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Regeneration of immunocompetent b lymphopoiesis from pluripotent stem cells guided by transcription factors

Cellular & Molecular Immunology 2022年第4期19卷 492-503页

作者： 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 CAS Key Laboratory of Regenerative biology Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou510530China bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory) Guangzhou510005China Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhou510530China University of Chinese Academy of Sciences Beijing100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing100101China GMU-GIbH Joint School of Life Sciences Guangzhou Medical UniversityGuangzhou511436China

Regeneration of functional b lymphopoiesis from pluripotent stem cells(PSCs)is challenging,and reliable methods have not been developed.Here,we unveiled the guiding role of three essential factors,Lhx2,Hoxa9,and Runx1,the simultaneous expression of which preferentially drives b lineage fate commitment and in vivo b lymphopoiesis using PSCs as a cell source.In the presence of Lhx2,Hoxa9,and Runx1 expression,PSC-derived induced hematopoietic progenitors(iHPCs)immediately gave rise to pro/pre-b cells in recipient bone marrow,which were able to further differentiate into entire b cell lineages,including innate b-1a,b-1b,and marginal zone b cells,as well as adaptive follicular b cells.In particular,the regenerative b cells produced adaptive humoral immune responses,sustained antigen-specific antibody production,and formed immune memory in response to antigen challenges.The regenerative b cells showed natural b cell development patterns of immunoglobulin chain switching and hypermutation via cross-talk with host T follicular helper cells,which eventually formed T cell-dependent humoral responses.This study exhibits de novo evidence that b lymphopoiesis can be regenerated from PSCs via an HSC-independent approach,which provides insights into treating b cell-related deficiencies using PSCs as an unlimited cell resource.

关键词： Lhx2 Hoxa9 Runx1 b lymphopoiesis pluripotent stem cells

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Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of b-cell precursors

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Cellular & Molecular Immunology 2014年第2期11卷 132-140页

作者： Qian Li Dongmei Han WeiWang Xiaoqing Liu Xiuyuan Sun Jun Zhang Rong Li Yu Zhang Department of Immunology Key Laboratory of Medical Immunology of Ministry of Health Peking University Health Science Center Beijing China and Department of Microbiology Faculty of Basic Medical Sciences Institute of Translational Medicine Nanchang University Nanchang China

Lipopolysaccharide （LPS） is known to be a potent activator of mature b cells by signaling through Toll-like receptor 4 （TLR4）. Its impact on early b-cell development, however, is not well defined. When comparing to C3H/HeN mice, TLR4-mutant C3H/HeJ mice showed an increase in the number of pro-b and pre-b cells in the bone marrow. When cultured in the presence of IL-7, the proliferation of pro-b and large pre-b cells was significantly inhibited by LPS, possibly due to reduced IL-7 receptor-a （IL-7Ra） expression. Meanwhile, the generation of IgM＋/IgD＋ b cells was greatly enhanced in IL-7 cultures of pro-b and pre-b cells. Consistent with these results, treatment with LPS facilitated the progression of adoptively transferred b220＋IgM-IgD- precursors into IgD＋ cells. Overall, these data suggest that LPS has a profound influence on early b-cell development, which may contribute to the deregulated b-cell development under physiological and pathological conditions such as bacterial infections.

关键词： b-cell differentiation b lymphopoiesis IL-7 lipopolysaccharide Toll-like receptor 4

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