Alhaj Hussen Kutaiba, Chabaane Emna, Nelson Elisabeth, Lekiashvili Shalva, Diop Samuel, Keita Seydou, Evrard Bertrand, Lardenois Aurélie, Delord Marc, Verhoeyen Els, Cornils Kerstin, Kasraian Zeinab, Macintyre Elizabeth A, Cumano Ana, Garrick David, Goodhardt Michele, Andrieu Guillaume P, Asnafi Vahid, Chalmel Frederic, Canque Bruno
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France.
Service de Biochimie, Université de Paris Saclay, Hôpital Paul Brousse, AP-HP, Villejuif, Paris, France.
iScience. 2023 Sep 9;26(10):107890. doi: 10.1016/j.isci.2023.107890. eCollection 2023 Oct 20.
The developmental cartography of human lymphopoiesis remains incompletely understood. Here, we establish a multimodal map demonstrating that lymphoid specification follows independent direct or stepwise hierarchic routes converging toward the emergence of newly characterized CD117 multi-lymphoid progenitors (MLPs) that undergo a proliferation arrest before entering the CD127 (NK/ILC/T) or CD127 (B) lymphoid pathways. While the differentiation of CD127 early lymphoid progenitors is mainly driven by Flt3 signaling, emergence of their CD127 counterparts is regulated cell-intrinsically and depends exclusively on the divisional history of their upstream precursors, including hematopoietic stem cells. Further, transcriptional mapping of differentiation trajectories reveals that whereas myeloid granulomonocytic lineages follow continuous differentiation pathways, lymphoid trajectories are intrinsically discontinuous and characterized by sequential waves of cell proliferation allowing pre-commitment amplification of lymphoid progenitor pools. Besides identifying new lymphoid specification pathways and regulatory checkpoints, our results demonstrate that NK/ILC/T and B lineages are under fundamentally distinct modes of regulation. (149 words).
人类淋巴细胞生成的发育图谱仍未被完全理解。在此，我们建立了一个多模态图谱，表明淋巴细胞特化遵循独立的直接或逐步分层途径，汇聚于新鉴定的CD117多淋巴细胞祖细胞（MLP）的出现，这些祖细胞在进入CD127（NK/ILC/T）或CD127（B）淋巴细胞途径之前经历增殖停滞。虽然CD127早期淋巴细胞祖细胞的分化主要由Flt3信号驱动，但其CD127对应物的出现是由细胞内在调节的，并且完全取决于其上游前体（包括造血干细胞）的分裂历史。此外，分化轨迹的转录图谱显示，髓系粒细胞-单核细胞谱系遵循连续的分化途径，而淋巴细胞轨迹本质上是不连续的，其特征是细胞增殖的连续波，允许淋巴细胞祖细胞池的预承诺扩增。除了识别新的淋巴细胞特化途径和调控检查点外，我们的结果还表明，NK/ILC/T和B谱系处于根本不同的调控模式。
