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 PDGFRα⁺/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.