Heaton Emma S, Hu Ming, Liu Tianzheng, Hui Huang, Tan Yinfei, Ye Kaiming, Jin Sha
Department of Biomedical Engineering, Thomas J. Watson College of Engineering and Applied Sciences, State University of New York at Binghamton, Binghamton, NY, USA.
Genomics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA.
J Tissue Eng. 2023 Jul 8;14:20417314231185858. doi: 10.1177/20417314231185858. eCollection 2023 Jan-Dec.
Induced pluripotent stem cells (iPSCs) have enormous potential in producing human tissues endlessly. We previously reported that type V collagen (COL5), a pancreatic extracellular matrix protein, promotes islet development and maturation from iPSCs. In this study, we identified a bioactive peptide domain of COL5, WWASKS, through bioinformatic analysis of decellularized pancreatic ECM (dpECM)-derived collagens. RNA-sequencing suggests that WWASKS induces the formation of pancreatic endocrine progenitors while suppressing the development of other types of organs. The expressions of hypoxic genes were significantly downregulated in the endocrine progenitors formed under peptide stimulation. Furthermore, we unveiled an enhancement of iPSC-derived islets' (i-islets) glucose sensitivity under peptide stimulation. These i-islets secrete insulin in a glucose responsive manner. They were comprised of α, β, δ, and γ cells and were assembled into a tissue architecture similar to that of human islets. Mechanistically, the peptide is able to activate the canonical Wnt signaling pathway, permitting the translocation of β-catenin from the cytoplasm to the nucleus for pancreatic progenitor development. Collectively, for the first time, we demonstrated that an ECM-derived peptide dictates iPSC fate toward the generation of endocrine progenitors and subsequent islet organoids.
诱导多能干细胞（iPSC）在无限量生成人体组织方面具有巨大潜力。我们之前报道过，V型胶原蛋白（COL5）作为一种胰腺细胞外基质蛋白，可促进iPSC向胰岛的发育和成熟。在本研究中，我们通过对脱细胞胰腺细胞外基质（dpECM）衍生的胶原蛋白进行生物信息学分析，鉴定出COL5的一个生物活性肽结构域WWASKS。RNA测序表明，WWASKS可诱导胰腺内分泌祖细胞的形成，同时抑制其他类型器官的发育。在肽刺激下形成的内分泌祖细胞中，缺氧基因的表达显著下调。此外，我们发现肽刺激可增强iPSC来源的胰岛（i-胰岛）的葡萄糖敏感性。这些i-胰岛以葡萄糖反应性方式分泌胰岛素。它们由α、β、δ和γ细胞组成，并组装成类似于人类胰岛的组织结构。从机制上讲，该肽能够激活经典的Wnt信号通路，使β-连环蛋白从细胞质转运到细胞核，以促进胰腺祖细胞的发育。总体而言，我们首次证明了一种源自细胞外基质的肽可决定iPSC向内分泌祖细胞及后续胰岛类器官生成的命运。
