Pre-adaptation of stem cell-derived islet organoids to hypoxia via zinc transportation inhibition drives angiogenesis

  • Cell Stem Cell. 2026 Apr 2;33(4):676-694.e10. doi: 10.1016/j.stem.2026.03.004.
Zhaoyue Wang  1 ,  Minglu Xu  1 ,  Rui Hu  1 ,  Xiangyi Chen  1 ,  Xushu Wang  1 ,  Guangyu Shi  1 ,  Sirun Lu  1 ,  Yiling Yang  1 ,  Yajuan Su  1 ,  Mengting Gong  1 ,  Rongrong Le  1 ,  Rui Zhao  2 ,  Meng Guo  3 ,  Yun Jin  4 ,  Yajie Wang  5 ,  Yingxin Fu  6 ,  Jiacong Yan  7 ,  Weida Li  8
Affiliations
  • 1. Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 2. Pulmongene (Beijing) Ltd., Beijing 102206, China.
  • 3. Department of Pathology, Changhai Hospital, Navy Medical University, Shanghai 200433, China.
  • 4. Department of Hepatopancreatobiliary Surgery, the First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, China.
  • 5. Department of Hematology, Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, China.
  • 6. First Department of kidney Transplant, Organ Transplant Institute, Shenzhen Third People's Hospital, The Second Affiliated Hospital, Southern University of Science and Technology, National Clinical Research Center for Infectious Disease, 29 Bulan Road, Longgang District, Shenzhen 518053, China.
  • 7. Department of Reproductive Medicine, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, First People's Hospital of Yunnan Province, Kunming 650500, China. Electronic address: [email protected].
  • 8. Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Reg-Verse Therapeutics (Shanghai) Co. Ltd., Shanghai 200120, China. Electronic address: [email protected].
PMID: 41932324 DOI: 10.1016/j.stem.2026.03.004
Abstract

The clinical application of human stem cell-derived islet organoids (SC-islets) is hindered by immaturity and ischemia-induced dysfunction post-transplantation. Hypoxia-driven angiogenesis is a common adaptation, but the metabolic fragility of SC-islet β cells leads to early functional damage and suppressed vascular endothelial growth factor A (VEGFA) expression, thereby delaying vascularization and causing graft loss. The key challenge in SC-islet transplantation is how to prevent hypoxia-induced stress and promote rapid angiogenesis. We found that excessive zinc in SC-islet β cells induces oxidative modification that inhibits AMP-activated protein kinase (AMPK) activity. Chemical inhibition of zinc transportation activates AMPK, enhances functional maturation, improves hypoxia resistance, and increases hypoxia-inducible factor 1α (HIF1A)-independent VEGFA expression to facilitate endothelial cell integration. In diabetic animal models, this approach significantly improved hypoxia resistance, accelerated angiogenesis, and enhanced glycemic control. Our findings demonstrate that chemical inhibition of zinc transportation boosts SC-islet functional competence, offering a potential strategy to advance pre-adaptation to stress in regenerative medicine.

Keywords
SC-islet organoids; angiogenesis; chemical inhibition; functional maturation; hypoxia resistance.
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