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

Zhang, Q.; Wu, B.; Weng, Q.; Hu, F.; Lin, Y.; Xia, C.; Peng, H.; Wang, Y.; Liu, X.; Liu, L.; Xiong, J.; Geng, Y.; Zhao, Y.; Zhang, M.; Du, J.; Wang, J.

doi:10.1101/2021.07.30.454442

bioRxiv · 10.1101/2021.07.30.454442

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

Zhang, Q.·Wu, B.·Weng, Q.·Hu, F.·Lin, Y.·Xia, C.·Peng, H.·Wang, Y.·Liu, X.·Liu, L.·Xiong, J.·Geng, Y.·Zhao, Y.·Zhang, M.·Du, J.·Wang, J.

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Abstract

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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Zhang, Q., Wu, B., Weng, Q., Hu, F., Lin, Y., Xia, C., Peng, H., Wang, Y., Liu, X., Liu, L., Xiong, J., Geng, Y., Zhao, Y., Zhang, M., Du, J., Wang, J.. 2021-07-30. Regeneration of humoral immunity from pluripotent stem cells by defined transcription factors. https://doi.org/10.1101/2021.07.30.454442

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