Stem cells are ideal tools to understand disease and develop new treatments because they can self-renew (generate more cells in a dish) and differentiate (become a wide variety of cell types). They can be differentiated into heart muscle cells, for example, which could then be used to replace damaged heart tissue. Where do scientists get stem cells? In the early days of stem cell research, investigators could isolate stem cells from pathological specimens of the brain or bone marrow. More recently, they have figured out how to make a special kind of stem cell called an induced pluripotent stem cell (iPS cell) from almost any type of adult cell, such as a skin cell. Researchers can then use iPS cells to study human development or to create “disease in a dish”, a technique that allows them to model an individual patient’s specific disease and screen for personalized treatments.
But generating iPS cells can be an arduous task. Reprogramming differentiated adult cells into iPS cells requires so many steps and so much time that the efficiency rate is very low – you might end up with only a few iPS cells even if you started with a million skin cells. So a team set out to improve the process. In a paper published February 1, 2011 in The EMBO Journal, they uncovered microRNAs (miRNAs) that are important during reprogramming and exploited them to make the transition from skin cell to iPS cell more efficient.
“We identified several molecular barriers early in the reprogramming process and figured out how to remove them using miRNA,” said Dr. Tariq Rana, senior author of the study. “This is significant because it will enhance our ability to use iPS cells to model diseases in the laboratory and search for new therapies.”
miRNAs are small strands of genetic material that may play a major role in many diseases by gumming up protein production. In this study, Dr. Rana and his colleagues observed that three groups of miRNAs, including two known individually as miR-93 and miR-106b, are activated as part of a defense mechanism that occurs when cells are stressed by the standard skin cell reprogramming process. Digging deeper, they determined that miR-93 and miR-106b target two proteins called Tgfbr2 and p21, which slow up the path to iPS cells by halting the cell cycle – the cell’s process of duplicating its DNA and dividing into two identical “daughter” cells – and promoting cell death.
Not only does this finding reveal more about the genetic underpinnings of iPS cell formation, but the researchers took advantage of this new information to speed up the process. When they added extra miR-93 and miR-106b to skin cells, Tgfbr2 and p21 were blocked, more cells survived and iPS cells were more readily obtained.
According to the study’s first author, graduate student Zhonghan Li, “Our study not only presents new mechanistic insights about the role of non-coding RNAs during somatic cell reprogramming but also provides proof of principle for using microRNAs as great enhancers for iPS cell generation.”
This concept could have far-reaching implications for research on many diseases and the search for new drugs to treat them.
“In some respects, this work may be regarded as a landmark contribution to the field of stem cell biology in general and cellular reprogramming in particular,” says Dr. Evan Y. Snyder, director of Sanford-Burnham’s Stem Cells and Regenerative Biology program. “Up until now, cellular differentiation and de-differentiation has focused principally on the expression of genes; this work indicates that the strategic non-expression of genes may be equally important. The work has demonstrated that miRNAs do function in the reprogramming process and that the generation of iPSCs can be greatly enhanced by modulating miRNA action. In addition to helping us generate better tools for the stem cell field, such findings inevitably facilitate our understanding of normal and abnormal stem cell behavior during development and in disease states.”
Li, Z., Yang, C., Nakashima, K., & Rana, T. (2011). Small RNA-mediated regulation of iPS cell generation The EMBO Journal DOI: 10.1038/emboj.2011.2