title: Allogenic adipose-derived stem cell therapy overcomes ischemia-induced microvessel rarefaction in the myocardium: systems biology study.
abstract: Myocardial microvascular loss after myocardial infarction (MI) remains a therapeutic challenge. Autologous stem cell therapy was considered as an alternative; however, it has shown modest benefits due to the impairing effects of cardiovascular risk factors on stem cells. Allogenic adipose-derived stem cells (ASCs) may overcome such limitations, and because of their low immunogenicity and paracrine potential may be good candidates for cell therapy. In the present study we investigated the effects of allogenic ASCs and their released products on cardiac rarefaction post MI.
  
  
  
  Pig subcutaneous adipose tissue ASCs were isolated, expanded and GFP-labeled. ASC angiogenic function was assessed by the in-vivo chick chorioallantoic membrane (CAM) model. Pigs underwent MI induction and 7 days after were randomized to receive: allogenic ASCs (intracoronary infusion); conditioned media (CM; intravenous infusion); ASCs + CM; or PBS/placebo (control). Cardiac damage and function were monitored by 3-T cardiac magnetic resonance imaging upon infusion (baseline CMR) and 1 and 3 weeks thereafter. We assessed in the myocardium: microvessel density; angiogenic markers (CD105, CD31, TF, VEGFR2, VEGFR1, vWF, eNOS, CD62); collagen deposition; and reparative fibrosis (TGFβ/TβRII/collagen). Differential proteomics of ASCs and CM was performed to characterize the ASC protein signature.
  
  
  
  CAM indicated a significant ASC proangiogenic capacity. In pigs after MI, only PBS/placebo animals displayed an impaired cardiac function 3 weeks after infusion (p < 0.05 vs baseline). Administration of ASCs + CM significantly enhanced neovessel formation and favored cardiac repair post MI (p < 0.05 vs the other groups). Molecular markers of angiogenesis were significantly upregulated both at transcriptional and protein levels (p < 0.05). The in-silico bioinformatics analysis of the ASC and CM proteome (interactome) indicated activation of a coordinated protein network involved in the formation of microvessels and the resolution of rarefaction.
  
  
  
  Coadministration of allogenic ASCs and their CM synergistically contribute to the neovascularization of the infarcted myocardium through a coordinated upregulation of the proangiogenic protein interactome.
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain.|CIBERCV, ISCIII, Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Vilahur
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Oñate
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Cubedo
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Béjar
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Arderiu
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain.|CIBERCV, ISCIII, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Peña
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain.|CIBERCV, ISCIII, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Casaní
authors.affiliation: Radiology Unit (HSCSP), Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Gutiérrez
authors.affiliation: Radiology Unit (HSCSP), Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Capdevila
authors.affiliation: Cardiology Unit (HSCSP), Barcelona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Pons-Lladó
authors.affiliation: Cardiology Unit (HSCSP), Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Carreras
authors.affiliation: Radiology Unit (HSCSP), Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Hidalgo
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC) Hospital de la Santa Creu i Sant Pau (HSCSP), c/Sant Antoni Ma Claret 167, 08025, Barcelona, Spain. lbadimon@csic-iccc.org.|CIBERCV, ISCIII, Madrid, Spain. lbadimon@csic-iccc.org.|Cardiovascular Research Chair, UAB (Autonomous University of Barcelona), Barcelona, Spain. lbadimon@csic-iccc.org.
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D064987:Cell- and Tissue-Based Therapy; D006801:Humans; D055806:Microvessels / Q000254:growth & development / Q000503:physiopathology; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D012307:Risk Factors; D033581:Stem Cell Transplantation; D013552:Swine; D049490:Systems Biology; D014182:Transplantation, Autologous
keywords: Allogenic adipose-derived stem cells; Angiogenesis; Conditioned media; Myocardial infarction; Proteomics; Systems biology