The Birth of a Pancreas

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Hey! Will you look at that! I was reading through the table of contents in the February issue of Diabetes, the American Diabetes Association’s research journal, and I saw a familiar name– Maike Sander. Just the other day, I received an email about an upcoming in-house seminar in which Maike Sander would be speaking about the controlling factors in the differentiation of insulin-producing beta-cells. And sure enough, the author noted in the Diabetes article is the very same Dr. Sander, hailing from my very own Department of Cellular and Molecular Medicine at UCSD. So, the first lesson here is: yay, UCSD! I love living where I live.

The second lesson, though, is that, for as much as I support the use and funding of stem cell research, I don’t know enough about what it will actually take to get embryonic stem cells to turn into beta-cells. Of course, no one yet knows exactly what it will take, but I should probably at least know more about what we know so far. Expecting, then, to hear Dr. Sander speak next week, here’s what I can say based on her review for Diabetes, (co-written by Philip Seymour, a member of her lab), “Current Perspectives in Beta-Cell Development1:

From the paper: “Gross morphology of the developing pancreas. Sox9-eGFP demarcates the dorsal pancreatic endoderm (dp) at e9.5 (A) and both dorsal (dp) and ventral (vp) pancreatic buds at e10.5 (B) (embryos shown at same scale). Staining for Pdx1 highlights the epithelium of the pancreatic buds, antral stomach (as), common bile duct (cbd), and duodenum (duo) at e10.5 (C) and e11.5 (D); early glucagon+ endocrine cells differentiate at the periphery of the dorsal pancreatic bud and, following a temporal delay, in the ventral pancreatic bud (z-stack projections shown at same scale). X-Gal staining for lacZ expressed from the Pdx1 locus highlights the dorsal bud-derived (dp) and ventral bud-derived (vp) pancreas, antral stomach (as), common bile duct (cbd), extrahepatic bile ducts (ehd), and duodenum (duo) at e12.5 (E) and e15.5 (F). Gross morphology of the perinatal (e18.5) (G) and adult (four-month-old) (H) pancreas: stom, stomach; spl, spleen. F–H: Pancreas tissue is demarcated by red dashed lines.”

My goodness, this is complicated! I tend to think of beta-cells as singular cells, and thus I assumed the problem of differentiated stem cells, or pancreatic progenitor, into beta cells was mostly one of expressing certain molecular signals and transcription factors within a single, homogenous population of cells.

However, what Dr. Sander’s review makes very clear is what I imagine is obvious to those who work intimately with embryonic stem cells: cells don’t exist in vacuums, or even in lovely in vitro plates. Cells exist within a complicated context of internal and external signals, which, as seen in the case of beta-cells, are key to the proper functioning of the cells.

In other words, it is already possible to turn stem cells, or even other pancreatic alpha- and duct-cells, into insulin-producing cells by forcing the expression of certain key genes. However, these insulin-producing cells do not perfectly imitate beta-cells, and thus far are not sufficient replacements. Why? Well, that’s still an open question, and the review aims to aid the pursuit of an answer by addressing in detail the natural progression of embryonic cells to a fully developed pancreas during gestation and embryonic development.

Much of the current scientific knowledge comes from elaborate knock-out experiments in mice (where certain genes can be “turned off,” allowing researchers to analyze the contributions of one gene and its resultant protein at a time). Luckily, though, much of this knowledge is applicable to human development as well, which is relatively similar (relative to the cost of mice versus the cost of humans, and relative to, say, trying to study human olfactory sensation through mice). Doctors Seymour and Sander present a very detailed listing of dozens of key factors that govern the development of the pancreas, from its first appearance as prepancreatic cells in the very first days of embryonic development.

The amazing thing to me about the description of the process was– I hadn’t even considered the fact that the pancreas itself must be developed! I had thought about the development of the cells as individual, beta-cells, but I had never considered the complexity of the surrounding forest for those beta-cell trees. The dorsal (upper) and ventral (lower) sections of the pancreas begin to appear at embryonic day 8.5, and there are two different, but parallel processes that control the proper development of each half. Certain key factors during this process ensure that the tissue that is created is pancreatic, with the proper multipotent pancreatic progenitor cells2. And if these factors are missing? You end up with liver tissue or duodenum tissue. Clearly, even before we reach the stage of talking about beta- versus alpha- versus whatever-cells, there is so much chemical signaling that has to go correctly to put the embryo in a position to have a pancreas at all.

And then, even with the pancreatic tissue in place, there are still many pieces to put in order. The correct number of progenitor cells have to be created for the organ to survive and grow, and then the progenitor cells must differentiate into five different types of pancreatic cells, with the particular fate determined by where they are in the pancreas and the resultant set of signals and factors in the local milieu that researchers have only begun to define. And only then can we even begin to think about whether these cells are the type that produce insulin!

So what does this all mean to me? If beta-cells were listing their relationship status, they would choose, “It’s complicated.” And that means that both sides of the type 1 diabetes puzzle– immune dysregulation and beta-cell regeneration– are hard problems to solve.

But not impossible. And not boring or insignificant, either, which is important– because that means there are good people working on these problems, and trying to define the borders and rules that decide the fates of embryonic stem cells. And that I like, because my fate is closely tied to the fate of those cells.

1. Seymour PA, Sander M. Historical Perspective: Beginnings of the {beta}-Cell: Current Perspectives in {beta}-Cell Development. Diabetes. 2011 Feb;60(2):364-76. PubMed PMID: 21270248; PubMed Central PMCID: PMC3028333.

2. Fun with names: one gene whose expression is essential for the formation of the pancreas is Shh, or Sonic hedgehog.

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