Efficient induction of pluripotent stem cells using small molecule compounds
Chemical induction of iPS cells
Reprogramming somatic cells to a pluripotent state could generate a rich supply of patient-specific stem cells for regenerative medicine. Recent work has demonstrated that exogenous expression of four transcription factors- Sox-2, Oct-4, Klf-4, and c-Myc, or Sox-2, Oct-4, Nanog, and Lin-28, can directly reprogram somatic cells to a pluripotent stem cell state. Unfortunately, the resulting induced pluripotent stem (iPS) cells are unsuitable for regenerative medicine and suboptimal for disease modeling because the viral transgenes can spontaneously re-activate, a process that has lead to cancer in mice generated from iPS cells. Furthermore, integrated viral DNA activated a proto-oncogene and led to the development of T-cell leukemia in patients in two gene therapy trials. Therefore clinical applications will require the elimination of the viral transgenes from iPS cells.
Innovations and Advantages
The Melton group of Harvard University has discovered that chemical induction of iPS cells using valproic acid (VPA), an HDAC inhibitor, improves reprogramming efficiency of mouse embryonic fibroblasts infected with four transcription factors (Oct4, Klf4, Sox2 and c-Myc) by more than 100-fold. VPA enables reprogramming of primary human fibroblasts with only two factors, Oct4 and Sox2, without the need for the oncogenes c-Myc or Klf4.
Intellectual Property Status: Patent pending.
Huangfu, Danwei, Maehr, René, Guo, Wenjun, Eijkelenboom, Astrid, Snitow, Melinda, Chen, Alice E, Melton, Douglas A. 2008. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nature Biotechnology, 26, 795-798.
Huangfu, Danwei, Osafune, Kenji, Maehr, René, Guo, Wenjun, Eijkelenboom, Astrid, Chen, Shuibing, Muhlestein, Whitney, Melton, Douglas A. 2008. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology, 26, 1269-1276.
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Reference Harvard Case #3152