Deciphering cell states and genealogies of human haematopoiesis

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.

Amulti-tracklandscape of haematopoiesis informed by cellular barcoding and agent-based modelling

“…This could be addressed using SIS-skew, which links a clone’s normal fate with its perturbed fate (Tian et al, 2021). Lastly, testing these models in human haematopoiesis (homeostatic, during ageing, and in instances of clonal haematopoiesis) will be challenging but necessary; either utilising in vitro or humanised models of human haematopoiesis (Lee et al, 2017; Notta et al, 2016), humanized mice, or inference using natural barcoding: (Lee-Six et al, 2018; Ludwig et al, 2019; Miller et al, 2022; Weng et al, 2024).…”

New insights into the endothelial origin of hematopoietic system inspired by “TIF” approaches

“…In addition, although Cre-mediated tracing and gene barcoding technologies are not applicable to human studies, lineage tracing technology represented by endogenous genomic mutations is expected to be an important tool in future for studying the developmental paths of diversified HSPCs in humans. 98 , 99 …”

Exploring haematopoietic stem cell dynamics through mitochondrial mutation profiling

“…By significantly improving the mutation detection rate, ReDeeM technology successfully generated clone-resolved single-cell transcriptome and chromatin maps of approximately 150,000 human hematopoietic cells. This offers a new perspective for deeply understanding the clonal behavior of hematopoietic stem cells (HSCs) in maintaining blood system function and in aging and disease [ 1 ]. Increasing evidence suggests that HSCs exhibit diverse clonal behaviors in aging and disease, such as clonal hematopoiesis, which is associated with acute myelocytic leukemia (AML) and an increased risk of cardiovascular disease [ 2 ].…”

“…To overcome the limitations of existing technologies and further explore the complexity of HSCs, Weng C et al introduced the ReDeeM technology. Through optimized mtDNA coverage and the application of unique molecular identifiers, ReDeeM technology can detect rare mutations with minimal heterogeneity, reconstruct the lineage tree and cell status of the human hematopoietic system, and offer new insights into human HSC clones [ 1 ].…”