Abstract 4293: Concentration Dependent Effects of Allogenic Mesenchymal Precursor Cell Injections on Structural Remodeling Following Myocardial Infarction
Targeted delivery of expanded bone marrow cells, such as specific mesenchymal precursor cell (MPC) lines, can modify LV remodeling following myocardial infarction (MI). However, whether and to what degree LV extracellular remodeling may be affected by MPC injection post-MI, and whether these effects are concentration specific remain unknown. Accordingly, collagen turnover (COLLturn), representative classes of matrix metalloproteinases (MMPs), MMP inhibitors (TIMPs) were quantified following delivery of increasing concentrations of MPCs post-MI. Allogenic MPCs were expanded from sheep bone marrow, and direct intra-myocardial injection performed within the border zone (BZ) one hour following MI induction (coronary ligation) in sheep at the following concentrations: 25×106 (BM25, n=5),75 ×106(BM75, n=5), 225 ×106(BM225, n=7), 450 ×10 6(BM450, n=6), and MPC free media only (MI only;n=7). LV end-diastolic volume (EDV; echo) was measured at 8 weeks post-MI/injection. COLLturn was measured by plasma telopeptides (ICTP), and abundance of MMP-1, MMP-2, membrane type (MT1-MMP), TIMP-1 and TIMP-4 were examined in the BZ and MI regions. MPC injection reduced LV dilation, but this effect was attenuated at higher MPC concentrations (TABLE⇓). COLLturn was increased in the low MPC group. In the BZ of the low MPC groups, MMP-1 was reduced and MMP-2 reduced by over 30% within the MI region with higher MPC concentrations. MT1-MMP, TIMP-1 and TIMP-4 levels were reduced within the BZ in all MPC groups. The unique findings of this study were 2-fold. First, allogenic MPC injections reduced the degree of collagen turnover and reduced LV dilation post-MI, but this effect was MPC concentration dependent. A mechanism for these effects was a differential cell concentration dependent effect on MMP and TIMP levels. Thus, MPC injections influence determinants of LV structural remodeling which are cell-concentration dependent.
This research has received full or partial funding support from the American Heart Association, AHA National Center.