Our lab employs genetically engineered mice to reveal critical aspects of beta-cell development and function to understand diabetes progression better and facilitate a cure to this disease.
Cell replacement therapy for diabetes requires a better understanding of the natural development of insulin-secreting beta-cells. To facilitate the generation of fully functional beta-cells, we focus on the role of the pancreatic microenvironment in beta-cell differentiation, proliferation, and functional maturation.
In the embryo, we found that mesenchymal cells are required for pancreas organogenesis by regulating organ size and cellular composition (Landsman et al., 2011; Hibsher et al., 2016; Harari et al., 2019).
After birth, we found that pericytes are required for postnatal beta-cell development. Pericytes promote neonatal beta-cell proliferation, which is needed to establish their proper mass (Epshtein et al., 2017). Beta-cells acquire their mature, functional phenotype in the postnatal period. We showed that pericytes secrete BMP4 to promote this maturation process in postnatal and stem-cell-derived beta-cells (Sakhneny et al., 2021b).
Beta-cell function and diabetes
Diabetes is associated with beta-cell dysfunction through a largely unknown mechanism. To better understand this phenomenon, we identify cues that maintain beta-cell function and insulin secretion in health and research how they change during disease progression.
We found that pericytes are required to maintain beta-cells in their functional state (Sasson et al., 2016; Sakhneny et al., 2018; Sakhneny et al., 2021a; Sakhneny et al., 2021b).
Furthermore, we identified pericytic factors that directly regulate beta-cell gene expression and function (Sakhneny et al., 2018; Sakhneny et al., 2021a; Sakhneny et al., 2021b).
Pericytes in many tissues have immuno-regulatory capacities. We are currently testing the hypothesis that pericytes regulate beta-cells by modulating islet inflammation.
Our findings propose that changes in the pancreas microenvironment may cause diabetes (Sakhneny et al., 2018; Alamca et al., 2020; Burganova, 2021).