Abstract 9402: Myocardial Infarction-Induced Acute Inflammation Impairs Therapeutic Efficacy of Bone Marrow Cells
Delivery of bone marrow cells (BMCs) to infarcted myocardium has been reported to be therapeutic in most animal experiments, but results in similar clinical trials of autologous BMC therapy have been less robust. We have demonstrated that donor MI impairs BMC therapeutic efficacy in mice. However, the mechanism of this impairment remains unknown. Acute MI leads to a localized host inflammatory response. We hypothesized that MI leads to an increased or activated inflammatory state in the bone marrow that impairs the therapeutic efficacy of BMCs. To investigate this, we implanted BMCs from healthy or post-MI donor mice under ultrasound guidance. Donors and recipients were subjected to MI by permanent left coronary artery ligation. MI recipients were always identical from experiment to experiment. Donor bone marrow at 3 days post-MI showed several characteristics consistent with increased inflammation, including fewer CD11c+ dendritic cells, increased MHC Class II expression on B cells, and more Ly6Chigh inflammatory myeloid cells. Donor BMCs harvested at varying times post-MI were increasingly impaired over the first 3 days but were less impaired when harvested after day 5, consistent with the time course of an inflammatory response (see figure). Recipient EF is shown measured at 28 days post-recipient-MI in groups injected with BMCs harvested at various times after donor MI. Serum from donors at 1 and 3 days post-MI but not 7 days showed an increase in several cytokines and related proteins including G-CSF, IL-1β, IL-1Ra, IL-6, MCP-1, TIMP-1 and TREM-1. Notably, anti-inflammatory treatment of donor mice post-MI with dexamethasone prevented the BMC impairment. BMCs harvested from sham-operated mice in which skin and bone were still wounded with no artery ligation were not substantially impaired. Our findings suggest that MI-induced acute inflammation impairs BMC therapeutic efficacy.
- © 2010 by American Heart Association, Inc.