Deciphering cell states and genealogies of human haematopoiesis

• 成果类型: Article
• 署名作者: Weng, Chen; Yu, Fulong; Yang, Dian; Poeschla, Michael; Liggett, L. Alexander; Jones, Matthew G.; Qiu, Xiaojie; Wahlster, Lara; Caulier, Alexis; Hussmann, Jeffrey A.; Schnell, Alexandra; Yost, Kathryn E.; Koblan, Luke W.; Martin-Rufino, Jorge D.; Min, Joseph; Hammond, Alessandro; Ssozi, Daniel; Bueno, Raphael; Mallidi, Hari; Kreso, Antonia; Escabi, Javier; Rideout, William M.; Jacks, Tyler; Hormoz, Sahand; van Galen, Peter; Weissman, Jonathan S.; Sankaran, Vijay G.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School; Massachusetts Institute of Technology (MIT); Whitehead Institute; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute; Massachusetts Institute of Technology (MIT); Stanford University; Stanford University; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Massachusetts Institute of Technology (MIT); Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Guangzhou Medical University; State Key Laboratory of Respiratory Disease; Columbia University; Stanford University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4324
• DOI: 10.1038/s41586-024-07066-z
• 发表日期: 2024-03-14
• 关键词: stem-cells; salicylic-acid; clonal dynamics; calcium-atpases; mutations; gene; cax1; expression; channel; kinase

摘要

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. 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, is used to define the clonal architecture of haematopoietic stem cells.