Understanding cellular reprogramming barriers could help regenerative medicine

Pluripotent stem cells — often termed 'true' stem cells because they have the potential to differentiate into almost any cell type in the body — hold enormous promise for regenerative medicine. Adult stem cells naturally found in the human body, however, have only limited differentiation potential, and they are rare and difficult to grow in large numbers. By combining genomic and computational approaches in biomedical research, researchers are beginning to understand the barriers to reprogramming somatic (body) cells to the so-called induced pluripotent stem cells (iPSCs) that are believed to be as good as true stem cells and can be engineered in labs.

“Cells generally become committed to increasingly differentiated fates during normal development, but experimental paradigms for cellular reprogramming have shown that differentiation is reversible,” explained Jun Song, a Founder Professor in the College of Engineering at Illinois. Song was one of the leaders of the study, “Systematic Identification of Barriers to Human iPSC Generation,” appearing in the July 2014 edition of the journal Cell. “Understanding the process of reprogramming may also shed light on events that take place during cellular transformation in cancer.

“In this work, we identified reprogramming barriers, including genes involved in transcription, chromatin regulation, ubiquitination, dephosphorylation, vesicular transport, and cell adhesion,” said Song, a theoretical biological physicist with joint appointments in the Department of Bioengineering and Department of Physics at Illinois.

“Reprogramming of somatic cells to induced pluripotent stem cells holds enormous promise for regenerative medicine,” Song added. “Our platform provides an integrative approach for identifying pathways that may act as barriers beyond the setting of reprogramming to pluripotency, including in cancer. We anticipate that this approach will be useful in the dissection of direct lineage reprogramming and may reveal shared and unique aspects of different reprogramming paradigms.”

The research team used a combination of computing and laboratory experiments in their approach to developing a better understanding of how cells can be reprogrammed — to provide a more efficient way of creating more iPSCs for a wide variety of research purposes — and the barriers that prevent reprogramming. The group also created an online interactive library to help other scientists better understand the complex issues related to cell reprogramming.

The research was originally conducted at the University of California, San Francisco, where Song was formerly an associate professor. Study co-authors included: Han Qin and Aaron Diaz (co-first authors), Laure Blouin, Robert Jan Lebbink, Weronika Patena, Priscilia Tanbun, Emily M. LeProust, Michael T. McManus, and Miguel Ramalho-Santos. This work was a major collaboration among the laboratories of Song, McManus, and Ramalho-Santos.

Song joined the Illinois faculty in January 2014. His research program in computational biology and biomedicine leverages the methodologies and tools of physics and mathematics to discover how transcription factors, chromatin structure, and non-coding RNAs regulate gene expression. He is particularly interested in the genomic study of cancer. Song's lab is located at the Institute of Genomic Biology, and he is member of the Center for the Physics of Living Cells, an NSF-funded Physics Frontier Center headquartered at Illinois.