Although stem cells hold considerable promises for the treatment of a number of devastating diseases (e.g. cardiovascular diseases, neurodegenerative diseases, diabetes and cancers), obstacles such as control of stem cell fate/function, immuno-rejection, and limited cell sources must be overcome before their therapeutic potentials can be realized. Recent studies have suggested that tissue-specific somatic cells may overcome their intrinsic lineage-restriction to de-differentiate or trans-differentiate (i.e. reprogramming) upon exposure to a specific set of signals (or ectopic expression of master transcription factors) in vitro and in vivo. Reprogramming of various rodent and human somatic cells to pluripotent ESC-like cells (i.e. induced pluripotent/iPS cells) has recently been achieved by viral transduction of four transcription factors (e.g. Oct4, cMyc, Sox2 and Klf4). More recently, we have reported that small molecules can replace certain transcription factors as well as substantially improve reprogramming efficiency and kinetics in generating iPS cells, and developed a method of generating and using recombinant cell-penetrating proteins to generate iPS cells without using any genetic materials and genetic manipulation (please see our preliminary results). With those proof-of-principle demonstrations, we propose to further develop/optimize the chemically defined, protein and small molecule-based reprogramming process in human cells to have highly robust and efficient method and to further in-depth characterize those cells.
Reprogramming of various rodent and human somatic cells to pluripotent ESC-like cells (i.e. induced pluripotent/iPS cells) has recently been achieved by viral transduction of four transcription factors (e.g. Oct4, cMyc, Sox2 and Klf4). More recently, we have reported that small molecules can replace certain transcription factors as well as substantially improve reprogramming efficiency and kinetics in generating iPS cells, and developed a method of generating and using recombinant cell-penetrating proteins to generate iPS cells without using any genetic materials and genetic manipulation (please see our preliminary results). With those proof-of-principle demonstrations, we propose to further develop/optimize the chemically defined, protein and small molecule-based reprogramming process in human cells to have highly robust and efficient method and to further in-depth characterize those cells. Collectively, the studies described in this proposal will provide novel chemical tools for producing unlimited amount of (autologous) pluripotent cells from differentiated/lineage-restricted cells for various applications as well as studying the underlying molecular mechanisms of pluripotency and epigenetic regulations, and may ultimately facilitate development of small molecule therapeutics to treat human diseases and stimulate tissue/organ regeneration in vivo. Principal Investigator/Program Director (Last, first, middle): Ding, Sheng Narrative: Reprogramming of various rodent and human somatic cells to pluripotent ESC-like cells (i.e. induced pluripotent/iPS cells) has recently been achieved by viral transduction of four transcription factors (e.g. Oct4, cMyc, Sox2 and Klf4). More recently, we have reported that small molecules can replace certain transcription factors as well as substantially improve reprogramming efficiency and kinetics in generating iPS cells, and developed a method of generating and using recombinant cell-penetrating proteins to generate iPS cells without using any genetic materials and genetic manipulation (please see our preliminary results). With those proof-of-principle demonstrations, we propose to further develop/optimize the chemically defined, protein and small molecule-based reprogramming process in human cells to have highly robust and efficient method and to further in-depth characterize those cells. Collectively, the studies described in this proposal will provide novel chemical tools for producing unlimited amount of (autologous) pluripotent cells from differentiated/lineage-restricted cells for various applications as well as studying the underlying molecular mechanisms of pluripotency and epigenetic regulations, and may ultimately facilitate development of small molecule therapeutics to treat human diseases and stimulate tissue/organ regeneration in vivo. PHS398/2590 (Rev. 05/01) Page ___ ____ Use 1/2-inch MARGINS. Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b.
| Wang, Haixia; Cao, Nan; Spencer, C Ian et al. (2014) Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4. Cell Rep 6:951-60 |
| Zhu, Saiyong; Rezvani, Milad; Harbell, Jack et al. (2014) Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature 508:93-7 |
| Yu, Chen; Liu, Kai; Tang, Shibing et al. (2014) Chemical approaches to cell reprogramming. Curr Opin Genet Dev 28:50-56 |
| Li, Ke; Zhu, Saiyong; Russ, Holger A et al. (2014) Small molecules facilitate the reprogramming of mouse fibroblasts into pancreatic lineages. Cell Stem Cell 14:228-36 |
| Xie, Min; Cao, Nan; Ding, Sheng (2014) Small molecules for cell reprogramming and heart repair: progress and perspective. ACS Chem Biol 9:34-44 |
| Lin, Changsheng; Yu, Chen; Ding, Sheng (2013) Toward directed reprogramming through exogenous factors. Curr Opin Genet Dev 23:519-25 |
| Ma, Tianhua; Xie, Min; Laurent, Timothy et al. (2013) Progress in the reprogramming of somatic cells. Circ Res 112:562-74 |
| Li, Wenlin; Jiang, Kai; Wei, Wanguo et al. (2013) Chemical approaches to studying stem cell biology. Cell Res 23:81-91 |
| Li, Jun; Huang, Ngan F; Zou, Jun et al. (2013) Conversion of human fibroblasts to functional endothelial cells by defined factors. Arterioscler Thromb Vasc Biol 33:1366-75 |
| Li, Wenlin; Li, Ke; Wei, Wanguo et al. (2013) Chemical approaches to stem cell biology and therapeutics. Cell Stem Cell 13:270-83 |
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