TY - JOUR AU - Li, Zongyi AU - Duan, Haoyun AU - Jia, Yanni AU - Zhao, Can AU - Li, Wenjing AU - Wang, Xin AU - Gong, Yajie AU - Dong, Chunxiao AU - Ma, Bochao AU - Dou, Shengqian AU - Zhang, Bin AU - Li, Dongfang AU - Cao, Yihai AU - Xie, Lixin AU - Zhou, Qingjun AU - Shi, Weiyun T1 - Long-term corneal recovery by simultaneous delivery of hPSC-derived corneal endothelial precursors and nicotinamide PY - 2022/01/04/ AB - Human pluripotent stem cells (hPSCs) hold great promise for the treatment of various human diseases. However, their therapeutic benefits and mechanisms for treating corneal endothelial dysfunction remain undefined. Here, we developed a therapeutic regimen consisting of the combination of hPSC-derived corneal endothelial precursors (CEPs) with nicotinamide (NAM) for effective treatment of corneal endothelial dysfunction. In rabbit and nonhuman primate models, intracameral injection of CEPs and NAM achieved long-term recovery of corneal clarity and thickness, similar with the therapeutic outcome of cultured human corneal endothelial cells (CECs). The transplanted human CEPs exhibited structural and functional integration with host resident CECs. However, the long-term recovery relied on the stimulation of endogenous endothelial regeneration in rabbits, but predominantly on the replacing function of transplanted cells during the 3-year follow-up in nonhuman primates, which resemble human corneal endothelium with limited regenerative capacity. Mechanistically, NAM ensured in vivo proper maturation of transplanted CEPs into functional CECs by preventing premature senescence and endothelial-mesenchymal transition within the TGF-β–enriched aqueous humor. Together, we provide compelling experimental evidence and mechanistic insights of simultaneous delivery of CEPs and NAM as a potential approach for treating corneal endothelial dysfunction. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI146658 VL - 132 IS - 1 UR - https://doi.org/10.1172/JCI146658 PB - The American Society for Clinical Investigation ER -