Graduate Student Korea Advanced Institute of Science and Technology (KAIST), Republic of Korea
Abstract: Although pancreatic β-cells derived from human pluripotent stem cells (hPSCs) hold promise for the therapy of diabetes mellitus, their clinical application is limited by low differentiation efficiency and insufficient functionality. While heparan sulfate (HS) is known to regulate stem cell fate in various contexts, its role in the differentiation of human embryonic stem cells (hESCs) toward the pancreatic lineage remains not well understood. Here, we demonstrate that HS acts as a key effector in the differentiation of hESCs into the pancreatic lineage, particularly during the transition from endocrine progenitor (EP) to endocrine cell (EC). Pancreatic ECs are derived from hESCs through a series of developmental processes, including the definitive endoderm (DE), pancreatic endoderm (PE), and EP stages. To investigate the effect of HS on pancreatic β-cell development, hESCs were treated with HS during the transition from EP to EC, a critical commitment phase. HS treatment enhanced the transcriptional activity of β-cell-associated genes in hESC-derived ECs. Furthermore, pancreatic islet-like organoids (PIOs) generated from HS-treated cells exhibited higher expression of β-cell-associated genes than those derived from untreated cells. Moreover, a glucose-stimulated insulin secretion (GSIS) assay revealed that insulin production was significantly higher in HS-treated PIOs than in untreated controls when exposed to a high glucose concentration (27.5 mM), indicating enhanced functionality. Notably, HS treatment did not alter the morphological characteristics of PIOs derived from hESC-derived ECs. Thus, HS treatment not only improves the differentiation efficiency of hESCs into pancreatic β-cells but also enhances their functionality. Our results suggest that HS is a potent modulator of pancreatic β-cell development.
Funding Source: Korean Fund for Regenerative Medicine (KFRM)
