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Increase of ABCG2/BCRP+ side population stem cells in myocardium after ventricular unloading
Jeremias Wohlschlaeger1, Bodo Levkau, Atsushi Takeda
1Department of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
Insights
Ventricular unloading significantly increases cardiac stem cells, specifically side population cells (SPCs) and c-kit positive cells. This suggests stem cell proliferation contributes to reverse cardiac remodeling and improved heart function.
Area of Science:
- Cardiovascular Science
- Stem Cell Biology
- Cardiac Regeneration
Background:
- Ventricular unloading leads to decreased cardiomyocyte DNA content and increased diploid cardiomyocytes, implying numerical cardiomyocyte increase.
- No mitoses were observed to explain cardiomyocyte proliferation, suggesting alternative mechanisms.
- The heart contains stem cell populations like c-kit (CD117)(+) stem cells and side population cells (SPCs) that may proliferate post-unloading.
Purpose of the Study:
- To investigate the proliferation of ABCG2(+) side population cells (SPCs) and CD117(+) stem cells after ventricular unloading.
- To determine if stem cell populations increase in the myocardium following unloading.
Main Methods:
- Paired myocardial samples were analyzed before and after left ventricular assist device (LVAD) implantation.
- Immunohistochemistry was used to quantify ABCG2, c-kit/CD117, and MEF-2 expressing cells.
- Cell counts were morphometrically determined and correlated with mean cardiomyocyte DNA content.
Main Results:
- A significant increase in SPCs (0.00013% to 0.0011%) and cells co-expressing c-kit and MEF-2 (0.013% to 0.035%) was observed after unloading (p = 0.001).
- Significant positive correlations were found between SPCs and c-kit/MEF-2 co-expressing cells (p = 0.007 and 0.01).
- No correlation was observed between SPC numbers and mean cardiomyocyte DNA content.
Conclusions:
- Ventricular unloading significantly increases SPCs in the myocardium.
- Stem cell proliferation appears to play a role in reverse cardiac remodeling.
- Proliferating stem cells may differentiate into cardiomyocytes or endothelial cells, potentially improving cardiac function.
Background:
A significant decrease in mean cardiomyocyte DNA content and increased numbers of diploid cardiomyocytes after unloading has been demonstrated, suggesting a numerical increase of cardiomyocytes. Despite a thorough search in that study, no mitoses explaining a potential net increase of cardiomyocytes has been observed. The heart harbors several stem cell populations, including c-kit (CD117)(+) stem cells and side population cells (SPC), which may proliferate after unloading and thus contribute to the generation of diploid cardiomyocytes. In this study we sought to determine, whether there is an increase of ABCG2(+) SPC and CD117(+) stem cells after unloading.
Methods:
In paired myocardial samples (prior to and after LVAD), the number of cells with immunoexpression of ABCG2, c-kit/CD117 and MEF-2 was assessed by immunohistochemistry. Their number was morphometrically determined and these data were correlated with the mean cardiomyocyte DNA content.
Results:
A significant increase of SPC and cells with coexpression of c-kit and MEF-2 after unloading was observed from 0.00013% in CHF to 0.0011%, and 0.013% to 0.035%, respectively after unloading (p = 0.001). A significant positive correlation between both SPC and cells with coexpression of c-kit and MEF-2 expression was observed (p = 0.007 and 0.01). No correlation was found between the number of SPC and the mean cardiomyocyte DNA content.
Conclusions:
SPC are increased significantly in the myocardium after ventricular unloading, suggesting a role for stem cell proliferation during "reverse cardiac remodeling." These cells might proliferate and commit to different cell lineages, such as cardiomyocytes or endothelium, and thus ameliorate cardiac function.
