A Clonal Population of Allogeneic Bone Marrow Fibroblasts Indirectly Mitigates Damage in Myocardial Infarction

Background:Reports of cell-based cardiac repair have been inconsistent, both among studies and within a single study. This is particularly true in response to the infusion of various preparations of marrow cells including mesenchymal stem/stromal cells (MSC). While there are many potential explanations for these inconsistent outcomes, we hypothesized that heterogeneity among the cells infused may be a contributing factor. To address this possibility we used an immortalized clonal population of canine marrow fibroblasts (DS-1) as a consistent therapeutic infused 2 weeks after an ischemia-reperfusion induced myocardial infarction (MI) in the canine model. Methods and Results:MI was induced in six dogs through percutaneous trans luminal catheterization. At 2 weeks post-MI, cardiac magnetic resonance (CMR) imaging demonstrated deterioration of left ventricular (LV) ejection fraction (EF) in all six dogs. After this initial CMR study, dogs were infused intravenously with either vehicle (as control) or DS-1 cells (107cells/kg). At 4 weeks post infusion, (6 weeks post MI) the DS-1 treated dogs had significantly better preserved LVEF (54.2 ± 1.2 %) compared to control dogs (47.6 ± 2.3 %; p = 0.01). The DS-1 treated group also had better LV diastolic function compared to controls (15.2 ± 1.2 compared to 23.0 ± 1.0, respectively; p< 0.001) for left atrial volume index; and 7.3 ± 1.2 vs. 14.6 ± 1.3, respectively, p = 0.002 for mitral E/e’). Although there was no statistically significant difference in arteriole density and fibrotic/infarct size between these two groups, the DS-1 treated animals had an increased amount of uniform collagen orientation, indicating a more parallel alignment of the collagen fibers in the treated dogs, which may have contributed to improved diastolic function. Conclusion: Our study demonstrated a therapeutic benefit of a single intravenous infusion of DS-1 cells during the subacute MI period. Based on cell out-growth and DS-1 specific PCR assays there were no detectable DS-1 cells in the dogs after 48hours. This corroborates previous studies that also indicated DS-1 cells do not engraft, but are sequestered and cleared in the lung within 48 hours. Given that circulating monocytes express activation antigens within hours of DS-1 infusion and that we previously showed monocytes in contact with this class of fibroblasts express genes associated with multicellular organismal development, we hypothesize that the DS-1 effect is indirect and mediated by monocyte derived activities. Further research is warranted to determine the precise mechanism responsible for this therapeutic benefit.