Most research on stem cells involves the manipulation of gene expression, to some degree or another. During stem cell differentiation, the expression of specific genes orchestrates the choices cells make along the path from stem cell to adult cell — a process known as differentiation.
Here’s how it works: the expression (or lack thereof) of single or combinations of genes will direct a specific cell fate. The guiding hand behind this expression is a collection of genetic interactions – or gene regulatory network. In addition to specifying a particular cell lineage, regulatory networks simultaneously repress networks that specify other cell types. For example, the pluripotency regulatory network maintains embryonic stem cell self-renewal while repressing regulatory networks that direct differentiation.
Columbia University researchers treated the Foxo1 deletion mice with a hyperglycemia (high blood glucose)-inducing drug. Both Foxo1 deletion mice and control mice were administered insulin for the first few days following hyperglycemia induction. Upon halting insulin administration, Foxo1 deletion mice were able to restore blood glucose levels whereas control mice did not survive.
Upon analysis of gut tissue in Foxo1 deletion mice, researchers discovered a high number of insulin+ cells. Interestingly, insulin+ cells in the gut generated by deletion of Foxo1 still maintain expression of some intestinal genes. This suggests that the deletion of Foxo1 has lifted repressive signals on the pancreatic beta cell gene regulatory program instead of inducing differentiation of gut epithelium into a pancreatic fate. In other words, the Foxo1 gene appears to be a critical factor that distinguishes between hormone-producing cells in the pancreas and hormone-producing cells in the gut.
This is not the first study to create insulin-producing cells from non insulin-producing cells in vivo. A few years ago Doug Melton’s group at the Harvard Stem Cell Institute used an additive strategy whereby three beta cell factors were added to exocrine cells of the pancreas, resulting in transdifferentiation of exocrine cells into insulin-producing beta cells.
While neither of these strategies are directly translatable to the clinic, these studies have provided scientists with greater insight into what it takes to create a pancreatic beta cell.
Angela C. H. McDonald
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