Cardiopulmonary support and physiology
Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis

https://doi.org/10.1016/j.jtcvs.2007.07.071Get rights and content
Under an Elsevier user license
open archive

Objectives

This study explored the novel strategy of hypoxic preconditioning of bone marrow mesenchymal stem cells before transplantation into the infarcted heart to promote their survival and therapeutic potential of mesenchymal stem cell transplantation after myocardial ischemia.

Methods

Mesenchymal stem cells from green fluorescent protein transgenic mice were cultured under normoxic or hypoxic (0.5% oxygen for 24 hours) conditions. Expression of growth factors and anti-apoptotic genes were examined by immunoblot. Normoxic or hypoxic stem cells were intramyocardially injected into the peri-infarct region of rats 30 minutes after permanent myocaridal infarction. Death of mesenchymal stem cells was assessed in vitro and in vivo after transplantation. Angiogenesis, infarct size, and heart function were measured 6 weeks after transplantation.

Results

Hypoxic preconditioning increased expression of pro-survival and pro-angiogenic factors including hypoxia-inducible factor 1, angiopoietin-1, vascular endothelial growth factor and its receptor, Flk-1, erythropoietin, Bcl-2, and Bcl-xL. Cell death of hypoxic stem cells and caspase-3 activation in these cells were significantly lower compared with that in normoxic stem cells both in vitro and in vivo. Transplantation of hypoxic versus normoxic mesenchymal stem cells after myocardial infarctiion resulted in an increase in angiogenesis, as well as enhanced morphologic and functional benefits of stem cell therapy.

Conclusions

Hypoxic preconditioning enhances the capacity of mesenchymal stem cells to repair infarcted myocardium, attributable to reduced cell death and apoptosis of implanted cells, increased angiogenesis/vascularization, and paracrine effects.

Abbreviations and Acronyms

dp/dt
rate of pressure rise
EPO
erythropoietin
EPOR
cognate receptor of erythropoietin
GFP
green fluorescent protein
HIF-1α
hypoxia-inducible factor-1α
H-MSC
hypoxic mesenchymal stem cell
HP
hypoxic preconditioning
LVEDP
left ventricular end-diastolic pressure
LVSP
left ventricular systolic pressure
MI
myocardial infarction
MSC
mesenchymal stem cell
N-MSC
normoxic mesenchymal stem cell
PBS
phosphate-buffered saline solution
TUNEL
terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling
VEGF
vascular endothelial growth factor

CTSNet classification

30
31
34

Cited by (0)

This work was supported by National Institutes of Health grants NS 37372, NS 045155, and NS 045810 and American Heart Association and Bugher Foundation (AHA-Bugher) Awards 0170064N and 0170063N. The work was also supported by National Institutes of Health grant C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.