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The postnatal pancreatic microenvironment guides β cell maturation through BMP4 production

Research output: Contribution to journalArticlepeer-review

Lina Sakhneny, Laura Mueller, Anat Schonblum, Sivan Azaria, Guzel Burganova, Alona Epshtein, Abigail Isaacson, Heather Wilson, Francesca M. Spagnoli, Limor Landsman

Original languageEnglish
Pages (from-to)2703-2711.e5
JournalDevelopmental Cell
Volume56
Issue number19
DOIs
Published11 Oct 2021

Bibliographical note

Funding Information: We thank Jana Omar (Tel Aviv University) for her technical assistance. This study was supported by the Israel Science Foundation (ISF; grant agreement no. 1605/18, to L.L), EFSD (grant agreement no. 1117775, to F.S.), JDRF Innovative grant (grant agreement no. 1-INO-2018-634-A-N, to F.S.), and the Zvi Yanai Scholarship for Israeli Arab, Druze, and Circassian students from the State of Israel Ministry of Science and Technology (to L.S.). This work was carried out in partial fulfillment of the requirements for a Ph.D. degree for L.S. from the Sackler Faculty of Medicine at Tel Aviv University. Graphical abstract was created with BioRender.com. Conceptualization, L.L.; investigation, L.S. L.M. A.S. S.A, A.E, A.I. and H.W; formal analysis, L.S. L.M. A.S. S.A. G.B. and F.M.S.; writing ? original Draft, L.S. and L.L; writing ? review & editing, A.S. S.A. A.E. and F.M.S.; funding acquisition, L.S. F.M.S. and L.L.; supervision, F.M.S. and L.L. The authors declare no competing interests. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. Funding Information: We thank Jana Omar (Tel Aviv University) for her technical assistance. This study was supported by the Israel Science Foundation (ISF; grant agreement no. 1605/18 , to L.L), EFSD (grant agreement no. 1117775 , to F.S.), JDRF Innovative grant (grant agreement no. 1-INO-2018-634-A-N , to F.S.), and the Zvi Yanai Scholarship for Israeli Arab, Druze, and Circassian students from the State of Israel Ministry of Science and Technology (to L.S.). This work was carried out in partial fulfillment of the requirements for a Ph.D. degree for L.S. from the Sackler Faculty of Medicine at Tel Aviv University. Graphical abstract was created with BioRender.com. Publisher Copyright: © 2021 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Glucose homeostasis depends on regulated insulin secretion from pancreatic β cells, which acquire their mature phenotype postnatally. The functional maturation of β cells is regulated by a combination of cell-autonomous and exogenous factors; the identity of the latter is mostly unknown. Here, we identify BMP4 as a critical component through which the pancreatic microenvironment regulates β cell function. By combining transgenic mouse models and human iPSCs, we show that BMP4 promotes the expression of core β cell genes and is required for proper insulin production and secretion. We identified pericytes as the primary pancreatic source of BMP4, which start producing this ligand midway through the postnatal period, at the age β cells mature. Overall, our findings show that the islet niche directly promotes β cell functional maturation through the timely production of BMP4. Our study highlights the need to recapitulate the physiological postnatal islet niche for generating fully functional stem-cell-derived β cells for cell replacement therapy for diabetes.

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