Abstract 3881: Acute Myocardial Infarction Increases Wnt Signaling And Activates Progenitor Cells In The Bone Marrow
Bone marrow - derived progenitor cells (BMC) may contribute as an endogenous repair mechanism to the recovery of left ventricular function after acute myocardial infarction (AMI). So far, there are no clinical data demonstrating alterations in the bone marrow (BM) niche after AMI, which may have a functional impact on BM-resident progenitor cells. Therefore, it was the aim of the current analysis to characterize the composition and functional activity of BMC in patients with AMI. Results: We analyzed BMC of 204 patients undergoing BM aspiration within 1 to 8 days after AMI. The overall number of mononuclear cells within the BM did not change over time after AMI. In contrast, however, there was a significant increase in the percentage of CD34+ (p=0.01) and CD133+ (p=0.002) progenitor cells. Importantly, functional activity as assessed by migratory capacity of mononuclear cells towards the chemoattractant SDF-1 was significantly (p=0.007) increased from day 1 to day 8 after AMI. In order to experimentally explore these clinical findings, we induced myocardial infarction in C57Bl6 mice. The induction of myocardial infarction time-dependently increased the number of total BMC with a maximum at 5 days (129±4 %; p<0.001). Likewise, the number of c-kit+sca-1+lin- cells and the number of GM-CFU was increased to 147±17% and 160±19%, respectively. The activation of the bone marrow by AMI was further documented by a significant increase in Wnt signaling, which is known to induce proliferation of hematopoietic stem cells. Thus, the mRNA of the Wnt-target Axin-2 was significantly increased 5 days after AMI (359±34; p<0.001). Activation of canonical Wnt signaling following AMI was further evidenced by using TOP-GAL transgenic mice carrying a β-galactosidase gene driven by a LEF/TCF/β-catenin responsive promoter.
Conclusion: AMI is associated with activation of progenitor cells within the bone marrow, as evidenced by upregulation of the numbers of hematopoietic progenitor cells, their functional activity, and Wnt signaling within days after AMI. These findings, for the first time, document activation of the stem cell niche within the bone marrow following AMI, which may have important implications for the optimal timing of cell therapy using BMC in patients with AMI.