Serial transplantation reveals a critical role for endoglin in hematopoietic stem cell quiescence

Luciene Borges, Vanessa K.P. Oliveira, June Baik, Sean C. Bendall, Rita C.R. Perlingeiro

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Transforming growth factor β (TGF-β) is well known for its important function in hematopoietic stem cell (HSC) quiescence. However, the molecular mechanism underlining this function remains obscure. Endoglin (Eng), a type III receptor for the TGF-β superfamily, has been shown to selectively mark long-term HSCs; however, its necessity in adult HSCs is unknown due to embryonic lethality. Using conditional deletion of Eng combined with serial transplantation, we show that this TGF-β receptor is critical to maintain the HSC pool. Transplantation of Eng-deleted whole bone marrow or purified HSCs into lethally irradiated mice results in a profound engraftment defect in tertiary and quaternary recipients. Cell cycle analysis of primary grafts revealed decreased frequency of HSCs in G 0, suggesting that lack of Eng impairs reentry of HSCs to quiescence. Using cytometry by time of flight (CyTOF) to evaluate the activity of signaling pathways in individual HSCs, we find that Eng is required within the Lin -Sca +Kit +-CD48 - CD150 + fraction for canonical and noncanonical TGF-β signaling, as indicated by decreased phosphorylation of SMAD2/3 and the p38 MAPK-activated protein kinase 2, respectively. These findings support an essential role for Eng in positively modulating TGF-β signaling to ensure maintenance of HSC quiescence.

Original languageEnglish (US)
Pages (from-to)688-696
Number of pages9
JournalBlood
Volume133
Issue number7
DOIs
StatePublished - Feb 14 2019

Bibliographical note

Publisher Copyright:
© 2019 by The American Society of Hematology.

Keywords

  • Animals
  • Cell Cycle
  • Endoglin/genetics
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells/cytology
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Signal Transduction
  • Transforming Growth Factor beta/metabolism

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural

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