2021年11月，中国科学院广州生物医药与健康研究所；中国科学院再生生物学重点实验室；中国科学院广州生物医药与卫生研究院；广东省干细胞与再生医学重点实验室；中国科学院大学；中国科学院干细胞与再生研究所；广州医学院；GMU-GIBH生命科学联合学院(CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China；Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China；Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China；University of Chinese Academy of Sciences, Beijing 100049, China；Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China；GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China.) Jinyong Wang老师研究团队在《Cellular & Molecular Immunology》上发表论文：
“Regeneration of immunocompetent B lymphopoiesis from pluripotent stem cells guided by transcription factors”
“转录因子诱导多能干细胞再生免疫活性B淋巴细胞”
Abstract
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.
摘要
从多能干细胞(PSCs)中再生功能性B淋巴细胞是具有挑战性的，目前还没有可靠的方法。在这里，我们揭示了三个关键因子Lhx2、Hoxa9和Runx1的指导作用，它们的同时表达优先驱动B谱系命运承诺和以PSCs为细胞源的体内B淋巴生成。在Lhx2、Hoxa9和Runx1表达的情况下，psc衍生的诱导造血祖细胞(iHPCs)立即在受体骨髓中产生pro/pre-B细胞，这些细胞能够进一步分化成完整的B细胞系，包括先天B-1a、B-1b和边缘区B细胞，以及适应性滤泡B细胞。特别是，再生B细胞产生适应性体液免疫反应，持续产生抗原特异性抗体，并在抗原挑战下形成免疫记忆。再生B细胞通过与宿主T滤泡辅助细胞的串扰，表现出免疫球蛋白链切换和超突变的自然B细胞发育模式，最终形成T细胞依赖性体液反应。这项研究提供了新的证据，证明通过hsc独立的方法可以从psc再生B淋巴系统，这为利用psc作为无限的细胞资源治疗B细胞相关缺陷提供了见解。
该论文中，OP9-DL1细胞(GFP+)的体外培养是使用Ausbian特级胎牛血清完成的。
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