title: Cardiac progenitor cell commitment is inhibited by nuclear Akt expression.
abstract: BACKGROUND
  Stem cell therapies to regenerate damaged cardiac tissue represent a novel approach to treat heart disease. However, the majority of adoptively transferred stem cells delivered to damaged myocardium do not survive long enough to impart protective benefits, resulting in modest functional improvements. Strategies to improve survival and proliferation of stem cells show promise for significantly enhancing cardiac function and regeneration.
  
  
  OBJECTIVE
  To determine whether injected cardiac progenitor cells (CPCs) genetically modified to overexpress nuclear Akt (CPCeA) increase structural and functional benefits to infarcted myocardium relative to control CPCs.
  
  
  RESULTS
  CPCeA exhibit significantly increased proliferation and secretion of paracrine factors compared with CPCs. However, CPCeA exhibit impaired capacity for lineage commitment in vitro. Infarcted hearts receiving intramyocardial injection of CPCeA have increased recruitment of endogenous c-kit cells compared with CPCs, but neither population provides long-term functional and structural improvements compared with saline-injected controls. Pharmacological inhibition of Akt alleviated blockade of lineage commitment in CPCeA.
  
  
  CONCLUSIONS
  Although overexpression of nuclear Akt promotes rapid proliferation and secretion of protective paracrine factors, the inability of CPCeA to undergo lineage commitment hinders their capacity to provide functional or structural benefits to infarcted hearts. Despite enhanced recruitment of endogenous CPCs, lack of functional improvement in CPCeA-treated hearts demonstrates CPC lineage commitment is essential to the regenerative response. Effective stem cell therapies must promote cellular survival and proliferation without inhibiting lineage commitment. Because CPCeA exhibit remarkable proliferative potential, an inducible system mediating nuclear Akt expression could be useful to augment cell therapy approaches.
authors.affiliation: San Diego State Heart Institute, San Diego State University, CA, USA.
authors.forename: Kimberlee M
authors.initials: KM
authors.lastname: Fischer
authors.forename: Shabana
authors.initials: S
authors.lastname: Din
authors.forename: Natalie
authors.initials: N
authors.lastname: Gude
authors.forename: Mathias H
authors.initials: MH
authors.lastname: Konstandin
authors.forename: Weitao
authors.initials: W
authors.lastname: Wu
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000235:genetics; D002467:Cell Nucleus / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D006131:Growth Inhibitors; D051057:Proto-Oncogene Proteins c-akt