Of Men and Newts

Regenerative medicine is one of the new buzzwords in science. The therapeutic promise is just too good to pass up. The concept that, for humans, science could one day reproduce the feats of a newt in regenerating a new limb is the stuff of science fiction. Yet, the potential and progress continue to astound us all. We have moved from somatic nuclear transfer in the 1960s, to transdifferentiation, cell fusion for adult pluripotent cells, and, most recently, the ability to program mouse and human differentiated cells into induced pluripotent cells (iPS) by the expression of a defined set of factors (Oct4, Sox2, c-Myc, Klf4).¹  All of these findings have been surprising in that the dogma was that the adult cells follow a series of sequential, unidirectional, developmental steps that were thought to be irreversible. The concept has been that the "attaining maturity" process leads to terminally differentiated cells.

Many of these studies have worked primarily with cells in tissue culture. A recent report suggests that it may not be necessary to reach back to the level of an iPS. Perhaps adult differentiated cells can be used and such reprogramming can be done in vivo. The investigators of this manuscript identified adult reprogramming factors by re-expressing multiple embryonic genes in living adult animals. The specific goal was to reprogram adult pancreatic exocrine cells into cells that resemble the islet beta cells, thereby potentially curing diabetes. A group of nine transcription factors was used initially in a mixture after which several were systematically removed so that the least number of transcription factors that could still give rise to the desired phenotype were used. A specific combination of three transcription factors, Ngn3, Pdx1, and Mafa, could reprogram pancreatic exocrine cells in adult mice into cells that closely resembled the beta cells of the islets in size, shape, and ultrastructure. Moreover, these cells express the genes that are essential for beta-cell function and could ameliorate hyperglycemia (although not completely) by producing and secreting insulin. Surprisingly, the reprogramming did not require proliferation and occurred rapidly with the first insulin-positive cells seen within three days. However, these reprogrammed cells did not organize into islets, and further studies are needed to understand how to aggregate these cells, thereby potentially optimizing their response to hyperglycemia. More studies are also necessary to ascertain that these cells do not become malignant.