Abstract 939: Human Mesenchymal Precursor Cells Promote Cardiomyocyte Survival and Hypertrophy, And Improve Cardiac Function Following Acute Infarction
Background: Using a novel monoclonal antibody, CA12, we have recently immunoselected a population of highly enriched multipotential mesenchymal precursor cells (MPC) from human bone marrow. Here, we examined the effects of MPC on cardiac functional recovery after acute ischemia and cardiomyocyte (CMy) function.
Methods: MPC immunoselected for CA12 were bulk expanded and used at 5th passage. MI was induced in athymic rats and baseline echo was performed 24h later. At 48h post-MI rats were randomized to receive saline (n=6) or 10^6 MPC by direct intramyocardial injection (IM, n=11) or tail vein delivery (IV, n=7). At 2 weeks post-injection a second echo study was performed and tissues were harvested for analyses. In in vitro experiments isolated neonatal rat CMy were cultured with conditioned medium (CM) from MPC or control medium, and total protein content was measured at 48h.
Results: Passage 5 MPC were positive for Stro-1/ CD13/ CD29/ CD44/ CD90/ CD146 and negative for CD34. IM injection of MPC 48h post-MI resulted in over 50% greater von Willebrand Factor-positive capillary density and 33% lower numbers of TUNEL-positive apoptotic CMy in the peri-infarct region cf. saline (both p=0.04). Moreover, IM injection of MPC augmented hypertrophy of surviving CMy, resulting in a 12.2% increase in CMy cross-sectional area in the peri-infarct region cf. saline (p=0.05). IM injection of MPC post-MI also inhibited LV dysfunction, with an increase in fractional shortening (FS) of 21.1±/−8.1% over the treatment period cf. a decrease of 19.2±/−8.6% in saline-treated rats, p=0.03. In contrast, IV delivery of MPC had no effect on FS. MPC CM stimulated 2-fold greater synthesis of cytoplasmic proteins in neonatal rat CMy than control medium (p=0.001). Cytokine arrays indicate specific patterns of soluble factors which may be responsible for these paracrine effects of MPC.
Conclusion: Direct IM delivery of immunoselected human MPC following acute MI resulted in enhanced CMy survival and hypertrophy, and increased vascularity in the peri-infarct region, and inhibition of LV dysfunction. Soluble paracrine factors released by these cells may contribute to these beneficial outcomes in part through induction of protein synthesis and hypertrophy of CMy.