Understanding barriers to reprogramming cells holds promise for regenerative medicine

The recent discovery that human somatic cells (the cells of the body) can be reprogrammed in the laboratory to generate pluripotent stem cells has enormous implications for regenerative medicine, a relatively young branch of biomedical research that could lead to revolutionary treatments for many chronic diseases, including cancer.

Pluripotency refers to the incredible ability of some stem cells to develop into any cell type of the body. Laboratory-generated induced pluripotent stem cells (iPSCs) appear to be equivalent in every way to these “true” stem cells. The stem cells found in human adults, on the other hand, are rare, difficult to grow in large quantities in the laboratory, and have only limited differentiation potential.

But somatic cells inherently resist reprogramming of gene expression. In fact, multiple cellular mechanisms inhibit it at each phase of the multi-step process in iPSC generation. Until recently, these barriers to reprogramming were poorly understood, limiting their production.

Now researchers have for the first time systematically catalogued the barriers to reprogramming of somatic cells to generate iPSCs.

“Cells generally become committed to increasingly differentiated fates during the course of their normal development,” explains University of Illinois Founder Professor of Physics and of Bioengineering Jun Song, who is one of the lead scientists on the project, “but experimental paradigms for cellular reprogramming have shown that differentiation is reversible.”

“In this work, we identified reprogramming barriers, including genes involved in transcription, chromatin regulation, ubiquitination, dephosphorylation, vesicular transport, and cell adhesion,” says Song.

Identification of these barriers is the first step to establishing more efficient methods of supplying iPSCs for stem cell research.

“Understanding the process of reprogramming may also shed light on events that take place during cellular transformation in cancer,” adds Song.

The research team used a combination of computing and laboratory experiments to complete the most comprehensive study of its kind to date. They also created an online interactive library to help other scientists better understand the complex issues related to cell reprogramming. .

“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 article, “Systematic Identification of Barriers to Human iPSC Generation,” was published in the July 2014 issue of the journal Cell.

Song originally conducted the research at his former post at the University of California, San Francisco School of Medicine, in collaboration with the laboratories of two colleagues at UCSF, Michael McManus and Miguel Ramalho-Santos. Other co-authors include Han Qin and Aaron Diaz (co-first authors), Laure Blouin, Robert Jan Lebbink, Weronika Patena, Priscilia Tanbun, and Emily M. LeProust.

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. His ongoing research has implications for prognosis and treatment of cancer, in particular of malignant melanoma, one of the deadliest cancers.

This work was supported by NOW Rubicon grant 825.06.030; Veni  grant 916.10.138; the UCSF Program for Breakthrough Biomedical Research; National Institute of Health grants 1U01CA168370, R01GM80783, and R01CA163336; a Sontag Foundation Distinguished Scientist Award; and CIRM grant RB4-06028. The conclusions presented are those of the scientists and not necessarily those of the funding agencies.