Despite ongoing clinical trials, the optimal time-point of BMC delivery following acute MI remains a point of debate. A review of current literature reveals few studies that have systematically addressed the issue of timing of BMC transplantation14
. This study was designed to determine the effects of timing of BMC delivery following acute MI in a standardized mouse LAD ligation model. Specifically, we have demonstrated that: (1) BMC transplantation in either acute or sub-acute myocardial infarction has a mildly positive effect on cardiac preservation, confirming earlier findings in animals models15
and clinical trials2
; (2) retention of BMC engraftment and preservation of cardiac function are not critically dependent on the timing of delivery; and (3) injection of BMCs into the inflammatory environment of myocardial infarction leads to early proliferation of donor cells, some of which adopt adult hematopoietic phenotypes.
Earlier studies from our laboratory using in vivo
BLI of transplanted BMCs revealed that the cells can effectively home in on and engraft into infarcted myocardium12, 13
. Although the present study confirms the therapeutic effect of BMC transplantation in the setting of acute MI, it also clearly shows that delivery of the cells in the time-window following the hostile acute inflammatory phase (7 days after MI) does not result in extended long-term survival of donor BMCs. In addition, no significant differences were found in the preservation of cardiac function between BMCs injected groups during a 6-week period of observation.
To our knowledge, timing of BMC delivery has thus far not been investigated in experimental models. However, other cell populations, such as BM-derived mesenchymal stem cells7
and fetal cardiomyocytes16
, showed therapeutic improvements in rat models when delivered in a the time-window of 1 to 2 weeks following MI. Most likely, the different observations made in our study are the results of the different cell populations used for transplantation. To represent the present clinical situation, we specifically used unfractionated BMCs. In addition to the survival data, we show that some of the BMCs that engraft intramyocardially seem to be of adult hematopoietic cell phenotype, rather than bone marrow-derived endothelial, endothelial progenitor, or cardiac cells, at least following acute delivery at the time-point tested. These findings strengthen the hypothesis that preservation of cardiac performance by BMC transplantation might be attributable to modulation of the natural process of myocardial inflammation and infarct healing17
. These experiments, however, only provide insight into the phenotype of the transplanted GFP+
donor BMCs, not at the endogenous BMC recruitment process, paracrine action of these cells, or their potential capability to activate resident progenitor cells that may aid in the cardiac repair process.
Investigations aimed to reveal the mechanism(s) by which stem cells might preserve cardiac function have been plenty. Early reports pointed toward the myocardial regeneration by repopulation of BM-derived endothelial cells and/or cardiomyocytes18
; however, subsequent studies failed to support those observations19
. Other proposed mechanisms include donor-host cell fusion and neovascularization by either vasculogenesis and/or secretion of paracrine factors leading to angiogenesis and arteriogenesis20
. Recently, studies have focused on additional mechanisms of action of transplanted BMCs, which could be by a direct paracrine effect on the inflammatory cascade. Burchfield et al. recently reported evidence that BMCs mediate cardiac protection by release of the immunomodulatory cytokine IL-10, leading to decreased intramyocardial accumulation of T-lymphocytes, which translated into reduced LV remodeling21
. Similarly, Ciulla et al. found transplanted BMCs to reduce serum levels of pro-inflammatory cytokines, which are known to contribute to myocardial apoptosis, necrosis, and scar formation22
. These findings, combined with the results presented in the present study, suggest that BM progenitors could ameliorate LV remodeling following MI by continuing to differentiate along the hematopoietic lineage.
The clinical relevance of this study is significant. A recent meta-analysis of randomized clinical trials of BMC transplantation in patients suffering from acute MI found no
significant difference in global LV function when the cells were delivered in either less than 5 days or 5 to 30 days window period2
. The present study provides similar conclusions to the the majority of clinical studies analyzed by Abdel-Latif et al2
. Specifically, long-term survival and modest therapeutic efficacy of BMCs seem to be relatively independent
of timing of cell delivery. Clinically significant improvements of cardiac function in patients suffering from acute MI may be achieved by repeated
cellular transplants, both in the acute and sub-acute phases of myocardial inflammation. Further studies will be needed to test this hypothesis.