title: Hypoxia-preconditioned mesenchymal stromal cells improve cardiac function in a swine model of chronic myocardial ischaemia.
abstract: OBJECTIVE
  Cell loss during cardiac injection and hostility of the host-tissue microenvironment have the potential to diminish the overall effect of stem cell therapy. The purposes of this study were to evaluate the effect of a hypoxic preconditioning of mesenchymal stromal cells (MSC), to determine its safety and effectiveness, and to improve the efficacy of cell therapy using MSC in the setting of chronic myocardial ischaemia in swine.
  
  
  METHODS
  Myocardial ischaemia was induced by an ameroid constrictor. Human MSC were cultured under normoxic (20% O2) or hypoxic conditions (1.5% O2) before transplantation. One month after ischaemia, pigs were randomly assigned to saline injection (sham), and 1 × 10(6)/kg normoxic or hypoxic MSC transplantation into the ischaemic inferior-lateral zone.
  
  
  RESULTS
  Twenty-seven pigs were operated on and the mortality rate was 33.3%. The remaining 18 animals were randomly assigned to sham (n = 4), normoxic (n = 8) or hypoxic MSC (n = 6) treatment. Global systolic (left ventricle ejection fraction, P = 0.04) and diastolic (E/Ea, P = 0.008) functions were increased in the hypoxic group compared with other groups. The peak of 2-dimensional longitudinal strain was less altered in the hypoxic group compared with other groups (P < 0.001). Haemodynamic data showed that dP/dT max was improved in the hypoxic group compared with the other group (P < 0.01). Capillary density was increased in the hypoxic group (P = 0.001). MSC density was significantly higher in the ischaemic zone in the hypoxic group (P < 0.01).
  
  
  CONCLUSIONS
  MSC engraftment with hypoxic preconditioning significantly improves capillary density and cell survival, resulting in improvement in global, regional and diastolic left ventricular functions. This highlights the therapeutic potential of transplanting hypoxic-preconditioned MSC in the setting of chronic ischaemic heart failure.
authors.affiliation: Adaptation cardiovasculaire à líschémie, INSERM, Pessac, France.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Jaussaud
authors.forename: Matthieu
authors.initials: M
authors.lastname: Biais
authors.forename: Joachim
authors.initials: J
authors.lastname: Calderon
authors.forename: Jean
authors.initials: J
authors.lastname: Chevaleyre
authors.forename: Pascale
authors.initials: P
authors.lastname: Duchez
authors.forename: Zoran
authors.initials: Z
authors.lastname: Ivanovic
authors.forename: Thierry
authors.initials: T
authors.lastname: Couffinhal
authors.forename: Laurent
authors.initials: L
authors.lastname: Barandon
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D004195:Disease Models, Animal; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D006651:Histocytochemistry; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000601:surgery*; D011897:Random Allocation; D013552:Swine