title: Bone marrow Oct3/4+ cells differentiate into cardiac myocytes via age-dependent paracrine mechanisms.
abstract: The mechanisms that govern the capacity of the bone marrow stem cells to generate cardiac myocytes are still unknown. Herein we demonstrate that the cardiomyogenic potential of bone marrow-derived Oct3/4(+)/cKit(+/-)/CXCR4(+/-)/CD34(-)/Sca1(-) cells is governed by age-dependent paracrine/juxtacrine platelet-derived growth factor (PDGF) pathways. Specifically, bone marrow cell cultures from both 3- and 18-month-old mice formed aggregates of Oct3/4(+) cells circumscribed by PDGFRalpha(+)/Oct3/4(-)/Sca1(+) cells. In young (3-month) bone marrow cell cultures, induction of PDGF-AB preceded the induction of cardiac genes and was required for the generation of cardiomyogenesis. Indeed, in old (18-month) cultures, diminished PDGF-B induction was associated with impaired cardiomyogenic potential, despite having Oct3/4 levels similar to those in the young cells. Importantly, supplementation with PDGF-AB specifically restored the cardiac differentiation capacity of the old bone marrow cells. Together these results demonstrate that, regardless of age, the bone marrow niche contains Oct3/4 stem cells that are capable of differentiating into cardiac myocytes. Moreover, this differentiation is governed by age-dependent PDGF-AB-mediated paracrine/juxtacrine pathways that may be essential in the translation of bone marrow cell-mediated cardiomyogenesis.
authors.affiliation: Departments of Medicine, Weill Medical College of Cornell University, New York, USA.
authors.forename: Benedetta A
authors.initials: BA
authors.lastname: Pallante
authors.forename: Inga
authors.initials: I
authors.lastname: Duignan
authors.forename: Daniel
authors.initials: D
authors.lastname: Okin
authors.forename: Andrew
authors.initials: A
authors.lastname: Chin
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bressan
authors.forename: Takashi
authors.initials: T
authors.lastname: Mikawa
authors.forename: Jay M
authors.initials: JM
authors.lastname: Edelberg
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002449:Cell Aggregation; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D008024:Ligands; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018874:Spheroids, Cellular / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D000099254:Organic Cation Transporter 3
chemical_list: D008024:Ligands; D050814:Octamer Transcription Factor-3; D027701:Organic Cation Transport Proteins; D010982:Platelet-Derived Growth Factor; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000099254:Organic Cation Transporter 3; C494174:Pou5f1 protein, mouse; C095477:platelet-derived growth factor AB