RFX3 Research in Human iPSC Pancreatic Differentiation and Islet Function

Abstract

Pancreatic β-cell dysfunction is the core pathological feature of diabetes, and human induced pluripotent stem cell (iPSC)-derived islets offer a promising alternative for cell therapy, but face bottlenecks like low functional β-cell proportion and non-target cell contamination. This paper analyzes the regulatory role of transcription factor RFX3 in iPSC-derived pancreatic differentiation and islet function. RFX3 has a full cycle effect, maintaining pancreatic lineage specificity in pancreatic progenitor cells (PP) by stabilizing PDX1/SOX9 expression and inhibiting exocrine differentiation. In endocrine progenitors (EPs), it inhibits enterochromaffin (EC) cell bias via repressing ASCL1. In mature islets, it regulates the glucose sensing-insulin secretion axis by activating GCK/SLC2A2 and protects β cells from apoptosis through the RFX3-TXNIP pathway. Compared with RFX6 (another RFX family member) and classical factors (e.g., PDX1, NEUROG3), RFX3 acts earlier, has broader functions, and correlates with type 2 diabetes (T2D). While current studies confirm its value in optimizing iPSC islet differentiation and elucidating T2D mechanisms, limitations remain, such as insufficient long-term in vivo validation. RFX3 provides a key target for advancing iPSC-based diabetes cell therapy and deepening pancreatic developmental biology research.