title: c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy.
abstract: BACKGROUND
  Hypoxia favors stem cell quiescence, whereas normoxia is required for stem cell activation, but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown.
  
  
  OBJECTIVE
  A balance between hypoxic and normoxic CSCs may be present in the young heart, although this homeostatic control may be disrupted with aging. Defects in tissue oxygenation occur in the old myocardium, and this phenomenon may expand the pool of hypoxic CSCs, which are no longer involved in myocyte renewal.
  
  
  RESULTS
  Here, we show that the senescent heart is characterized by an increased number of quiescent CSCs with intact telomeres that cannot re-enter the cell cycle and form a differentiated progeny. Conversely, myocyte replacement is controlled only by frequently dividing CSCs with shortened telomeres; these CSCs generate a myocyte population that is chronologically young but phenotypically old. Telomere dysfunction dictates their actual age and mechanical behavior. However, the residual subset of quiescent young CSCs can be stimulated in situ by stem cell factor reversing the aging myopathy.
  
  
  CONCLUSIONS
  Our findings support the notion that strategies targeting CSC activation and growth interfere with the manifestations of myocardial aging in an animal model. Although caution has to be exercised in the translation of animal studies to human beings, our data strongly suggest that a pool of functionally competent CSCs persists in the senescent heart and that this stem cell compartment can promote myocyte regeneration effectively, partly correcting the aging myopathy.
authors.affiliation: From the Departments of Anesthesia (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., P.G., J.K., T.H., M. Rota, P.A., A.L.) and Medicine (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., E.I., M.A.P., P.G., J.K., T.H., M. Rota, P.A., A.L.), and Divisions of Cardiovascular Medicine (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., P.G., J.K., T.H., M. Rota, P.A., A.L.), Pulmonary and Critical Care Medicine (E.I., M.A.P., A.M.C.), and Newborn Medicine (M.A.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.forename: Junghyun
authors.initials: J
authors.lastname: Kim
authors.forename: Anna
authors.initials: A
authors.lastname: Czarna
authors.forename: Noel Yan-Ki
authors.initials: NY
authors.lastname: Chan
authors.forename: Sergio
authors.initials: S
authors.lastname: Signore
authors.forename: Barbara
authors.initials: B
authors.lastname: Ogórek
authors.forename: Kazuya
authors.initials: K
authors.lastname: Isobe
authors.forename: Ewa
authors.initials: E
authors.lastname: Wybieralska
authors.forename: Giulia
authors.initials: G
authors.lastname: Borghetti
authors.forename: Ada
authors.initials: A
authors.lastname: Pesapane
authors.forename: Andrea
authors.initials: A
authors.lastname: Sorrentino
authors.forename: Emily
authors.initials: E
authors.lastname: Mangano
authors.forename: Donato
authors.initials: D
authors.lastname: Cappetta
authors.forename: Chiara
authors.initials: C
authors.lastname: Mangiaracina
authors.forename: Mario
authors.initials: M
authors.lastname: Ricciardi
authors.forename: Maria
authors.initials: M
authors.lastname: Cimini
authors.forename: Emeka
authors.initials: E
authors.lastname: Ifedigbo
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.forename: Augustine M
authors.initials: AM
authors.lastname: Choi
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoda
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D019070:Cell Lineage; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D019089:Stem Cell Factor / Q000494:pharmacology* / Q000627:therapeutic use; D055153:Stem Cell Niche; D059505:Telomere Homeostasis
chemical_list: D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit
keywords: stem cell factor