Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion

Ingmar Bruns, Daniel Lucas, Sandra Pinho, Jalal Ahmed, Michele P. Lambert, Yuya Kunisaki, Christoph Scheiermann, Lauren Schiff, Mortimer Poncz, Aviv Bergman, Paul S. Frenette

Research output: Contribution to journalArticle

253 Scopus citations

Abstract

In the bone marrow, hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control the proliferative state of HSCs to adapt to the varying needs for replenishment of blood cells while also preventing HSC exhaustion1. All putative niche cells suggested thus far have a nonhematopoietic origin2,3,4,5,6,7,8. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust their proliferation. Here we show that megakaryocytes (MKs) can directly regulate HSC pool size in mice. Three-dimensional whole-mount imaging revealed that endogenous HSCs are frequently located adjacent to MKs in a nonrandom fashion. Selective in vivo depletion of MKs resulted in specific loss of HSC quiescence and led to a marked expansion of functional HSCs. Gene expression analyses revealed that MKs are the source of chemokine C-X-C motif ligand 4 (CXCL4, also named platelet factor 4 or PF4) in the bone marrow, and we found that CXCL4 regulates HSC cell cycle activity. CXCL4 injection into mice resulted in a reduced number of HSCs because of their increased quiescence. By contrast, Cxcl4−/− mice exhibited an increased number of HSCs and increased HSC proliferation. Combined use of whole-mount imaging and computational modeling was highly suggestive of a megakaryocytic niche capable of independently influencing HSC maintenance by regulating quiescence. These results indicate that a terminally differentiated cell type derived from HSCs contributes to the HSC niche, directly regulating HSC behavior.

Original languageEnglish (US)
Pages (from-to)1315-1320
Number of pages6
JournalNature Medicine
Volume20
Issue number11
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Bruns, I., Lucas, D., Pinho, S., Ahmed, J., Lambert, M. P., Kunisaki, Y., Scheiermann, C., Schiff, L., Poncz, M., Bergman, A., & Frenette, P. S. (2014). Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nature Medicine, 20(11), 1315-1320. https://doi.org/10.1038/nm.3707