Deciphering cell states and genealogies of human hematopoiesis
Name
HSC_Lineage tracing MS.pdf
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311.02 KB
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Adobe PDF
Checksum (MD5)
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Author(s)
Weng, Chen
Yu, Fulong
Yang, Dian
Poeschla, Michael
Liggett, L. Alexander
Jones, Matthew G.
Qiu, Xiaojie
Wahlster, Lara
Caulier, Alexis
Hussmann, Jeffrey A.
Date Issued
January 22, 2024
Publisher
Springer Science and Business Media LLC
Citation
Weng, C., Yu, F., Yang, D. et al. Deciphering cell states and genealogies of human hematopoiesis. Nature (2024).
Version
Author's final manuscript
Abstract
The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs)1. Perturbations to this process underlie diverse diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems4,5,16,17, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) 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 differences in total HSC output as well as biases toward the production of different mature cell types. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
Subjects
Multidisciplinary
MIT Department
Massachusetts Institute of Technology. Department of Biology
Howard Hughes Medical Institute
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1038/s41586-024-07066-z
