Cellular Choice: Liver or Pancreas?
Multipotent progenitor cells play a vital role in the development and regeneration of various types of mature tissues, including diseases like cancer. So it’s important to understand the mechanisms of how they differentiate into some tissues and organs, but not others.
That’s what Chong Shin, researcher in the Petit Institute for Bioengineering and Bioscience, is working on. Recently published research from her lab explains how the common progenitors of the liver and the pancreas make that developmental choice – to become a liver or pancreas. Their findings will allow researchers to predict the development potential of a progenitor while enhancing stem cell differentiation into specific liver or pancreas lineages.
The liver and pancreas originate from a common multipotent source – hepatopancreatic progenitors. Previously during her postdoctoral training at the University of California at San Francisco, Shin showed that Bone morphogenetic protein 2b (Bmp2b) signaling is essential for determining which direction these progenitors will take – liver or pancreas.
“But we didn’t understand what is beneath the mechanism, how it’s controlled. We didn’t understand the details,” says Shin, assistant professor in the School of Biology and the corresponding author of the paper, entitled, “Four and a Half LIM Domains 1b (Fhl1b) Is Essential for Regulating the Liver versus Pancreas Fate Decision and for β-Cell Regeneration,” published recently in PLOS Genetics.
Through transcriptome profiling of endodermal tissues exposed to increased or decreased Bmp2b signaling, the researchers discovered a zebrafish gene, four and a half LIM domains 1b (fhl1b), as a novel target of Bmp2b signaling. Primarily expressed in the embryonic liver, fhl1b generally suppresses specification of the pancreas and induces the liver.
The researchers employed a form of fate mapping called single-cell lineage tracing to show that depletion of fhl1b caused a liver-to-pancreas fate switch (i.e., liver development is suppressed and the pancreas is induced), while overexpression of fhl1b redirected pancreatic progenitors to become liver cells.
“We were able to basically track a single progenitor cell and all of its progeny, so it’s a very cool technique,” says Jin Xu, a graduate student researcher in Shin’s lab and the lead author of the paper. “Using this technique, we discovered that we can precisely tell what happens when we have more or less of this gene being expressed.”
Additionally, they discovered that fhl1b regulates regeneration of insulin-secreting beta cells. Loss of fhl1b increased the regenerative capacity of beta cells by increasing pdx1 gene, which is essential for pancreatic development.
Taken altogether, the researchers’ data reveals novel and critical functions of fhl1b in the hepatic versus pancreatic fate decision and in beta cell regeneration. It’s information that Shin says could lead to, “another way of enhancing the development of healthy organs through directed differentiation,” since effective Bmp suppression is critical for the induction of PDX1 and the subsequent generation of beta cells in human pluripotent stem cells (hESCs).
In addition to Shin and Xu (based in the School of Biology), other authors of the research paper included two researchers from the Max Planck Institute for Polymer Research in Germany – Jiaxi Cui and Aranzazu Del Campo who synthesized the compound for the single-cell lineage tracing.
Shin credits Xu with carrying the biggest load, performing the experiments.
“I’m so proud of him,” Shin says. “It took 11 months from the initial submission to the final acceptance, and that included a lot of late nights, including plenty of all-nighters.”
This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K01DK081351), the Regenerative Engineering and Medicine Research Center (2731336 and 1411318), the National Science Foundation (1354837), and the School of Biology (Georgia Institute of Technology).
Citation: Xu J, Cui J, Del Campo A, Shin CH (2016) Four and a Half LIM Domains 1b (Fhl1b) Is Essential for Regulating the Liver versus Pancreas Fate Decision and for β-Cell Regeneration. PLoS Genet 12(2): e1005831. doi:10.1371/journal.pgen.1005831 (http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005831)
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