) with EGF and a Notch inhibitor;
- and
- (c) contacting the cell of step (3)(b) with bFGF and nicotinamide;
- thereby differentiating the non-pluripotent animal cell into the pancreatic beta cell.
7 more elements
Dependencies are inferred from the claim text.