Pancreatic pericytes support β-cell function in a Tcf7l2-dependent manner

Lina Sakhneny, Eleonor Rachi, Alona Epshtein, Helen C. Guez, Shane Wald-Altman, Michal Lisnyansky, Laura Khalifa-Malka, Adina Hazan, Daria Baer, Avi Priel, Miguel Weil, Limor Landsman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Polymorphism in TCF7L2, a component of the canonical Wnt signaling pathway, has a strong association with β-cell dysfunction and type 2 diabetes through a mechanism that has yet to be defined. β-Cells rely on cells in their microenvironment, including pericytes, for their proper function. Here, we show that Tcf7l2 activity in pancreatic pericytes is required for β-cell function. Transgenic mice in which Tcf7l2 was selectively inactivated in their pancreatic pericytes exhibited impaired glucose tolerance due to compromised β-cell function and glucose-stimulated insulin secretion. Inactivation of pericytic Tcf7l2 was associated with impaired expression of genes required for β-cell function and maturity in isolated islets. In addition, we identified Tcf7l2-dependent pericytic expression of secreted factors shown to promote β-cell function, including bone morphogenetic protein 4 (BMP4). Finally, we show that exogenous BMP4 is sufficient to rescue the impaired glucose-stimulated insulin secretion of transgenic mice, pointing to a potential mechanism through which pericytic Tcf7l2 activity affects β-cells. To conclude, we suggest that pancreatic pericytes produce secreted factors, including BMP4, in a Tcf7l2-dependent manner to support β-cell function. Our findings thus propose a potential cellular mechanism through which abnormal TCF7L2 activity predisposes individuals to diabetes and implicates abnormalities in the islet microenvironment in this disease.

Original languageAmerican English
Pages (from-to)437-447
Number of pages11
Issue number3
StatePublished - 1 Mar 2018

Bibliographical note

Funding Information:
This work was performed in partial fulfillment of the requirements for a PhD degree for L.S. from the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Funding. This work was supported by European Research Council starting grant (336204) to L.L. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. L.S. conducted experiments, acquired and analyzed data, and wrote the manuscript. E.R., A.E., and H.C.G. conducted experiments and acquired and analyzed data. S.W.-A. analyzed data. M.L., L.K.-M., A.H., and D.B. conducted experiments and acquired data. A.P. and M.W. provided reagents. L.L. designed and supervised research, analyzed data, and wrote the manuscript. L.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 2nd Joint Meeting of the European Association for the Study of Diabetes (EASD) Islet Study Group and Beta Cell Workshop, Dresden, Germany, 7–11 May 2017, and at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9– 13 June 2017.

Publisher Copyright:
© 2017 by the American Diabetes Association.


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