Abstract 940: Human Mesenchymal Precursor Cells Secrete Paracrine Factors which Protect Cardiac Myocytes, Prevent LV Remodelling, and Improve Functional Cardiac Recovery Following Acute Ischemia
Background: We have previously demonstrated that intramyocardial (IM) injection of human immunoselected Stro-1 positive mesenchymal precursor cells (MPC) induces arteriogenesis, enhances cardiomyocyte survival, and improves functional cardiac recovery following MI in athymic rats. Here we examined the role of paracrine factors released by MPC on these outcomes.
Methods: Human immunoselected Stro-1+ MPC were isolated and bulk expanded to passages 3– 4 in serum supplemented growth medium. Conditioned medium (CM) from 10^6 cells was generated by replacing growth medium with fresh serum-free (SF) medium for 48h. MI was induced in athymic rats and baseline echo was performed 24h later. Concentrated CM or saline was injected IM at 48h post-MI (n=6/group). A second echo study was performed at 1 week post-injection and tissue was harvested for analyses.
Results: Intramyocardial injection of CM derived from the cultured MPC had dramatic effects on survival and size of cardiomyocytes at the peri-infarct region. Rats receiving CM demonstrated 30% lower numbers of apoptotic myocytes than those receiving saline (p=0.05), and a 17.4% increase in mean myocyte cross-sectional area (p=0.05). Whereas ischemic rats receiving saline demonstrated a decrease in fractional area change (FAC) of 18.7+/−6% and a decrease in anterior wall thickness of 10.4+/−2%, rats receiving CM demonstrated an increase in FAC of 10.5+/−5% (p=0.03) and an increase in wall thickness of 14.1+/− 5.1% (p<0.05). Moreover, CM injection was accompanied by 43% reduction in mean LV end diastolic volumes compared with saline (p=0.04), Using antibody-capture arrays to screen the CM obtained from multiple batches of cultured MPC, we have identified specific patterns of soluble factors which are inducible under hypoxic conditions and which may be responsible for the paracrine effects of the implanted MPC.
Conclusions: Paracrine effects of soluble factors secreted by human immunoselected and culture-expanded Stro-1 MPC may contribute significantly to the positive effects of these cells on cardiomyocyte survival, LV remodeling and functional cardiac recovery after acute ischemia.