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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Version of Record online: 3 MAR 2010
Copyright © 2010 AlphaMed Press
Volume 28, Issue 4, pages 713–720, April 2010
How to Cite
Mali, P., Chou, B.-K., Yen, J., Ye, Z., Zou, J., Dowey, S., Brodsky, R. A., Ohm, J. E., Yu, W., Baylin, S. B., Yusa, K., Bradley, A., Meyers, D. J., Mukherjee, C., Cole, P. A. and Cheng, L. (2010), Butyrate Greatly Enhances Derivation of Human Induced Pluripotent Stem Cells by Promoting Epigenetic Remodeling and the Expression of Pluripotency-Associated Genes. STEM CELLS, 28: 713–720. doi: 10.1002/stem.402
Author contributions: P.M.: Conception and design, provision of study material, collection and assembly of data, data analysis and interpretation, and manuscript writing; B.-K. C.: Provision of study material, collection and analysis of data; J.Y., Z.Y., J.Z., S.D.: Collection and analysis of data; J.E.O., W.Y.: Collection and assembly of data; S.B.B.: Data analysis and interpretation; R.A.B., K.Y., A.B, D.J.M., C.M., P.A.C.: Provision of study material or patients; L.C.: Conception and design, data analysis and interpretation, financial and administrative support, and manuscript writing.
First published online in STEM CELLS EXPRESS March 3, 2010.
Disclosure of potential conflicts of interest is found at the end of this article.
- Issue online: 14 APR 2010
- Version of Record online: 3 MAR 2010
- Manuscript Accepted: 12 FEB 2010
- Manuscript Received: 8 JAN 2010
- Institute for Cell Engineering and NIH. Grant Numbers: RC2 HL101582, NIH GM62437
- Flight Attendant Medical Research Institute (FAMRI) Foundation
- Taiwan Merit Scholarship. Grant Number: NSC-095-SAF-I-564-019-TMS
- Japan Society for Promotion of Science
- Induced pluripotent stem cells;
- Sodium butyrate;
- piggyBac DNA transposition;
- Sickle cell disease
We report here that butyrate, a naturally occurring fatty acid commonly used as a nutritional supplement and differentiation agent, greatly enhances the efficiency of induced pluripotent stem (iPS) cell derivation from human adult or fetal fibroblasts. After transient butyrate treatment, the iPS cell derivation efficiency is enhanced by 15- to 51-fold using either retroviral or piggyBac transposon vectors expressing 4 to 5 reprogramming genes. Butyrate stimulation is more remarkable (>100- to 200-fold) on reprogramming in the absence of either KLF4 or MYC transgene. Butyrate treatment did not negatively affect properties of iPS cell lines established by either 3 or 4 retroviral vectors or a single piggyBac DNA transposon vector. These characterized iPS cell lines, including those derived from an adult patient with sickle cell disease by either the piggyBac or retroviral vectors, show normal karyotypes and pluripotency. To gain insights into the underlying mechanisms of butyrate stimulation, we conducted genome-wide gene expression and promoter DNA methylation microarrays and other epigenetic analyses on established iPS cells and cells from intermediate stages of the reprogramming process. By days 6 to 12 during reprogramming, butyrate treatment enhanced histone H3 acetylation, promoter DNA demethylation, and the expression of endogenous pluripotency-associated genes, including DPPA2, whose overexpression partially substitutes for butyrate stimulation. Thus, butyrate as a cell permeable small molecule provides a simple tool to further investigate molecular mechanisms of cellular reprogramming. Moreover, butyrate stimulation provides an efficient method for reprogramming various human adult somatic cells, including cells from patients that are more refractory to reprogramming. STEM CELLS 2010;28:713–72028:713–720