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Establishing cell-intrinsic limitations in cell cycle progression controls graft growth and promotes differentiation of pancreatic endocrine cells

By Lina Sui, Yurong Xin, Daniela Georgieva, Giacomo Diedenhofen, Leena Haataja, Qi Su, Yong Wang, Michael Zuccaro, Jinrang Kim, Jiayu Fu, Yuan Xing, Danielle Baum, Robin S. Goland, Jose Oberholzer, Fabrizio Barbetti, Peter Arvan, Sandra Kleiner, Dieter Egli

Posted 14 Mar 2020
bioRxiv DOI: 10.1101/2020.03.13.990812

Beta cells have a low proliferative potential, which limits regeneration, but how these limitations are established is largely unknown. Understanding proliferation potential is important for the safty of cell replacement therapy with cell products made from stem cell with unlimited proliferative potential. Here we test a novel hypothesis, that these limitations are established through limitations in S-phase progression. We exposed differentiating stem cells to small molecules that interfere with cell cycle progression either by inducing G1 arrest, impairing S-phase entry, or S-phase completion. Upon release from these molecules, we determined growth potential, differentiation and function of insulin-producing cells in vitro and in vivo. We found that the combination of G1 arrest with a compromised DNA replication completion promoted the differentiation of progenitor cells towards insulin-producing cells, improved the stability of the differentiated state, and protected mice from diabetes without formation of cystic growths. Therefore, a compromised ability to enter S-phase and replicate the genome is a functionally important property of pancreatic endocrine differentiation, and can be exploited to generate insulin-producing organoids with predictable growth potential.

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