Our lab studies the development and function of insulin-producing beta-cells, focusing on the role of the pancreatic microenvironment.
How do mesenchymal cells regulate pancreas development?
The pancreas comprises of various cell types that share common progenitors in the embryo. We showed that mesenchymal cells guide pancreas and beta-cell development, and are required to establish organ size and shape (Landsman et al., 2011). We further showed that mesenchymal cells dictate the ratio between pancreatic endocrine cell populations (Hibsher et al., 2016). Our findings facilitate cell replacement therapy for diabetes. Recently, we demonstrated that the pancreatic mesenchyme gives rise to pericytes of the adult organs (Harari et al., 2019)
How do pericytes support beta-cell function and glucose regulation?
Insulin-producing beta-cells rely on their microenvironment for their functionality and mass. Pericytes, along with endothelial cells, make up the islets of Langerhans dense capillary network. However, while the role of endothelial cells in beta-cell function is well-established, our understanding of the role of pericytes lags behind. We showed that pericytes are required for maintaining beta-cell function and glucose-stimulated insulin secretion (Sasson, Rachi, Sakhneny, et al., 2016). Moreso, we found that in the neonatal pancreas, pericytes promote beta-cell proliferation (Epshtein et al., 2017). We now use transgenic mouse models to further define the pericyte/beta-cell axis and its requirement for glucose homeostasis.
Does abnormal pericyte function contribute to diabetes?
Impaired function of beta-cells is a critical factor in type 2 diabetes. We recently showed that TCF7L2, which confers a high genetic risk of type 2 diabetes through a yet to be described mechanism, is required for proper function of pancreatic pericytes. Inactivation of this transcription factor specifically in pancreatic pericytes leads to impaired glucose response due to impaired beta-cell function (Sakhneny et al., 2018). Our findings thus implicate abnormalities in the islet microenvironment as an underlying cause of diabetes.
Our research is funded by: