title: Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells.
abstract: Multiple bone marrow stromal cell types have been identified as hematopoietic stem cell (HSC)-regulating niche cells. However, whether HSC progeny can serve directly as HSC niche cells has not previously been shown. Here we report a dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress. We show that MKs are physically associated with HSCs in the bone marrow of mice and that MK ablation led to activation of quiescent HSCs and increased HSC proliferation. RNA sequencing (RNA-seq) analysis revealed that transforming growth factor β1 (encoded by Tgfb1) is expressed at higher levels in MKs as compared to other stromal niche cells. MK ablation led to reduced levels of biologically active TGF-β1 protein in the bone marrow and nuclear-localized phosphorylated SMAD2/3 (pSMAD2/3) in HSCs, suggesting that MKs maintain HSC quiescence through TGF-β-SMAD signaling. Indeed, TGF-β1 injection into mice in which MKs had been ablated restored HSC quiescence, and conditional deletion of Tgfb1 in MKs increased HSC activation and proliferation. These data demonstrate that TGF-β1 is a dominant signal emanating from MKs that maintains HSC quiescence. However, under conditions of chemotherapeutic challenge, MK ablation resulted in a severe defect in HSC expansion. In response to stress, fibroblast growth factor 1 (FGF1) signaling from MKs transiently dominates over TGF-β inhibitory signaling to stimulate HSC expansion. Overall, these observations demonstrate that MKs serve as HSC-derived niche cells to dynamically regulate HSC function.
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Perry
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Marshall
authors.affiliation: 1] Stowers Institute for Medical Research, Kansas City, Missouri, USA. [2] Centre for Stem Cell Research, Christian Medical College, Vellore, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Venkatraman
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, USA.
authors.forename: Pengxu
authors.initials: P
authors.lastname: Qian
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri, USA.
authors.forename: Xi C
authors.initials: XC
authors.lastname: He
authors.affiliation: Laboratory of Blood and Vascular Biology, Rockefeller University, New York, New York, USA.
authors.forename: Jasimuddin
authors.initials: J
authors.lastname: Ahamed
authors.affiliation: 1] Stowers Institute for Medical Research, Kansas City, Missouri, USA. [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Linheng
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006706:Homeostasis / Q000187:drug effects; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D012038:Regeneration / Q000187:drug effects; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D016220:Fibroblast Growth Factor 1; D005472:Fluorouracil