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<p>Stem cell-derived glucagon-(α) and insulin-producing (β) cells allow to engineer in vitro biomimetics of islet of Langerhans, the micro-organ controlling glycemia; however, a knowledge gap in the mechanism by which human stem cell-derived α and β cells are specified persists. Mouse studies postulated that Aristaless Related homeobox (Arx) and Paired box 4 (Pax4) transcription factors cross-inhibit each other in endocrine progenitors to promote α/β fate allocation, respectively. To test this model in human, we combine lineage labelling with single-cell multiomic analysis in our newly generated <i>ARX</i><sup><i>CFP/CFP</i></sup>; <i>PAX4</i><sup><i>mCherry/mCherry</i></sup> knock-in induced pluripotent stem cell reporter line. Lineage tracing, proteomic and gene regulatory network analysis and potency assays reveal a human specific regulation of α/β cell fate allocation. Pharmacological perturbations previously proposed to trigger α-to-β transdifferentiation or identified by our gene regulatory network lead to enhanced endocrine induction and directed α/β cell fate. Studying mechanisms of endocrinogenesis and fate segregation enables the engineering of islets in vitro, and has broader implications for cell-replacement therapy, disease modelling and drug screening.</p>

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Resolving human α versus β cell fate allocation for the generation of stem cell-derived islets

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Melis Akgün Canan,
  • Corinna Cozzitorto,
  • Michael Sterr,
  • Lama Saber,
  • Eunike S. A. Setyono,
  • Alessandro Dema,
  • Kei Kozawa,
  • Xianming Wang,
  • Juliane Merl-Pham,
  • Tobias Greisle,
  • Ingo Burtscher,
  • Heiko Lickert

摘要

Stem cell-derived glucagon-(α) and insulin-producing (β) cells allow to engineer in vitro biomimetics of islet of Langerhans, the micro-organ controlling glycemia; however, a knowledge gap in the mechanism by which human stem cell-derived α and β cells are specified persists. Mouse studies postulated that Aristaless Related homeobox (Arx) and Paired box 4 (Pax4) transcription factors cross-inhibit each other in endocrine progenitors to promote α/β fate allocation, respectively. To test this model in human, we combine lineage labelling with single-cell multiomic analysis in our newly generated ARXCFP/CFP; PAX4mCherry/mCherry knock-in induced pluripotent stem cell reporter line. Lineage tracing, proteomic and gene regulatory network analysis and potency assays reveal a human specific regulation of α/β cell fate allocation. Pharmacological perturbations previously proposed to trigger α-to-β transdifferentiation or identified by our gene regulatory network lead to enhanced endocrine induction and directed α/β cell fate. Studying mechanisms of endocrinogenesis and fate segregation enables the engineering of islets in vitro, and has broader implications for cell-replacement therapy, disease modelling and drug screening.