Abstract
BackgroundPoor cell survival after transplantation restricts the therapeutic potential of mesenchymal stem cell (MSC) transplantation into infarcted hearts, particularly in older individuals. TPP1, a component of the shelterin complex that is involved in telomere protection, is highly expressed in young MSCs but declines in aged ones. Here, we explore whether TPP1 overexpression in aged mouse MSCs improves cell viability in vivo and in vitro.MethodsAged mouse MSCs overexpressing TPP1 were injected into the peri-infarct area of the mouse heart after left anterior descending coronary artery ligation. In parallel, to evaluate cellular-level effects, H2O2 was applied to MSCs in vitro to mimic the microenvironment of myocardial injury.ResultsIn vivo, the transplantation of aged MSCs overexpressing TPP1 resulted in improved cell survival, enhanced cardiac function, and reduced fibrosis compared to unmodified aged MSCs. In vitro, TPP1 overexpression protected aged MSCs from H2O2-induced apoptosis and enhanced DNA double-strand break (DSB) repair. In addition, the phosphorylation of AKT and the key DSB repair protein MRE11 were both significantly upregulated in aged MSCs that overexpressed TPP1.ConclusionsOur results reveal that TPP1 can enhance DNA repair through the AKT/MRE11 pathway, thereby improving the therapeutic effects of aged MSC transplantation and offering significant potential for the clinical application of autologous transplantation in aged patients.
Highlights
Mesenchymal stem cells (MSCs) are a promising cell type for treating ischemic heart diseases due to their multipotency, capacity for self-renewal, and immune-privileged status (Williams et al, 2011; Broughton and Sussman, 2016; Golpanian et al, 2016)
TPP1 expression was found to be upregulated in SIRT1-overexpressing aged MSC (OMSC), which significantly enhanced the ability of these cells to survive after injection following myocardial infarction (Chen et al, 2014)
We found that the level of TPP1 expression was significantly decreased in OMSCs compared to young MSCs (Supplementary Figure 2A); we chose to overexpress TPP1 in OMSCs (Supplementary Figure 2B)
Summary
Mesenchymal stem cells (MSCs) are a promising cell type for treating ischemic heart diseases due to their multipotency, capacity for self-renewal, and immune-privileged status (Williams et al, 2011; Broughton and Sussman, 2016; Golpanian et al, 2016). MSCs from older patients (the source of autologous stem cell therapy) have shorter telomere length than those of their young, healthy counterparts, as well as impaired stem cell properties, including proliferation, differentiation, and paracrine secretion. These observations likely explain the fact that clinical trials of autologous cell transplantation show limited therapeutic effects in the setting of myocardial infarction in older patients (Nurkovic et al, 2016). Telomere length decreases with aging, and some premature aging syndromes have been linked to shelterin protein mutations, including in TIN2, TRF1, and TRF2 (Carroll and Ly, 2009) It is unknown whether TPP1 plays a part in DNA damage and repair in aged MSCs or whether targeting damage and repair impacts the therapeutic efficacy of these cells. We explore whether TPP1 overexpression in aged mouse MSCs improves cell viability in vivo and in vitro
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