Abstract 3759: Attenuated Endogenous Regenerative Capacity of Skeletal Muscle-derived c-kit+ Progenitor Cells in Patients With Chronic Heart Failure
Patients (Pt) with chronic heart failure (CHF) are restricted in their physical activity due to skeletal muscle (SM) atrophy. Interestingly, the SM contains tissue-derived progenitor cells, which might promote regeneration. It is currently unknown into which lineages these cells differentiate and whether their number is attenuated in Pt with CHF.
Methods: Mononuclear cells (MNC) were recovered from SM. The population of c-kit+ cells, which was negative for hematopoietic lineage (lin) markers CD45/B220, CD3e, Ter119, CD11b, Gr-1 was selected by FACS sorting from MNCs and further characterized using antibodies: anti-CD34 (stem cell marker), anti-flk (endothelial lineage marker), anti-E-cadherin (epithelial lineage marker). The potential of c-kit+/lin− cells to differentiate was assessed in cell culture as well. Additionally, the number of c-kit+ cells was determined by immunohistochemistry in SM biopsies of forty Pt with CHF (LVEF 21±2%) and fourteen age-matched healthy subjects (HS). Myocyte-lineage and endothelial-lineage commitment of c-kit+ cells was recognized by co-expression of myocyte enhancer factor 2 (MEF2) or von Willebrand factor, respectively.
Results: SM-derived c-kit+/lin− cells co-expressed CD34 in 73±4% of the cases, 6±2% of c-kit+/lin- cells were positive for the endothelial lineage marker flk, and 2±1% expressed E-cadherin suggestive of an epithelial lineage commitment, respectively. After 20 days in culture, c-kit+/lin− had adopted the phenotype of mature epithelial, endothelial as well as smooth muscle cells and expressed marker proteins of the respective lineages. In CHF, the number of c-kit+ cells in the SM (23±2 cells/cm2 SM area) was 70% lower in comparison with healthy subjects (77±14 cells/cm2, p<0.05 vs. CHF). The amount of c-kit/MEF2+ myocyte precursor cells and of c-kit/vWF+ endothelial precursor cells was found to be reduced by 63% and 56% in CHF (p<0.05 vs. HS), respectively, which is suggestive of an attenuated cell differentiation.
Conclusion: The SM contains c-kit+/lin− progenitor cells, which give rise to different cell lineages. The reduced number and function of tissue-derived c-kit+ cells in advanced CHF might partially explain the impaired endogenous SM regeneration in these patients.