In search of pancreatic beta cells with a regenerative potential
Shiran Rachel Peretz
Depletion of β cell mass is a key characteristic of diabetes, impairing insulin production and glucose regulation, which sparks interest in restoring beta cell mass through regeneration. While β cells rarely divide, their expansion under specific conditions such as high-fat diet, pregnancy, or pancreatic injury suggests that regulating mature β cell proliferation is possible. A key question is whether all beta cells can proliferate or, alternatively, certain beta cell subsets have higher proliferative capacity.
Characterizing dormant stem cell sub-populations is methodologically challenging because the only way to determine if a cell has the potential to divide is to observe it proliferate, but post-division, its pre-proliferative characters may be lost and no longer observable.
To overcome the limitations of conditions that induce β cell proliferation, we use an insulin receptor antagonist (S961), which acutely elevates blood glucose levels and mimics the type 2 diabetes state, characterized by β cell proliferation.
To establish whether all beta cells can divide or not, we adapted a CRISPR-based lineage tracing model (CARLIN) to become β cell specific, enabling cell-specific genetic barcoding, followed by triggering of beta cell replication. Disproportionate proliferation should lead to non-uniform barcode distribution, and thereby answer the question unequivocally.
To characterize the proliferative cells further, we combine S961-inducible replication with a tamoxifen-induced Ki67 Cre/loxp-TdTomato mouse model (M/T), which permanently labels dividing β cells and facilitates tracking them over time. Our results support the existence of a subpopulation of proliferative β cells, which is present in most islets.
