Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development

Abstract

In this study, we have investigated the role of the embryonic mesenchyme in the development of the pancreas. We have compared the development in vitro of E12.5 rat pancreatic rudiments grown in the presence or absence of mesenchyme. When the E12.5 pancreatic epithelial rudiment is cultured in the presence of its surrounding mesenchyme, both morphogenesis and cytodifferentiation of the exocrine component of the pancreas are completely achieved, while only a few immature endocrine cells develop. The pancreatic rudiments grown in the absence of mesenchyme develop in a completely different way; the exocrine tissue develops poorly and fails to undergo acinar morphogenesis, while the endocrine tissue develops actively. Four times more insulin-positive cells develop after removal of the mesenchyme than in the cultures performed in the presence of mesenchyme. Moreover, the insulin-expressing cells developed in the mesenchyme-depleted rudiments appear mature since they do not coexpress glucagon, express the glucose transporter Glut-2 and express Rab3A, a molecule associated with the secretory granules. Moreover, these endocrine cells are able to associate and form true islets. Both the inductive effect of the mesenchyme on the proper development of the exocrine tissue and its repressive effect on the development of the endocrine cells are mediated by soluble factors. Follistatin, which is expressed by E12.5 pancreatic mesenchyme, can mimic both inductive and repressive effects of the mesenchyme. Follistatin could thus represent one of the mesenchymal factors required for the development of the exocrine tissue while exerting a repressive role on the differentiation of the endocrine cells.

Pancreas morphogenesis: Branching in and then out

“…This is notably the case for the canonical WNT pathway, which controls acinar and progenitor proliferation from E12.5 (Baumgartner, Cash, Hansen, Ostler, & Murtaugh, 2014;Heiser, Lau, Taketo, Herrera, & Hebrok, 2006;Heller et al, 2002) and for Activin, which was shown to impact proliferation and branching in several organs, including the pancreas (Ritvos et al, 1995). Though Activin is expressed in the mesenchyme and epithelium, Follistatin, its antagonist, appears strictly mesenchymal (Miralles, Czernichow, & Scharfmann, 1998;Ritvos et al, 1995;Zhang et al, 2004). This is also the case for EGFR, which controls both epithelial proliferation and the early establishment of apico-basal polarity, which is expected to impact branching (L€ of-€ Ohlin et al, 2017;Miettinen et al, 2000).…”

Human pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling

“…In pancreas, the microenvironment provides mechanical and chemical cues that are indispensable for the initial fate commitment, developmental growth, spatial organization and functional maturation of endocrine and exocrine cells 21 – 24 . Multiple signaling pathways controlling pancreatic epithelium development regulated by microenvironment-released factors were identified, including FGFR2, retinoic acid, BMP, TGFβ, Notch, Hedgehog and canonical Wnt pathways 25 – 34 . This knowledge has been adapted for human β-cell in vitro differentiation, enabling great advancements in pancreatic cell derivation.…”

Expression of follistatin is associated with egg formation in the oviduct of laying hens

“…In Madin Darby Canine Kidney (MDCK) cells, follistatin produced in the mesenchymal cells promotes tubulogenesis by inhibiting the action of activin A (Kojima, Maeshima, & Zhang, 2001). A similar function of the follistatin was also observed in the pancreas (Miralles, Czernichow, & Scharfmann, 1998). These results confirm that there is the interplay between activin and follistatin which help in the epithelial tubule morphogenesis and based on these we can postulate that a similar system is likely involved in the uterus/shell gland of the laying hen at around 20 hr p.o.…”