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The Developing Pancreas Uses the Force to Choose Between Lineages!

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Review of “Mechanosignalling via integrins directs fate decisions of pancreatic progenitors” from Nature by Stuart P. Atkinson 

The human pancreas secretes several essential hormones into the blood, thereby functioning as an endocrine gland, but also discharges bicarbonate and digestive enzymes into the duodenum, thereby functioning as an exocrine gland. During development, the pancreas arises from epithelial foregut evaginations composed of multipotent epithelial progenitors that give rise to epithelial branches whose trunks contain bipotent pancreatic progenitors  [1, 2]. Bipotent pancreatic progenitors then give rise to the all-important endocrine and exocrine ductal lineages; however, the exact signaling mechanisms coordinating the fate-determining transcriptional events behind these lineage decisions remain unresolved. 

Now, a new article in Nature from Henrik Semb (University of Copenhagen, Denmark/Helmholtz Zentrum München, Neuherberg, Germany) has employed single-cell analysis to delineate the processes controlling fate decisions in the developing pancreas. Fascinatingly, Mamidi at al. report that altered levels of interaction between specific integrins with the extracellular matrix alter the intracellular forces that determine transcriptional output from the mechanoresponsive Yes-Associated Protein 1 (YAP1) and bipotent pancreatic progenitor differentiation propensity [3]. 

The study began by seeding human embryonic stem cell-derived bipotent pancreatic progenitors [4] on glass slides micropatterned with different matrix proteins to assess how each progenitor reacted to their surroundings. Fascinatingly, the culture of pancreatic progenitors on laminin/collagen-based substrates promoted cell confinement and subsequently reduced integrin α5β1 expression. The decreased levels of this specific integrin limit interactions between the extracellular matrix and integrin α5β1, reduces intracellular mechanical force generation, and encourages differentiation to the endocrine lineage. However, the exposure of pancreatic progenitors to fibronectin-/vitronectin-enriched extracellular matrix promoted cell spreading and the maintenance of integrin α5β1 expression, which promotes the interaction of integrin α5β1 with the extracellular matrix, generates significant intracellular forces, and so ushers pancreatic progenitors towards a ductal fate instead. 

The increased mechanical force within pancreatic progenitors stimulated F-actin bundling and increased focal adhesion kinase (FAK) signaling, which subsequently prompted an increase in the expression of the YAP1 transcription factor [5, 6]. The elevated expression of YAP1 then acts to inhibit endocrine lineage differentiation and promote ductal differentiation by activating HES1 transcription and co-repressing NGN3 transcription through chromatin looping of distant YAP1–TEAD binding sites. However, lower YAP1 expression levels in pancreatic progenitors generate low intracellular forces and instead boost endocrine lineage differentiation.

While contributing significantly to our understanding of the developing pancreas, the authors also believe that their findings will aid the cost-effective and robust generation of endocrine cells, such as insulin-producing beta cells, from human pluripotent stem cell-derived pancreatic progenitors through the application of small molecule inhibitors that target specific components of the identified mechanosignaling pathway. 

For more on how pancreatic progenitors within the developing pancreas use the force to choose between lineages, stay tuned to the Stem Cells Portal.

References

  1. Shih HP, Wang A, and Sander M, Pancreas Organogenesis: From Lineage Determination to Morphogenesis. Annual Review of Cell and Developmental Biology 2013;29:81-105.
  2. Pan FC and Wright C, Pancreas organogenesis: From bud to plexus to gland. 2011;240:530-565.
  3. Mamidi A, Prawiro C, Seymour PA, et al., Mechanosignalling via integrins directs fate decisions of pancreatic progenitors. Nature 2018;564:114-118.
  4. Rezania A, Bruin JE, Riedel MJ, et al., Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 2012;61:2016-29.
  5. Dupont S, Morsut L, Aragona M, et al., Role of YAP/TAZ in mechanotransduction. Nature 2011;474:179-83.
  6. Cebola I, Rodriguez-Segui SA, Cho CH, et al., TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors. Nat Cell Biol 2015;17:615-626.