title: Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion.
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 exhaustion. All putative niche cells suggested thus far have a nonhematopoietic origin. 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.
authors.affiliation: 1] Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany. [3] Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Bruns
authors.affiliation: 1] Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lucas
authors.affiliation: 1] Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinho
authors.affiliation: 1] Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Jalal
authors.initials: J
authors.lastname: Ahmed
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Michele P
authors.initials: MP
authors.lastname: Lambert
authors.affiliation: 1] Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kunisaki
authors.affiliation: 1] Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheiermann
authors.affiliation: 1] Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Schiff
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Bergman
authors.affiliation: 1] Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Mount Sinai School of Medicine, New York, New York, USA. [4] Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000818:Animals; D001160:Arterioles / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology; D002453:Cell Cycle; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010978:Platelet Factor 4 / Q000378:metabolism*; D055153:Stem Cell Niche
chemical_list: D010978:Platelet Factor 4