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Single-cell lineage tracing unveils a role for TCF15 in haematopoiesis

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  • Alejo E. Rodriguez-Fraticelli

    (Harvard University
    Boston Children’s Hospital Stem Cell Program and Department of Hematology/Oncology
    Harvard Stem Cell Institute
    Department of Pediatrics)

  • Caleb Weinreb

    (Department of Systems Biology)

  • Shou-Wen Wang

    (Department of Systems Biology)

  • Rosa P. Migueles

    (The University of Edinburgh)

  • Maja Jankovic

    (Harvard University
    Boston Children’s Hospital Stem Cell Program and Department of Hematology/Oncology)

  • Marc Usart

    (Harvard University
    Boston Children’s Hospital Stem Cell Program and Department of Hematology/Oncology)

  • Allon M. Klein

    (Department of Systems Biology)

  • Sally Lowell

    (The University of Edinburgh)

  • Fernando D. Camargo

    (Harvard University
    Boston Children’s Hospital Stem Cell Program and Department of Hematology/Oncology
    Harvard Stem Cell Institute
    Department of Pediatrics)

Abstract

Bone marrow transplantation therapy relies on the life-long regenerative capacity of haematopoietic stem cells (HSCs)1,2. HSCs present a complex variety of regenerative behaviours at the clonal level, but the mechanisms underlying this diversity are still undetermined3–11. Recent advances in single-cell RNA sequencing have revealed transcriptional differences among HSCs, providing a possible explanation for their functional heterogeneity12–17. However, the destructive nature of sequencing assays prevents simultaneous observation of stem cell state and function. To solve this challenge, we implemented expressible lentiviral barcoding, which enabled simultaneous analysis of lineages and transcriptomes from single adult HSCs and their clonal trajectories during long-term bone marrow reconstitution. Analysis of differential gene expression between clones with distinct behaviour revealed an intrinsic molecular signature that characterizes functional long-term repopulating HSCs. Probing this signature through in vivo CRISPR screening, we found the transcription factor TCF15 to be required and sufficient to drive HSC quiescence and long-term self-renewal. In situ, Tcf15 expression labels the most primitive subset of true multipotent HSCs. In conclusion, our work elucidates clone-intrinsic molecular programmes associated with functional stem cell heterogeneity and identifies a mechanism for the maintenance of the self-renewing HSC state.

Suggested Citation

  • Alejo E. Rodriguez-Fraticelli & Caleb Weinreb & Shou-Wen Wang & Rosa P. Migueles & Maja Jankovic & Marc Usart & Allon M. Klein & Sally Lowell & Fernando D. Camargo, 2020. "Single-cell lineage tracing unveils a role for TCF15 in haematopoiesis," Nature, Nature, vol. 583(7817), pages 585-589, July.
  • Handle: RePEc:nat:nature:v:583:y:2020:i:7817:d:10.1038_s41586-020-2503-6
    DOI: 10.1038/s41586-020-2503-6
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    Cited by:

    1. Jos Urbanus & Jason Cosgrove & Joost B. Beltman & Yuval Elhanati & Rafael A. Moral & Cecile Conrad & Jeroen W. Heijst & Emilie Tubeuf & Arno Velds & Lianne Kok & Candice Merle & Jens P. Magnusson & Lé, 2023. "DRAG in situ barcoding reveals an increased number of HSPCs contributing to myelopoiesis with age," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Florisela Herrejon Chavez & Hanzhi Luo & Paolo Cifani & Alli Pine & Eren L. Chu & Suhasini Joshi & Ersilia Barin & Alexandra Schurer & Mandy Chan & Kathryn Chang & Grace Y. Q. Han & Aspen J. Pierson &, 2023. "RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Mina N. F. Morcos & Congxin Li & Clara M. Munz & Alessandro Greco & Nicole Dressel & Susanne Reinhardt & Katrin Sameith & Andreas Dahl & Nils B. Becker & Axel Roers & Thomas Höfer & Alexander Gerbaule, 2022. "Fate mapping of hematopoietic stem cells reveals two pathways of native thrombopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Humberto Contreras-Trujillo & Jiya Eerdeng & Samir Akre & Du Jiang & Jorge Contreras & Basia Gala & Mary C. Vergel-Rodriguez & Yeachan Lee & Aparna Jorapur & Areen Andreasian & Lisa Harton & Charles S, 2021. "Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    5. Giulia Schiroli & Vinay Kartha & Fabiana M. Duarte & Trine A. Kristiansen & Christina Mayerhofer & Rojesh Shrestha & Andrew Earl & Yan Hu & Tristan Tay & Catherine Rhee & Jason D. Buenrostro & David T, 2024. "Cell of origin epigenetic priming determines susceptibility to Tet2 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    6. Kyung Mok Kim & Anna Mura-Meszaros & Marie Tollot & Murali Shyam Krishnan & Marco Gründl & Laura Neubert & Marco Groth & Alejo Rodriguez-Fraticelli & Arthur Flohr Svendsen & Stefano Campaner & Nico An, 2022. "Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Kim Vanuytsel & Carlos Villacorta-Martin & Jonathan Lindstrom-Vautrin & Zhe Wang & Wilfredo F. Garcia-Beltran & Vladimir Vrbanac & Dylan Parsons & Evan C. Lam & Taylor M. Matte & Todd W. Dowrey & Sara, 2022. "Multi-modal profiling of human fetal liver hematopoietic stem cells reveals the molecular signature of engraftment," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    8. A. S. Eisele & M. Tarbier & A. A. Dormann & V. Pelechano & D. M. Suter, 2024. "Gene-expression memory-based prediction of cell lineages from scRNA-seq datasets," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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