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Cellular composition of the pancreas: elucidating the role of mesenchymal signaling pathways

Final Report Summary - EMPANMES (Cellular composition of the pancreas: elucidating the role of mesenchymal signaling pathways)

The pancreas constitutes of various cell types with distinctive function. Exocrine cells produce and secrete digestive enzymes while endocrine cells, including insulin-producing beta-cells and glucagon-secreted alpha-cells, secrete hormones that regulate glucose homeostasis. The proportional quantity of the different pancreatic cell populations is well defined, when exocrine cells encompass majority of the tissue mass. Moreover, islet composition and the proportional quantity of the different endocrine cells are well defined, when in the mouse beta-cells encompass more than 70% of the islet mass. However, while the establishment of pancreas and islet cellular composition during embryogenesis has been well acknowledged, its regulation is far from being elucidated. While cell intrinsic cues were shown to influent this process in the developing pancreas, the role of extrinsic signals is less understood. Here, we focused on the role of the pancreatic mesenchyme, a key component of the embryonic pancreas microenvironment, in order to elucidate how proper pancreas cellular composition and mass are established.
One of the goals set in the research proposal was the establishment of a functional pancreas development research group. Indeed, I was able to establish a research group ( in Tel Aviv University that includes graduate and undergraduate students, and research assistants. Work in my lab yielded six scientific publications in scientific journals, including high impact journal as Diabetes and Journal of Experimental Medicine. The findings of the funded project were recently published in Scientific Reports (Hibsher, D. et al. Pancreatic Mesenchyme Regulates Islet Cellular Composition in a Patched/Hedgehog-Dependent Manner. Sci. Rep. 6, 38008; doi: 10.1038/srep38008 (2016)).

To elucidate the role of extrinsic cues in pancreas and beta-cell development, we deregulated the Hedgehog (Hh) signaling pathway in the pancreatic mesenchyme and analyzed the resultant effect on pancreas organogenesis. Pancreas development requires restrained Hh signaling activation. While deregulated Hh signaling in the pancreatic mesenchyme has been long suggested to be detrimental for proper organogenesis, this association was not directly shown. Ptch1 is a negative regulator of the Hh signaling pathway. To increase Hh signaling in the pancreatic mesenchyme of mouse embryos, we deleted Patched1 (Ptch1) in these cells.
Our findings indicate that deregulated Hh signaling in mesenchymal cells was sufficient to impair pancreas development, affecting both endocrine and exocrine cells. Notably, transgenic embryos displayed disrupted islet cellular composition and morphology, with a reduced beta-cell portion. Our results indicate that the cell-specific growth rates of pancreatic cell populations, found during normal development, require regulated mesenchymal Hh signaling. In addition, we detected hyperplasia of mesenchymal cells upon elevated Hh signaling, accompanied by them acquiring smooth-muscle like phenotype.

In this study, we directly show that regulated mesenchymal Hh signaling is required for pancreas organogenesis and establishment of its proper cellular composition. By specifically manipulating mesenchymal cells, our findings provide direct evidence for the non-autonomous regulation of beta-cell development by the pancreatic mesenchyme. The findings of this study allow better understanding of the extrinsic requirements during beta-cell development, and the regulation of pancreas cellular composition.

Potential socio-economic impact:
In today’s Europe, about 60 million people live with diabetes. Worldwide, high blood glucose kills about 3.4 million people annually. Work over the last years has demonstrated decreased beta-cells mass or their impaired function in types 1 and 2 diabetes, respectively. Thus, increasing the number of functional beta-cells would help to combat the disease in both types of diabetes patients. A promising approach to cure diabetes is a cell replacement-based therapy, in which beta-cells are transplanted in patients. However, due to a limited number of beta-cells accessible from cadavers, such therapy relies on either expansion of beta-cells in vitro or their de novo differentiation from pluripotent stem cells. Developing such protocols requires in depth understanding of the native in vivo beta-cell differentiation and proliferation processes, as taken place during embryogenesis. Our findings indicate that beta-cell population size and proliferation are dependent on mesenchymal factors. Therefore, the findings obtained in this study enhance our understanding on the extrinsic requirements for beta-cells expansion and would aid the development of reliable protocols to generate and expand beta-cells upon will, as a potential cure for diabetes.