Panhematopoietic RNA barcoding enables kinetic measurements of nucleate and anucleate lineages and the activation of myeloid clones following acute platelet depletion

Edyta E. Wojtowicz, Jayna J. Mistry, Vladimir Uzun, Charlotte Hellmich, Anita Scoones, Desmond W. Chin, Laura M. Kettyle, Francesca Grasso, Allegra M. Lord, David J. Wright, Graham J. Etherington, Petter S. Woll, Mirjam E. Belderbos, Kristian M. Bowles, Claus Nerlov, Wilfried Haerty, Leonid V. Bystrykh, Sten Eirik W. Jacobsen, Stuart A. Rushworth, Iain C. Macaulay

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Platelets and erythrocytes constitute over 95% of all hematopoietic stem cell output. However, the clonal dynamics of HSC contribution to these lineages remains largely unexplored. Results: We use lentiviral genetic labeling of mouse hematopoietic stem cells to quantify output from all lineages, nucleate, and anucleate, simultaneously linking these with stem and progenitor cell transcriptomic phenotypes using single-cell RNA-sequencing. We observe dynamic shifts of clonal behaviors through time in same-animal peripheral blood and demonstrate that acute platelet depletion shifts the output of multipotent hematopoietic stem cells to the exclusive production of platelets. Additionally, we observe the emergence of new myeloid-biased clones, which support short- and long-term production of blood cells. Conclusions: Our approach enables kinetic studies of multi-lineage output in the peripheral blood and transcriptional heterogeneity of individual hematopoietic stem cells. Our results give a unique insight into hematopoietic stem cell reactivation upon platelet depletion and of clonal dynamics in both steady state and under stress.

Original languageEnglish
Article number152
JournalGenome Biology
Volume24
DOIs
Publication statusPublished - 27 Jun 2023

Keywords

  • Clonal switching
  • Hematopoiesis
  • Lineage tracing
  • Platelet depletion
  • Platelets

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