Friday Science Review: June 14, 2013
June 14, 2013
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Embryonic stem cells are pluripotent, meaning they have the ability to differentiate into multiple cell types. Due to this, embryonic stem cells have the potential to be used in cell-based therapies to treat diseases in which specific cell types are lost, such as Alzheimer’s or diabetes, or to promote recovery following traumatic events, such as spinal cord injury or stroke. However, the use of embryonic stem cells is controversial for a number of ethical reasons, with specific concern surrounding how they are harvested. Induced pluripotent stem cells (iPSCs) offer an alternative to embryonic stem cells, because they can be derived from differentiated host tissue. Because changes in gene expression within embryonic stem cells lead to their differentiation and loss of pluripotency, iPSCs can be produced from differentiated cells by essentially reversing these changes. New work published in Nature from the lab of Dr. Benjamin Blencowe at the University of Toronto identifies muscleblind-like RNA binding proteins (MBNL1 and MBNL2) as regulators of specific gene splicing events that differ between embryonic stem cells and differentiated cells. Using high-throughput sequence profiling and quantitative polymerase chain reaction, the authors found that MBNL proteins are expressed less in embryonic stem cells and iPSCs than in differentiated cells. This led the authors to hypothesize that MBNL proteins repress expression of certain sequences of RNA that maintain the pluripotent state of embryonic stem cells. To examine if this was the case, the authors used small interfering RNA to decrease the amount of MBNL1 and 2 protein expressed in cultured mouse and human cells. In approximately half of these cells, decreasing the MBNL proteins altered the splicing of the FOXP1 gene, a gene important for triggering a switch between embryonic stem cells and differentiated cells, and returned the cells to an embryonic stem cell-like pattern of FOXP1 expression. It was also possible to do the opposite: over-expression of the MBNL1 and 2 proteins in mouse embryonic stem cells caused these cells to quickly adopt the FOXP1 splicing pattern seen in differentiated cells. Importantly, knockdown of MBNL proteins increased the level of several transcription factors that are critical for maintaining pluripotency of embryonic stem cells, and significantly increased the number of iPSC colonies. These results demonstrate that MBNL proteins 1 and 2 are directly involved in the control of embryonic stem cell pluripotency, and that reduction of their expression in differentiated cells can lead to induction of iPSCs. MBNL expression is therefore an attractive therapeutic target to create pluripotent cells for use in cell-based therapies, as the use of iPSCs eliminates many of the ethical concerns surrounding the use of embryonic stem cells for such therapies.