In The Field

ISSCR 2008: Making Beta Cells (and cutting out the middleman)

Harvard’s Doug Melton, in a plenary talk this afternoon to open the International Society for Stem Cell Research (ISSCR) meeting in Philadelphia, actually didn’t talk about stem cells at all. Rather he discussed new results showing direct differentiation of pancreatic tissue into the elusive and important Beta cells, skipping stem cells altogether.

It was clear from the opening session, that a large part of the conference would focus not on the derivation of stem cells, but rather their re-differentation into useful tissues, which is not so easy as one might think. Take the beta cell for example. Melton has had a long-standing project to derive beta cells from es cells. The potential is obvious. For folks with type 1 diabetes, beta cells can be transplanted with limited success, but are currently in short supply (cells from two cadavers are required for the so-called Edmonton protocol).

After four years of work trying to use chemical compounds to edge stem cells down the developmental path of the insulin producing beta cells, he found two with 70% efficiency in moving the cells the very first step in a process that looks to contain maybe six. So, his group began experiments to short circuit the process. Rather than taking an undifferentiated stem cell, could one take a fully developed adult cell and switch its fate using transcription factors without reverting to stem cells? The answer, ostensibly seems to be yes. Screening for upwards of 1000 factors in 5000 mouse embryonic tissue samples, Melton’s lab identified 28 factors that appeared closely related to beta cell differentiation formation. Paring down brought the number to nine. Using a virus to inject the genes that encode these transcription factors into the pancreas of living mice, they were able to cause exocrine cells in the pancreas to start producing insulin and look just like beta cells in every way they’ve looked. Melton says, it’s “not the case that they’ve just turned on the insulin genes. There’s a panoply of genes turned on and off in response to these transcription factors.” They even started producing VEGF and promoting angiogenesis to get blood supply. The group has been able to reliably convert cells to insulin producing beta cells using just three of the nine genes: Ngn3, Pdx1, and Mafa. Mice in which islets had been chemically ablated achieved some level of blood sugar control, but not that of wild type. And despite waning expression of the three genes they injected, the phenotype of the transformed cells remained for several months. Melton says he wouldn’t necessarily predict a gene therapy approach based on his findings, but if in vitro technologies could be adapted, they might increase the number of beta cells for transplant operations. This type of cellular reprogramming involved here is fascinating. I remember when few believed de-differentiation from adult cells to pluripotent stem cells was possible with out the help of egg cytoplasm. iPS cells proved that wrong. This fate-jumping reprogramming without intervening de-differentiation is even more astonishing.

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