title: Myocardial Infarction Activates CCR2(+) Hematopoietic Stem and Progenitor Cells.
abstract: Following myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlates closely with mortality. The origin of these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2(+)CD150(+)CD48(-) LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. This subset has 4-fold higher proliferation rates than CCR2(-)CD150(+)CD48(-) LSK cells, displays a myeloid differentiation bias, and dominates the migratory HSPC population. We further demonstrate that the myeloid translocation gene 16 (Mtg16) regulates CCR2(+) HSPC emergence. Mtg16(-/-) mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury and identify potential therapeutic targets to modulate leukocyte output after MI.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA. Electronic address: dutta.partha@mgh.harvard.edu.
authors.forename: Partha
authors.initials: P
authors.lastname: Dutta
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Hendrik B
authors.initials: HB
authors.lastname: Sager
authors.affiliation: Department of Biochemistry, Vanderbilt School of Medicine, Nashville, TN 37235, USA.
authors.forename: Kristy R
authors.initials: KR
authors.lastname: Stengel
authors.affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02144, USA.
authors.forename: Kamila
authors.initials: K
authors.lastname: Naxerova
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Courties
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Borja
authors.initials: B
authors.lastname: Saez
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Lev
authors.initials: L
authors.lastname: Silberstein
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Timo
authors.initials: T
authors.lastname: Heidt
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Sebas
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Wojtkiewicz
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Paolo Fumene
authors.initials: PF
authors.lastname: Feruglio
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: King
authors.affiliation: Department of Cardiac Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02144, USA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Baker
authors.affiliation: Department of Cardiology, Academic Medical Center, University of Amsterdam, P.O. Box 22660, Amsterdam, the Netherlands.
authors.forename: Anja M
authors.initials: AM
authors.lastname: van der Laan
authors.affiliation: Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Borodovsky
authors.affiliation: Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Maarten
authors.initials: M
authors.lastname: Hulsmans
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Hoyer
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Vinegoni
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Di Carli
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: Department of Biochemistry, Vanderbilt School of Medicine, Nashville, TN 37235, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Hiebert
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA. Electronic address: mnahrendorf@mgh.harvard.edu.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009000:Monocytes / Q000502:physiology*; D022423:Myeloid Cells / Q000502:physiology*; D038042:Myelopoiesis / Q000235:genetics; D009203:Myocardial Infarction / Q000276:immunology* / Q000601:surgery; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics
chemical_list: C117411:Cbfa2t3 protein, mouse; C515335:Ccr2 protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D054390:Receptors, CCR2; D012097:Repressor Proteins; D014157:Transcription Factors