PhD. Candidate Center for Excellence in Molecular Cell Science, CAS (Shanghai Institute of Biochemistry and Cell Biology), Shanghai, China (People's Republic)
Abstract: Inducing beta cell proliferation is theoretically a straightforward and effective strategy to increase the absolute beta cell mass and develop new regenerative approaches for pancreatic islets. However, little is known about these proliferating beta cells, and the challenge of isolating them remains unresolved. In this study, we have identified a surface marker indicative of proliferating cells within adult murine and human pancreatic islets. Through single-cell RNA sequencing analysis, we identified a population characterized by high proliferative activity. Among the signature genes of this population, we focused on a gene encoding a surface protein. Fluorescence-activated cell sorting (FACS) analysis confirmed that this protein labels proliferating cells, which represent approximately 0.6% of islet cells in adult mice and 2% in neonatal mice. Immunostaining further indicated that these cells are specifically in the G2/M phase of the cell cycle. To further investigate the division behavior and progeny cell fates of these proliferating cells, we engineered CreER mice. In vivo lineage tracing revealed that cells labeled shortly after tamoxifen administration rapidly divided into two Nkx6.1-low immature beta cells. After a two-month tracing period, 90% of these cells matured into Nkx6.1-high beta cells. Additional clonal analysis indicated that a subset of these proliferating islet cells possess multipotent capabilities. Notably, the surface marker is conserved in humans, as it also identifies proliferating cells in human pancreatic neuroendocrine tumors. Collectively, our findings unveil a surface marker that identifies proliferating islet cells during both homeostasis and in the context of endocrine tumors. This discovery provides novel insights into the processes of islet cell proliferation, differentiation, and maturation.
