轉錄因子誘導多能干細胞再生免疫活性B淋巴細胞

2021年11月，中國科學院廣州生物醫藥與健康研究所；中國科學院再生生物學重點實驗室；中國科學院廣州生物醫藥與衛生研究院；廣東省干細胞與再生醫學重點實驗室；中國科學院大學；中國科學院干細胞與再生研究所；廣州醫學院；GMU-GIBH生命科學聯合學院(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老師研究團隊在《Cellular & Molecular Immunology》上發表論文：

“Regeneration of immunocompetent B lymphopoiesis from pluripotent stem cells guided by transcription factors”

“轉錄因子誘導多能干細胞再生免疫活性B淋巴細胞”

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：

從多能干細胞(PSCs)中再生功能性B淋巴細胞是具有挑戰性的，目前還沒有可靠的方法。在這里，我們揭示了三個關鍵因子Lhx2、Hoxa9和Runx1的指導作用，它們的同時表達優先驅動B譜系命運承諾和以PSCs為細胞源的體內B淋巴生成。在Lhx2、Hoxa9和Runx1表達的情況下，psc衍生的誘導造血祖細胞(iHPCs)立即在受體骨髓中產生pro/pre-B細胞，這些細胞能夠進一步分化成完整的B細胞系，包括先天B-1a、B-1b和邊緣區B細胞，以及適應性濾泡B細胞。特別是，再生B細胞產生適應性體液免疫反應，持續產生抗原特異性抗體，并在抗原挑戰下形成免疫記憶。再生B細胞通過與宿主T濾泡輔助細胞的串擾，表現出免疫球蛋白鏈切換和超突變的自然B細胞發育模式，最終形成T細胞依賴性體液反應。這項研究提供了新的證據，證明通過hsc獨立的方法可以從psc再生B淋巴系統，這為利用psc作為無限的細胞資源治療B細胞相關缺陷提供了見解。

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