Multimodal Cartography of Human Lymphopoiesis Reveals B and T/NK/ILC Lineages are Subjected to Differential Regulation

Kutaiba Alhaj Hussen; Emna Chabaane; Elisabeth Nelson; Shalva Lekiashvili; Samuel Diop; Seydou Keita; Bertrand Evrard; Aurélie Lardenois; Marc Delord; Els Verhoeyen

doi:10.1016/j.isci.2023.107890

Multimodal Cartography of Human Lymphopoiesis Reveals B and T/NK/ILC Lineages are Subjected to Differential Regulation

Kutaiba Alhaj Hussen, Emna Chabaane, Elisabeth Nelson, Shalva Lekiashvili, Samuel Diop, Seydou Keita, Bertrand Evrard, Aurélie Lardenois, Marc Delord, Els Verhoeyen

Population Health Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

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^lo 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.

Original language	English
Article number	107890
Pages (from-to)	107890
Number of pages	1
Journal	iScience
Volume	26
Issue number	10
DOIs	https://doi.org/10.1016/j.isci.2023.107890
Publication status	Published - 20 Oct 2023

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@article{17f0172c21454d6d9824702261cf0d7b,

title = "Multimodal Cartography of Human Lymphopoiesis Reveals B and T/NK/ILC Lineages are Subjected to Differential Regulation",

abstract = "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 CD117lo 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.",

author = "Hussen, {Kutaiba Alhaj} and Emna Chabaane and Elisabeth Nelson and Shalva Lekiashvili and Samuel Diop and Seydou Keita and Bertrand Evrard and Aur{\'e}lie Lardenois and Marc Delord and Els Verhoeyen",

note = "Funding Information: The authors thank Christelle Doliger and Niclas Setterblad (Plateforme d'Imagerie et de Tri Cellulaire, IRSL, Paris France). We are grateful to Laurent David (Inserm 1064, Nantes) and Bernard Jost (GenomEast platform, IGBMC, Strasbourg, France). We thank Justine Poirot for help in single cell analyses. We acknowledge the contribution of AniRA lentivectors production facility from the CELPHEDIA Infrastructure and SFR Biosciences (UAR3444/CNRS, US8/Inserm, ENS de Lyon, UCBL), especially Gis{\`e}le Froment, Didier N{\`e}gre and Caroline Costa. We also thank Sophie Ezine and Bela Papp for critical discussions. This work was supported by the Agence de la Biom{\'e}decine, Agence National de la Recherche (ANR EpiDev), the Institut National Du Cancer (InCA B-REC), the Fondation Ramsay G{\'e}n{\'e}rale de Sant{\'e} and by the Inserm HuDeCA network. Conceptualization: BC, KAH. Methodology: EN, SL, BE, MD, SD, GPA, FC, AL. Investigation: KAH, EC, SL, SK, EV, KC, ZK. Funding acquisition: BC, DG, MG, AC. Writing – original draft: BC, KAH, EAM, VA, ZK, AC, FC. Supervision: BC. The authors have no conflict of interest. Funding Information: The authors thank Christelle Doliger and Niclas Setterblad (Plateforme d{\textquoteright}Imagerie et de Tri Cellulaire, IRSL, Paris France). We are grateful to Laurent David (Inserm 1064, Nantes) and Bernard Jost (GenomEast platform, IGBMC, Strasbourg, France). We thank Justine Poirot for help in single cell analyses. We acknowledge the contribution of AniRA lentivectors production facility from the CELPHEDIA Infrastructure and SFR Biosciences (UAR3444/CNRS, US8/Inserm, ENS de Lyon, UCBL), especially Gis{\`e}le Froment, Didier N{\`e}gre and Caroline Costa. We also thank Sophie Ezine and Bela Papp for critical discussions. This work was supported by the Agence de la Biom{\'e}decine , Agence National de la Recherche (ANR EpiDev), the Institut National Du Cancer (InCA B-REC), the Fondation Ramsay G{\'e}n{\'e}rale de Sant{\'e} and by the Inserm HuDeCA network. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = oct,

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doi = "10.1016/j.isci.2023.107890",

language = "English",

volume = "26",

pages = "107890",

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T1 - Multimodal Cartography of Human Lymphopoiesis Reveals B and T/NK/ILC Lineages are Subjected to Differential Regulation

AU - Hussen, Kutaiba Alhaj

AU - Chabaane, Emna

AU - Nelson, Elisabeth

AU - Lekiashvili, Shalva

AU - Diop, Samuel

AU - Keita, Seydou

AU - Evrard, Bertrand

AU - Lardenois, Aurélie

AU - Delord, Marc

AU - Verhoeyen, Els

N1 - Funding Information: The authors thank Christelle Doliger and Niclas Setterblad (Plateforme d'Imagerie et de Tri Cellulaire, IRSL, Paris France). We are grateful to Laurent David (Inserm 1064, Nantes) and Bernard Jost (GenomEast platform, IGBMC, Strasbourg, France). We thank Justine Poirot for help in single cell analyses. We acknowledge the contribution of AniRA lentivectors production facility from the CELPHEDIA Infrastructure and SFR Biosciences (UAR3444/CNRS, US8/Inserm, ENS de Lyon, UCBL), especially Gisèle Froment, Didier Nègre and Caroline Costa. We also thank Sophie Ezine and Bela Papp for critical discussions. This work was supported by the Agence de la Biomédecine, Agence National de la Recherche (ANR EpiDev), the Institut National Du Cancer (InCA B-REC), the Fondation Ramsay Générale de Santé and by the Inserm HuDeCA network. Conceptualization: BC, KAH. Methodology: EN, SL, BE, MD, SD, GPA, FC, AL. Investigation: KAH, EC, SL, SK, EV, KC, ZK. Funding acquisition: BC, DG, MG, AC. Writing – original draft: BC, KAH, EAM, VA, ZK, AC, FC. Supervision: BC. The authors have no conflict of interest. Funding Information: The authors thank Christelle Doliger and Niclas Setterblad (Plateforme d’Imagerie et de Tri Cellulaire, IRSL, Paris France). We are grateful to Laurent David (Inserm 1064, Nantes) and Bernard Jost (GenomEast platform, IGBMC, Strasbourg, France). We thank Justine Poirot for help in single cell analyses. We acknowledge the contribution of AniRA lentivectors production facility from the CELPHEDIA Infrastructure and SFR Biosciences (UAR3444/CNRS, US8/Inserm, ENS de Lyon, UCBL), especially Gisèle Froment, Didier Nègre and Caroline Costa. We also thank Sophie Ezine and Bela Papp for critical discussions. This work was supported by the Agence de la Biomédecine , Agence National de la Recherche (ANR EpiDev), the Institut National Du Cancer (InCA B-REC), the Fondation Ramsay Générale de Santé and by the Inserm HuDeCA network. Publisher Copyright: © 2023 The Author(s)

PY - 2023/10/20

Y1 - 2023/10/20

N2 - 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 CD117lo 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.

AB - 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 CD117lo 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.

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U2 - 10.1016/j.isci.2023.107890

DO - 10.1016/j.isci.2023.107890

M3 - Article

SN - 2589-0042

VL - 26

SP - 107890

JO - iScience

JF - iScience

IS - 10

M1 - 107890

ER -

Multimodal Cartography of Human Lymphopoiesis Reveals B and T/NK/ILC Lineages are Subjected to Differential Regulation

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