Identification of a human hematopoietic stem cell subset that retains memory of inflammatory stress

Zeng, Andy G.X.; Nagree, Murtaza S.; Jakobsen, Niels Asger; Shah, Sayyam; Murison, Alex; Cheong, Jin-Gyu; Turkalj, Sven; Lim, Isabel N.X.; Jin, Liqing; Araújo, Joana; Aguilar-Navarro, Alicia G.; Parris, Darrien; McLeod, Jessica; Kim, Hyerin; Lee, Ho Seok; Zhang, Lin; Boulanger, Mason; Wagenblast, Elvin; Flores-Figueroa, Eugenia; Wang, Bo; Schwartz, Gregory W.; Shultz, Leonard D.; Josefowicz, Steven Z.; Vyas, Paresh; Dick, John E.; Xie, Stephanie Z.

doi:10.1101/2023.09.11.557271

Cited by 6 publications

(1 citation statement)

References 107 publications

(270 reference statements)

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“…Recent single cell data suggest that all HSCs within in a CH bone marrow environment have transcriptional signatures of inflammation but that this is less pronounced in selected HSCs 33 . This raises the hypothesis that selected HSCs with a dampened response to inflammation, may function better in an inflammatory environment 40 . Third, as our data are time averaged from single timepoint measurements it would be fascinating to apply SCIFER suggest to measure HSC parameters (division rates and birth of clones) serially in longitudinal samples across an individual’s lifetime.…”

Section: Discussionmentioning

confidence: 99%

Detecting and quantifying clonal selection in somatic stem cells

Koerber

Ansari-Pour

Jakobsen

et al. 2021

Preprint

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Dividing somatic stem cells acquire DNA changes marking different clones. With time, clones can become large, either stochastically through neutral drift, or increased fitness and consequent selection. We present a simple, direct, and general approach that distinguishes between these two processes in normal somatic tissue in individuals. The method relies on single time point whole genome sequencing to study somatic mosaicism as tissues age. Using this method, we show that in human clonal hemopoiesis (CH), clones with CH driver mutations, that comprise a median of 24% of hematopoiesis originate decades before they are detected. They expand, through selection by a median of 26% per year. Overall, there is a 3-fold increased rate of stem cell division and an 8.6-fold increase in active long-term stem cells.One sentence summaryWe present an approach to distinguish genetic drift from selection, as subclones arise in somatic tissues, in individuals.

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Section: Discussionmentioning

confidence: 99%

Detecting and quantifying clonal selection in somatic stem cells

Koerber

Ansari-Pour

Jakobsen

et al. 2021

Preprint

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Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche

Winter,

Götze,

Hecker

et al. 2024

Leukemia

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Clonal hematopoiesis (CH) defines a premalignant state predominantly found in older persons that increases the risk of developing hematologic malignancies and age-related inflammatory diseases. However, the risk for malignant transformation or non-malignant disorders is variable and difficult to predict, and defining the clinical relevance of specific candidate driver mutations in individual carriers has proved to be challenging. In addition to the cell-intrinsic mechanisms, mutant cells rely on and alter cell-extrinsic factors from the bone marrow (BM) niche, which complicates the prediction of a mutant cell’s fate in a shifting pre-malignant microenvironment. Therefore, identifying the insidious and potentially broad impact of driver mutations on supportive niches and immune function in CH aims to understand the subtle differences that enable driver mutations to yield different clinical outcomes. Here, we review the changes in the aging BM niche and the emerging evidence supporting the concept that CH can progressively alter components of the local BM microenvironment. These alterations may have profound implications for the functionality of the osteo-hematopoietic niche and overall bone health, consequently fostering a conducive environment for the continued development and progression of CH. We also provide an overview of the latest technology developments to study the spatiotemporal dependencies in the CH BM niche, ideally in the context of longitudinal studies following CH over time. Finally, we discuss aspects of CH carrier management in clinical practice, based on work from our group and others.

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Deciphering cell states and genealogies of human haematopoiesis

Weng,

Yu,

Yang

et al. 2024

Nature

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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.

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Identification of a human hematopoietic stem cell subset that retains memory of inflammatory stress

Cited by 6 publications

References 107 publications

Detecting and quantifying clonal selection in somatic stem cells

Detecting and quantifying clonal selection in somatic stem cells

Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche

Deciphering cell states and genealogies of human haematopoiesis

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