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ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro
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posted on 2021-10-12, 12:46 authored by Fiona M. Docherty, Kent A. Riemondy, Roberto Castro-Gutierrez, JaeAnn M. Dwulet, Ali H. Shilleh, Maria S. Hansen, Shane P. M. Williams, Lucas H. Armitage, Katherine E. Santostefano, Mark A. Wallet, Clayton E. Mathews, Taylor M. Triolo, Richard K. P. Benninger, Holger A. RussStem cell derived beta-like cells (sBC) carry
the promise of providing an abundant source of insulin-producing cells for use
in cell replacement therapy for patients with diabetes, potentially allowing
widespread implementation of a practical cure. To achieve their clinical
promise, sBC need to function comparably to mature adult beta cells, but as yet
they display varying degrees of maturity. Indeed, detailed knowledge of the
events resulting in human beta cell maturation remains obscure. Here we show
that sBC spontaneously self-enrich into discreet islet-like cap structures
within in vitro cultures, independent
of exogenous maturation conditions. Multiple complementary assays demonstrate
that this process is accompanied by functional maturation of the self-enriched
sBC (seBC); however, the seBC still contain distinct subpopulations displaying
different maturation levels. Interestingly, the surface protein ENTPD3 (also
known as nucleoside triphosphate diphosphohydrolase-3 (NDPTase3)) is a specific
marker of the most mature seBC population and can be used for mature seBC identification
and sorting. Our results illuminate critical aspects of in vitro sBC maturation and provide important insights towards
developing functionally mature sBC for diabetes cell replacement therapy.