A repair "kit" for the infarcted heart

Abstract

Transplanted, c-kit expressing marrow-derived progenitors can enhance the function of an infarcted heart, but the mechanism remains unclear. In this issue of Cell Stem Cell, Loffredo et al. (2011) provide evidence that hematopoietic precursors do not differentiate into new cardiomyocytes but, rather, stimulate production of new cardiomyocytes from endogenous progenitors.

Figure 1. Genetic lineage tracing system for the detection of cardiomyocytes regeneration

The constitutively active β-actin promoter drives expression of a loxP flanked β-galactosidase gene (β-gal; shown in blue). In the presence of cre-recombinase, the β-gal gene is floxed out, now allowing the β-actin promoter to drive EGFP expression (shown in green). In this double transgenic system, the Cre recombinase is under the transcriptional control of the Myh6 promoter, confining expression to mature cardiomyocytes. The cre-recombinase is also fused to the mutant estrogen receptor “Mer” which constrains the protein to the cytoplasm until tamoxifen is present. By administering a daily dose of tamoxifen to 6 week old mice for two weeks, Loffredo et al. were able to label 80% of mature cardiomyocytes permanently green. Following myocardial infarction, this percentage falls to 60% in the infarct border zone as new cardiomyocytes arise. If, at the time of myocardial infarction, bone marrow derived c-kit⁺ cells are administered to the heart, even more new cardiomyocytes are made and the percentage of green-cardiomyocytes in the infarction border zone falls to only 50% of cardiomyocytes. No increase in new cardiomyocytes is seen over sham control if mesenchymal stem cells (MSCs) or resident cardiac c-Kit+ cells are added.