Extracellular matrix-derived peptide stimulates the generation of endocrine progenitors and islet organoids from iPSCs

Abstract

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.

Application and challenge of pancreatic organoids in therapeutic research

“…As an indicator for adult stem cells in multiple organs, Lgr5 is expressed in injured and regenerated pancreatic ducts, while Lgr5 + duct cells can produce pancreatic exocrine organoids in vitro and differentiate into ducts and endocrine cells after transplantation induction (Huch et al, 2013). A peptide originating from the extracellular matrix determines the destiny of induced PSCs, leading to the creation of endocrine progenitors and later islet organoids (Heaton et al, 2023) (see Figure 1).…”

Oxygenated Scaffolds for Pancreatic Endocrine Differentiation from Induced Pluripotent Stem Cells

“…[6] Our recent study discovered that a short peptide motif developed from a pancreatic extracellular matrix (ECM) protein is able to boost the glucose sensitivity for glucose responsive insulin secretion from iPSC-derived islets. [7] Nevertheless, generating biologically functional islets that consisting of all major types of islet cells, including 𝛼, 𝛽, 𝛿, and 𝛾 cells remains a significant challenge. It has been reported that decellularized pancreatic materials induce the formation of human islets that harbor all major pancreatic endocrine cell types.…”