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Virgin Β-Cells at the Neogenic Niche Proliferate Normally and Mature

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Virgin Β-Cells at the Neogenic Niche Proliferate Normally and Mature 1070 Diabetes Volume 70, May 2021 Virgin b-Cells at the Neogenic Niche Proliferate Normally and Mature Slowly Sharon Lee,1 Jing Zhang,1 Supraja Saravanakumar,1 Marcus F. Flisher,1 David R. Grimm,1 Talitha van der Meulen,1 and Mark O. Huising1,2 Diabetes 2021;70:1070 –1083 | https://doi.org/10.2337/db20-0679 Proliferation of pancreatic b-cells has long been known with diabetes (2). Thus, a great interest continues in strat- to reach its peak in the neonatal stages and decline egies that promote the regeneration of b-cells from various during adulthood. However, b-cell proliferation has been cell sources (3,4). Despite these efforts, clinically meaningful studied under the assumption that all b-cells constitute restoration of b-cell mass has not yet been achieved, illus- a single, homogenous population. It is unknown whether trating the ongoing need for strategies to regenerate b-cells. b a subpopulation of -cells retains the capacity to pro- During late pancreas development, b-cell mass expands liferate at a higher rate and thus contributes dispropor- rapidly by self-replication of young b-cells. Seminal experi- b tionately to the maintenance of mature -cell mass in ments by Dor et al. (5) established, by pulse-chase labeling adults. We therefore assessed the proliferative capacity of b-cells, that self-replication is the main mechanism to and turnover potential of virgin b-cells, a novel popula- maintain b-cell mass—a conclusion that is noncontrover- tion of immature b-cells found at the islet periphery. We sial (6,7). However, b-cell proliferation declines rapidly with demonstrate that virgin b-cells can proliferate but do so age in mice (8–10), with even lower proliferation rates at rates similar to those of mature b-cells from the same islet under normal and challenged conditions. Virgin observed in human islets (11), which complicates the chal- lenge of restoring b-cell mass secondary to diabetes- ISLET STUDIES b-cell proliferation rates also conform to the age- b dependent decline previously reported for b-cells at associated -cell loss. Against this backdrop, numerous large. We further show that virgin b-cells represent reports of insulin-positive multipotent precursors (12,13), a d b – a long-lived, stable subpopulation of b-cells with low transdifferentiation of - and -cells to -cells (14 16), turnover into mature b-cells under healthy conditions. transdifferentiation of exocrine cells to b-cells (17,18), and, Our observations indicate that virgin b-cells at the islet most recently, the existence of a population of protein C periphery can divide but do not contribute dispropor- receptor (ProCr)-positive islet-resident stem cells (19) continue tionately to the maintenance of adult b-cell mass. to raise the prospect that alternative paths to generation of b-cells exist and could be targeted in diabetes. Adding to these potential alternative b-cell sources, we More than 30 million Americans currently have diabetes, recently identified a new population of immature b-cells which results from progressive b-cell loss caused by either that we named virgin b-cells, as lineage-tracing studies autoimmune attack or lifestyle and genetic factors (1). revealed that these cells express insulin but have never Because b-cells are the only cells in the body capable of expressed the maturity marker urocortin 3 (Ucn3) (20). secreting insulin, a major therapeutic goal for diabetes has Virgin b-cells occur exclusively near the islet periphery, been to replace b-cells lost during disease. Islet or whole- which we therefore referred to as the neogenic niche. They pancreas transplantation has had some success in achieve- constitute a stable fraction of ;1.5% of all b-cells and lack ment of insulin independence, but limited donor availability, key maturity markers in addition to Ucn3, such as G6pc2, immunological complications, and transplant survival make MafA, and Ero1lb (20). Virgin b-cells also lack cell-surface this process not a viable option for the majority of patients expression of Glut2—a feature that they share with b-cells 1Department of Neurobiology, Physiology and Behavior, College of Biological S.L. and J.Z. contributed equally. Sciences, University of California, Davis, Davis, CA © 2021 by the American Diabetes Association. Readers may use this article as 2 Department of Physiology and Membrane Biology, School of Medicine, University long as the work is properly cited, the use is educational and not for profit, and the of California, Davis, Davis, CA work is not altered. More information is available at https://www.diabetesjournals Corresponding author: Mark O. Huising, [email protected] .org/content/license. Received 29 June 2020 and accepted 25 January 2021 diabetes.diabetesjournals.org Lee and Associates 1071 that occur in small clusters outside of conventional islets Islet Isolation (21,22). As virgin b-cells share many of the features of Islets were isolated by injection of 2 mL of 0.8 mg/mL immature b-cells during late pancreas development, this collagenase P (Invitrogen) dissolved in Hanks’ balanced raises the possibility that virgin b-cells may possess a rel- salt solution (HBSS) (Roche Diagnostics) into the pancreas atively high proliferation rate, similar to developing im- via the common bile duct while the ampulla of Vater was mature b-cells. However, the ability of virgin b-cells to clamped. The injected pancreas was then collected in an proliferate, the rate at which they do, and their turnover additional 2 mL collagenase, incubated at 37°C for 11 min, potential all remain unknown. and dissociated by gentle manual shaking followed by In this study, we examined the proliferation capacity three washes with cold HBSS containing 5% newborn and the maturation potential of virgin b-cells at the calf serum (NCS). The suspension was passed through neogenic niche using DNA synthesis labeling and pulse- a nylon mesh (pore size 425 mm) (Small Parts, Inc.), chase lineage-tracing experiments. We hypothesized and islets were isolated by density gradient centrifugation virgin b-cells to be more proliferative than mature b-cells on a Histopaque gradient (1.077 g/mL) (Sigma-Aldrich) for based on their resemblance to immature b-cells during 20 min at 1,400g without brake. Islets were collected from pancreas development. However, our data demonstrate the interface, washed once with cold HBSS containing 5% that proliferating b-cells do not occur more frequently NCS, and handpicked several times under a dissecting near the islet periphery but, instead, occur randomly microscope prior to culture in RPMI medium (Roche across the cross-sectional surface of the islets. Similarly, Diagnostics) containing 5.5 mmol/L glucose, 10% FBS, when we specifically addressed the proliferation rate of and penicillin-streptomycin (Gibco). virgin and mature b-cells, we observed that virgin b-cells proliferate but do so at rates similar to those of mature Flow Cytometry b-cellsfromthesameisletsunderbasalconditionsandin mIns1-H2b-mCherry 3 Ucn3-EGFP islets were isolated as response to metabolic challenges such as pregnancy or described a day prior to dissociationbyincubationin0.25% experimentally induced insulin resistance. Overall, it trypsin-EDTA (Gibco) for 2 min complemented by gentle follows that virgin b-cells in adult islets represent a stable trituration with a p200 pipette, washed once in HBSS (Roche subset of b-cells that demonstrate limited turnover into Diagnostics) containing 5% NCS, and then stained for EdU mature b-cells. detection with use of a modified Click-iT Plus EdU Flow Cytometry Assay Kit (C10634; Thermo Fisher Scientific) RESEARCH DESIGN AND METHODS following the manufacturer’sguidelinesandimmediately Animals processed on the cytometer. All flow data were collected Mice were maintained in group housing on a 12-h light/ with the Beckman Coulter CytoFLEX except for the 9-month- 12-h dark cycle with free access to water and standard old cohort in Fig. 3C due to unexpected technical issues with rodent chow. C57BL/6 mice were purchased from Envigo. the CytoFLEX; a Beckman Coulter Astrios EQ equivalent to All mouse procedures were approved by the Institutional the CytoFLEX was used for this data collection. Animal Care and Use Committee of University of Cal- ifornia, Davis (UC Davis), or the Salk Institute for Bi- Three-dimensional Imaging of Intact Islets ological Studies, and were performed in compliance with Islets isolated from mIns1-H2b-mCherry 3 Ucn3-EGFP the Animal Welfare Act and the Institute for Laboratory mice that received EdU in vivo were cultured on uncoated Animal Research Guide to the Care and Use of Labora- no. 1.5 glass-bottom 35-mm culture dishes (MatTek Cor- tory Animals. poration) in RPMI medium (Roche Diagnostics) containing 10% FBS, 5.5 mmol/L glucose, and penicillin-streptomycin. Administration of 5-Ethynyl-29-Deoxyuridine and S961 Islets were allowed to attach onto the glass bottom for two Mice were injected once daily with 5-ethynyl-29-deoxyuridine nights before fixation with 4% paraformaldehyde (EMD (EdU) (Life Technologies) intraperitoneally at 50 mg/kgMillipore) for 15 min followed by EdU staining with Click-iT body wt dissolved at 10 mg/mL in 0.9% saline as indicated.Plus EdU Cell Proliferation Kit (C10640; Thermo Fisher EdU was prepared fresh right before administration. S961 Scientific) according to the manufacturer’sguidelinesand (NNC0069-0961) was generously provided by Novo Nordisk then imaged in x, y, and z on a Nikon A1R1 confocal Compound Sharing. Osmotic pumps (Alzet 2001) filled with microscope. 10 nmol S961 or PBS only, released at an estimated dose of 0.05 nmol/h, were implanted subcutaneously. Pulse-Chase of mIns-CreER Mice mIns-CreER 3 lsl-mT/mG mice were treated by oral gavage Glucose Tolerance Test with 125 mg/kg body wt tamoxifen (T5648; Sigma-Aldrich) Mice were weighed after an overnight fast and then given dissolved at 20 mg/mL in sunflower oil.
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