Abstract: Islet organoids derived from pluripotent stem cells offer a promising solution for the shortage of cadaveric donors in diabetes treatment. However, great challenges in the improvement in differentiation, viability, functional maturity, and engraftment of iPSC-derived islet organoids remain prominent. Here, we reported the generation of improved islet organoids with high viability and functionality by employing decellularized extracellular matrix (ECM) hydrogel of amniotic membrane (dAM) as a mechanical and physiological support. dAM sheet is able to facilitate islet organoid engraftment and rapidly restore normoglycemia in diabetic mice, accompanied by increased body weight and augmented insulin release in response to glucose. Interestingly, Collagen VI (Col VI) was identified as a key component of islet niche, enhancing islet cell viability and biological function. Col VI-based biomimetic ECM scaffold recapitulates the native environment for islet organoids and exhibits better physiological properties both in vitro and in vivo. Importantly, the cellular composition and endocrine function of optimized hiPSC-derived islet organoids are comparable to those of human islets. Our findings thus offer a unique and valuable platform for future endeavors in organoid transplantation-based therapy of diabetes.
Funding Source: NSFC （81821003, 82273180, and 82472713), NSFG (2024A1515011365), High-level Hospital Construction Project (KJ012021074 and KJ012019517) and Guangdong Basic and Applied Basic Research Foundation (2021B1515130004)
