Human expandable pancreatic progenitor–derived β cells ameliorate diabetes
Xiaojie Ma, Yunkun Lu, Ziyu Zhou, Qin Li, Xi Chen, Weiyun Wang, Yan Jin, Zhensheng Hu, Chen Guo, Qian Deng, Weina Shang, Hao Wang, Hongxing Fu, Xiangwei He, Xin‐Hua Feng, Saiyong Zhu
Abstract
An unlimited source of human pancreatic β cells is in high demand. Even with recent advances in pancreatic differentiation from human pluripotent stem cells, major hurdles remain in large-scale and cost-effective production of functional β cells. Here, through chemical screening, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor I-BET151 can robustly promote the expansion of PDX1 + NKX6.1 + pancreatic progenitors (PPs). These expandable PPs (ePPs) maintain pancreatic progenitor cell status in the long term and can efficiently differentiate into functional pancreatic β (ePP-β) cells. Notably, transplantation of ePP-β cells rapidly ameliorated diabetes in mice, suggesting strong potential for cell replacement therapy. Mechanistically, I-BET151 activates Notch signaling and promotes the expression of key PP-associated genes, underscoring the importance of epigenetic and transcriptional modulations for lineage-specific progenitor self-renewal. In summary, our studies achieve the long-term goal of robust expansion of PPs and represent a substantial step toward unlimited supplies of functional β cells for biomedical research and regenerative medicine.