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Temporal multimodal single-cell profiling of native hematopoiesis illuminates altered differentiation trajectories with age

Konturek-Ciesla, Anna, Dhapola, Parashar, Zhang, Qinyu, Säwén, Petter, Wan, Haixia, Karlsson, Göran, Bryder, David·2023·Cell Reports
DOI 10.1016/j.celrep.2023.112304
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Abstract

Aging negatively affects hematopoiesis, with consequences for immunity and acquired blood cell disorders. Although impairments in hematopoietic stem cell (HSC) function contribute to this, the in vivo dynamics of such changes remain obscure. Here, we integrate extensive longitudinal functional assessments of HSC-specific lineage tracing with single-cell transcriptome and epitope profiling. In contrast to recent suggestions from single-cell RNA sequencing alone, our data favor a defined structure of HSC/progenitor differentiation that deviates substantially from HSC-derived hematopoiesis following transplantation. Native age-dependent attrition in HSC differentiation manifests as drastically reduced lymphoid output through an early lymphoid-primed progenitor (MPP Ly-I). While in vitro activation fails to rescue lymphoid differentiation from most aged HSCs, robust lymphopoiesis can be achieved by culturing elevated numbers of candidate HSCs. Therefore, our data position rare chronologically aged HSC clones, fully competent at producing lymphoid offspring, as a prime target for approaches aimed to improve lymphopoiesis in the elderly.

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Cited by

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Metadata

Authors
Konturek-Ciesla, A., Dhapola, P., Zhang, Q., Säwén, P., Wan, H., Karlsson, G., & Bryder, D.
Venue
Cell Reports
Publisher
Elsevier BV
Published
2023-04
Volume
42
Issue
4
Pages
112304
ISSN
2211-1247
DOI
10.1016/j.celrep.2023.112304
Cited by
48
References
14
Language
en
Licence
Funders
  • Vetenskapsrådet
  • Barncancerfonden
  • Cancerfonden
  • Knut och Alice Wallenbergs Stiftelse

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