Decline in cellular function of aged mouse c-kit+ cardiac progenitor cells

Abstract

Therapeutic use of c-kit⁺ cardiac progenitor cells (CPCs) is being evaluated for regenerative therapy in older patients with ischemic heart failure. Our understanding of the biology of these CPCs has however, largely come from studies of young cells and animal models. In the present study we examined characteristics of CPCs isolated from young (3 months) and aged (24 month) mice that could underlie the diverse outcomes reported for CPC-based therapeutics. We observed morphological differences and altered senescence indicated by increased senescence associated markers β-galactosidase and p16 mRNA in aged CPCs. The aged CPCs also proliferated more slowly than their young counterpart and expressed lower levels of the stemness marker LIN28. We subsequently treated the cells with Dex, routinely used to induce commitment in CPCs, for 7 days and analysed expression of cardiac lineage marker genes. While MEF2C, GATA4, GATA6 and PECAM mRNAs were significantly upregulated in response to Dex treatment in young CPCs, their expression was not increased in aged CPCs. Interestingly, Dex treatment of aged CPCs also failed to increase mitochondrial biogenesis and expression of the mitochondrial proteins Complex III and IV, consistent with a defect in mitochondria complex assembly in the aged CPCs. Dex treated aged CPCs also had impaired ability to upregulate expression of paracrine factor genes and the conditioned media from these cells had reduced ability to induce angiogenesis in vitro. These findings could impact the design of future CPC-based therapeutic approaches for the treatment of older patients suffering from cardiac injury.

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