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Mount Sinai Hospital team collaborate with University of Toronto researchers to uncover important new clues in the biology of stem cells

(Toronto, ON—September 23, 2011) A University of Toronto team including Mount Sinai Hospital scientists Drs. Andras Nagy and Jeff Wrana have discovered pivotal new insights into the biology of stem cells, which will help improve the efficiency of stem cell creation for use in tissue regeneration and in the development of new drugs. The study was published in the late September issue of the journal Cell.

The research represents the first project of its kind focused on a process called alternative splicing—whereby one gene is edited to produce many unique genetic messages (via messenger RNAs) and proteins—to the study of reprogramming cells into stem cells. University of Toronto scientist and lead investigator Dr. Ben Blencowe specializes in studying alternative splicing in various biological contexts. Until now, however, the role and significance of the process in stem cell biology was poorly understood.

“This work has narrowed in on a ‘tipping point’ between an embryonic stem cell’s pluripotency—its ability to develop into most other cell types—and the mechanisms that lead to differentiation,” said Payman Samavarchi-Tehrani, a PhD student in Dr. Wrana’s lab. “This is a major step forward in understanding the molecular factors and pathways underlying stem cell biology, which we hope will advance the many applications of regenerative medicine.”

Dr. Blencowe’s studies were aided by the stem cell expertise and experimental techniques developed at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, where Drs. Wrana and Nagy are exploring the generation of induced pluripotent stem (iPS) cells, and finding more efficient and safer means to do so. Their recent work has focused on understanding the process of changing fully mature cells of the body (known as somatic cells) into these iPS cells, and assessing the molecular and genetic changes that occur during the cells’ reprogramming.

Mathieu Gabut, a postdoctoral fellow in the Blencowe laboratory and first author on the study, used microarray profiling and RNA interference screening to compare patterns of alternative splicing in undifferentiated and differentiated embryonic stem cells. His results showed that, among the set of changes discovered, a key alternative splicing event changes the DNA binding properties of a gene called FOXP1 in such a way to sustain stem cell pluripotency, while concurrently suppressing the genes required for differentiation (the process where a cell becomes a specific tissue or organ). The event was also shown to play a key role in the reprogramming process, whereby adult cells are coaxed to become iPS cells.

“This alternative splicing event functions as a control switch that is activated in embryonic stem cells and silent during differentiation,” said Payman, who will begin post-doctoral work at Harvard University next month. “In essence, this change in DNA binding specificity by FOXP1 due to alternative splicing results in enhanced acquisition and maintenance of the stem cell state. These findings highlight alternative splicing as an important mechanism to investigate in ongoing stem cell research, and give us another tool to improve the efficiency of iPS formation.”

The findings are just one of over one hundred alternative splicing ‘events’ that may be pivotal to stem cell generation, and represent new therapeutic targets to repair/replace damaged tissues in diseases such as heart disease, diabetes, spinal cord injury and Alzheimer’s disease.

The fruitfulness of this collaboration between Dr. Blencowe’s lab at the University and researchers at the Lunenfeld has fostered ongoing projects that will utilize the high-throughput screening facilities at Mount Sinai to further elucidate the role of alternative splicing in stem cell biology.

For this study, Drs. Wrana and Nagy received support from the Canadian Institutes of Health Research, the Ontario Ministry of Research and Innovation, the Ontario Research Fund, the Howard Hughes Medical Institute, and the Canadian Stem Cell Network.



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