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Regeneration of humoral immunity from pluripotent stem cells by defined transcription factors

By Qi Zhang, Bingyan Wu, Qitong Weng, Fangxiao Hu, Yunqing Lin, Chengxiang Xia, Huan Peng, Yao Wang, Xiaofei Liu, Lijuan Liu, Jiapin Xiong, Yang Geng, Yalan Zhao, Mengyun Zhang, Juan Du, Jinyong Wang

Posted 30 Jul 2021
bioRxiv DOI: 10.1101/2021.07.30.454442

Regeneration of humoral immunity from pluripotent stem cells (PSCs) is a crucial aim in translational medicine. However, reconstitution of complete, sustained, and functional B lymphopoiesis from PSCs has not yet been developed. Here, we successfully achieved regenerative B lymphopoiesis in B-cell deficient animals transplanted with PSC-derived hematopoietic progenitors (iHPCs) guided by synergistic expression of Runx1, Hoxa9, and Lhx2. Upon transplantation, the iHPCs immediately gave rise to pro/pre-B cells in recipients' bone marrow, which were able to further differentiate into the entire B cell lineages, including innate B-1a, B-1b, MZ B cells, as well as adaptive FO B cells. In responding to antigen stimuli, the regenerative B cells produced adaptive humoral immune responses, sustained a prolonged antigen-specific antibody production, and formed immune-memory. Particularly, the regenerative B cells in spleen showed developing patterns of immunoglobulin chain-switch and hyper-mutation via a cross-talk with the host T follicular helper cells, which eventually formed T cell-dependent humoral responses. This study provides de novo evidence that B lymphopoiesis can be regenerated from PSCs via a HSC-independent approach, which provides insights into treating B-cell related humoral deficiencies using PSCs as unlimited cell resource.

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