Chemical combinations potentiate human pluripotent stem cell-derived 3D pancreatic progenitor clusters toward functional β cells
Haisong Liu, Ronghui Li, Hsin‐Kai Liao, Zheying Min, Chao Wang, Yang Yu, Lei Shi, Jiameng Dan, Alberto Hayek, Llanos Martinez Martinez, Estrella Núñez‐Delicado, Juan Carlos Izpisúa Belmonte
Abstract
Human pluripotent stem cell (hPSC)-derived pancreatic β cells are an attractive cell source for treating diabetes. However, current derivation methods remain inefficient, heterogeneous, and cell line dependent. To address these issues, we first devised a strategy to efficiently cluster hPSC-derived pancreatic progenitors into 3D structures. Through a systematic study, we discovered 10 chemicals that not only retain the pancreatic progenitors in 3D clusters but also enhance their potentiality towards NKX6.1+/INS+ β cells. We further systematically screened signaling pathway modulators in the three steps from pancreatic progenitors toward β cells. The implementation of all these strategies and chemical combinations resulted in generating β cells from different sources of hPSCs with high efficiency. The derived β cells are functional and can reverse hyperglycemia in mice within two weeks. Our protocol provides a robust platform for studying human β cells and developing hPSC-derived β cells for cell replacement therapy.