“Our group investigates how pancreatic β-cell identity is acquired during development and impaired in response to metabolic stress.”
One of the fundamental questions in biology is how the identity of a cell is preserved in adult organisms and undergo a physiological interconversion in response to environmental cues to maintain tissue homeostasis. Our research group aims at addressing this by understanding how genetic predisposition, environmental stimuli, metabolic stress and aging impacts on the molecular mechanisms regulating endocrine cells fate decisions and plasticity in the pancreas.
Dedifferentiation of pancreatic insulin-producing beta-cells has been revealed as a novel mechanism of insulin insufficiency in diabetes. These cells do not undergo apoptosis, but loose expression of insulin and other differentiation markers and can regress to a primitive multipotent endocrine intermediate facilitating their conversion into other endocrine cells type. How, when and why beta-cells undergo this interconversion in Type 2 Diabetes (T2D) remains unclear and answering these questions is fundamental toward developing new regenerative therapies that foster the identity of pancreatic beta-cells in diabetes.
Our group use a wide array of cutting-edge methodologies including genomics, proteomics, bioinformatics and genetic manipulation in mice to identify the molecular networks regulating beta-cells function and identity.
Mouse pancreatic islets revealed by indirect immunofluorescence using Insulin (green) and Glucagon (red) antibodies. Note the unique arrangement of islets with a core of Insulin-producing β-cells surrounded by Glucagon-secreting cells. Cell nucleus detected by DAPI staining (blue) (200x)
Daniel S. de Jesus, Tracy C.S. Mak, Yi-Fang Wang, Yorrick von Ohlen, Ying Bai, Eva Kane, Pauline Chabosseau, Catherine M. Chahrour, Walter Distaso, Victoria Salem, Alejandra Tomas, Markus Stoffel, Guy A. Rutter, Mathieu Latreille. (2021). Dysregulation of the Pdx1/Ovol2/Zeb2 axis in dedifferentiated β-cells triggers the induction of genes associated with epithelial–mesenchymal transition in diabetes Molecular Metabolism, Vol 53, Nov 2021, doi: 10.1016/j.molmet.2021.101248.
Millership SJ, Da Silva Xavier G, Choudhury AI, Bertazzo S, Chabosseau P Pedroni SM, Irvine EE, Montoya A, Faull P, Taylor WR, Kerr-Conte J, Pattou F, Ferrer J, Christian M, John RM, Latreille M, Liu M1 Rutter GA, Scott J, Withers DJ. (2018). Neuronatin regulates pancreatic β cell insulin content and secretion J Clin Invest 1, 128(8), 3369-3381 doi: 10.1172/JCI120115.
Martinez-Sanchez A, Rutter GA, Latreille M. (2017). MiRNAs in β-Cell Development, Identity, and Disease. Front Genet 11, 7, 226. doi: 10.3389/fgene.2016.00226.
Ahmed K, LaPierre MP, Gasser E, Denzler R, Yang Y, Rülicke T, Kero J, Latreille M, Stoffel M. (2017). Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility. J Clin Invest 1, 127(3), 1061-1074.
Latreille, M., Herrmanns, K., Renwick, N., Tuschl, T., Malecki, M.T., McCarthy, M.I., Owen, K.R., Rülicke, T., Stoffel, M. (2015). miR-375 gene dosage in pancreatic β-cells: implications for regulation of β-cell mass and biomarker development. Journal of Molecular Medicine [Epub ahead of print] May 28.
Belgardt BF, Ahmed K, Spranger M, Latreille M, Denzler R, Kondratiuk N, von Meyenn F, Villena FN, Herrmanns K, Bosco D, Kerr-Conte J, Pattou F, Rülicke T, Stoffel M. (2015). The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes. Nature Medicine 21(6), 619-27.
Latreille M, Hausser J, Stützer I, Zhang Q, Hastoy B, Gargani S, Kerr-Conte J, Pattou F, Zavolan M, Esguerra JL, Eliasson L, Rülicke T, Rorsman P, Stoffel M. (2014). MicroRNA-7a regulates pancreatic β cell function. The Journal of Clinical Investigation 124(6), 2722–35.