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Stress-mediated p38 activation promotes iPSC generation
Update time: 2012-10-11
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Embryonic stem cells (ESCs) could potentially revolutionize medicine by providing an unlimited renewable source of cells capable of replacing or repairing damaged tissues in almost all degenerative diseases. Recent works demonstrated that ectopic expression of defined transcription factors (Oct4, Sox2, Klf4, c-Myc and et al) could reprogram murine and human somatic cells to induced pluripotent stem cells (iPSCs). The iPSC technology has attracted enormous interests due to its potential biomedical applications. Patient-specific iPSCs could be created by reprogramming and they could be further differentiated into functional autologous cells for cell-based therapy without immuno-compatibility issues and ethical concerns. However, iPS cell applications are hindered by safety concerns due to the use of oncogenes and incorporation of viral DNA sequences. Many efforts have been taken to make iPSCs more amenable for therapeutic application.

On October 9, 2012, a new way to enhance the reprogramming efficiency was published online by Cell Research. Graduate students XU Xinxiu and WANG Quan  from Dr. XIE Xin‘s group developed a screening system with 96-well plates and unexpectedly found that reprogramming efficiency was higher in the corner wells. After ruling out the possible effect of pH and nutritional changes, they discovered that it was the increased osmotic pressure in the corner wells that facilitated iPSC generation. Hyperosmosis not only facilitated four factor-mediated reprogramming, but also enhanced two or one factor-induced iPS cell generation in combination with other chemicals. Hyperosmosis-induced p38 activation plays critical role in this process. Constitutive active p38 mimics the positive effect of hyperosmosis, while dominant negative p38 and p38 inhibitor block the effect of hyperosmosis. Further study indicated stress-mediated p38 activation might promote reprogramming by reducing the global DNA methylation level and enhancing the expression of pluripotency genes. Environmental stress-mediated adaptation plays essential roles in the evolution of life. This study demonstrated how simple environmental stress like hyperosmosis helps to alter the fate of cells via intracellular signaling and epigenetic modulation.

This work was supervised by Dr.  XIE Xin, a Principle Investigator of Shanghai Institute of Materia Medica (SIMM), the deputy director of the National Center for Drug Screening, and an Adjunct Professor of Tongji University. Her research is mainly focused on GPCR-based drug discovery and chemical biology of stem cells. Last year her group reported that anti-psychotic drug LiCl greatly enhances the induction of iPSCs (Cell Research, 2011; 21(10):1424-35).

This work was supported by grants from Chinese Academy of Sciences, Ministry of Science and Technology of China, and Shanghai Commission of Science and Technology.

Original article:

Stress-mediated p38 activation enhances iPSC generagion. A. Hyperosmosis promotes the induction of iPSCs; B. Pluripotency of iPSCs; C. Blocking p38 activation blocks the effect of hyperosmosis in enhancing reprogramming; D. p38 activation reduces global DNA methylation level; G. Schematic representation of p38-facilitated reprogramming.

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