Deciphering cell states and genealogies of human haematopoiesis

Chen Weng, Fulong Yu, Dian Yang, Michael Poeschla, L. Alexander Liggett, Matthew G. Jones, Xiaojie Qiu, Lara Wahlster, Alexis Caulier, Jeffrey A. Hussmann, Alexandra Schnell, Kathryn E. Yost, Luke W. Koblan, Jorge D. Martin-Rufino, Joseph Min, Alessandro Hammond, Daniel Ssozi, Raphael Bueno, Hari Mallidi, Antonia Kreso, Javier Escabi, William M. Rideout, Tyler Jacks, Sahand Hormoz, Peter van Galen, Jonathan S. Weissman () and Vijay G. Sankaran ()
Additional contact information
Chen Weng: Boston Children’s Hospital, Harvard Medical School
Fulong Yu: Boston Children’s Hospital, Harvard Medical School
Dian Yang: Whitehead Institute for Biomedical Research
Michael Poeschla: Boston Children’s Hospital, Harvard Medical School
L. Alexander Liggett: Boston Children’s Hospital, Harvard Medical School
Matthew G. Jones: Whitehead Institute for Biomedical Research
Xiaojie Qiu: Whitehead Institute for Biomedical Research
Lara Wahlster: Boston Children’s Hospital, Harvard Medical School
Alexis Caulier: Boston Children’s Hospital, Harvard Medical School
Jeffrey A. Hussmann: Whitehead Institute for Biomedical Research
Alexandra Schnell: Whitehead Institute for Biomedical Research
Kathryn E. Yost: Whitehead Institute for Biomedical Research
Luke W. Koblan: Whitehead Institute for Biomedical Research
Jorge D. Martin-Rufino: Boston Children’s Hospital, Harvard Medical School
Joseph Min: Whitehead Institute for Biomedical Research
Alessandro Hammond: Boston Children’s Hospital, Harvard Medical School
Daniel Ssozi: Broad Institute of MIT and Harvard
Raphael Bueno: Brigham and Women’s Hospital
Hari Mallidi: Brigham and Women’s Hospital
Antonia Kreso: Massachusetts General Hospital
Javier Escabi: Harvard Medical School
William M. Rideout: Koch Institute For Integrative Cancer Research at MIT, MIT
Tyler Jacks: Koch Institute For Integrative Cancer Research at MIT, MIT
Sahand Hormoz: Broad Institute of MIT and Harvard
Peter van Galen: Broad Institute of MIT and Harvard
Jonathan S. Weissman: Whitehead Institute for Biomedical Research
Vijay G. Sankaran: Boston Children’s Hospital, Harvard Medical School

Nature, 2024, vol. 627, issue 8003, 389-398

Abstract: Abstract The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived haematopoietic stem cells (HSCs)1. Perturbations to this process underlie diverse diseases, but the clonal contributions to human haematopoiesis and how this changes with age remain incompletely understood. Although recent insights have emerged from barcoding studies in model systems2–5, simultaneous detection of cell states and phylogenies from natural barcodes in humans remains challenging. Here we introduce an improved, single-cell lineage-tracing system based on deep detection of naturally occurring mitochondrial DNA mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as both differences in total HSC output and biases towards the production of different mature cell types. We also find that the diversity of HSC clones decreases markedly with age, leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides a clonally resolved and cell-state-aware atlas of human haematopoiesis at single-cell resolution, showing an unappreciated functional diversity of human HSC clones and, more broadly, paving the way for refined studies of clonal dynamics across a range of tissues in human health and disease.

Date: 2024
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DOI: 10.1038/s41586-024-07066-z

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