Pancreatic Pericytes Support b-Cell Function in a Tcf7l2-Dependent Manner Lina Sakhneny, 1 Eleonor Rachi, 1 Alona Epshtein, 1 Helen C. Guez, 1 Shane Wald-Altman, 2 Michal Lisnyansky, 1 Laura Khalifa-Malka, 1 Adina Hazan, 3 Daria Baer, 1 Avi Priel, 3 Miguel Weil, 2 and Limor Landsman 1 Diabetes 2018;67:437–447 | https://doi.org/10.2337/db17-0697 Polymorphism in TCF7L2, a component of the canonical Wnt signaling pathway, has a strong association with b-cell dysfunction and type 2 diabetes through a mechanism that has yet to be defined. b-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 b-cell function. Transgenic mice in which Tcf7l2 was selectively inactivated in their pancre- atic pericytes exhibited impaired glucose tolerance due to compromised b-cell function and glucose-stimulated insulin secretion. Inactivation of pericytic Tcf7l2 was as- sociated with impaired expression of genes required for b-cell function and maturity in isolated islets. In addition, we identified Tcf7l2-dependent pericytic expression of se- creted factors shown to promote b-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 b-cells. To conclude, we suggest that pancreatic pericytes produce secreted factors, in- cluding BMP4, in a Tcf7l2-dependent manner to support b-cell function. Our findings thus propose a potential cel- lular mechanism through which abnormal TCF7L2 activity predisposes individuals to diabetes and implicates ab- normalities in the islet microenvironment in this disease. Type 2 diabetes has a strong genetic component, with a number of genetic variations associated with an increased risk to develop this disease (1,2). In particular, polymorphism in TCF7L2 (TCF4) is associated with increased risk to di- abetes (3). This gene encodes a member of T-cell factor/ lymphoid enhancer factor (TCF/LEF) transcription factors family, which functions downstream of the canonical Wnt sig- naling pathway by recruiting b-catenin to target genes (4). Diabetes-associated alleles of TCF7L2, such as the T allele of the single-nucleotide polymorphism in rs7903146, are as- sociated with impaired glucose-stimulated insulin secretion (GSIS) and insulin production but intact hepatic function and insulin sensitivity (3,5–8). The T allele of the rs7903146 variant was predicted to result in an inactive protein lack- ing its DNA-binding domain (9). However, how TCF7L2 functions to regulate glucose homeostasis remains an open question. To date, the use of mouse systems to determine the cellular mechanism(s) through which abnormal Tcf7l2 activity contributes to b-cell dysfunction has produced conflicting results. As opposed to humans, hepatic phenotypes domi- nate the abnormal glucose levels observed upon body-wide deregulation of Tcf7l2 expression in mice (10–12). b-Cell– specific inference with Tcf7l2 activity using mouse genetic tools yielded discrepant results, with some studies showing reduced b-cell mass and glucose intolerance and others showing normal glucose response (12–17). This contradiction could partially stem from the use of different approaches to interfere with Tcf7l2 activity, such as knocking down the en- dogenous gene (12,14,15) versus overexpressing a dominant- negative (DN) form (13,16). Tcf7 (Tcf1), a member of the TCF/LEF family with high homology to Tcf7l2, was recently shown to play a central role in maintaining b-cell mass (18), 1 Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 2 Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel 3 Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel Corresponding author: Limor Landsman, limorl@post.tau.ac.il. Received 17 June 2017 and accepted 6 December 2017. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db17-0697/-/DC1. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. Diabetes Volume 67, March 2018 437 ISLET STUDIES