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TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway.

ABSTRACT: Background:Poor 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. Methods:Aged 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. Results:In 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. Conclusions:Our 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.

SUBMITTER: Yu K

PROVIDER: S-EPMC7658181 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway.

Yu Kaixiang K Zeng Zhiru Z Cheng Si S Hu Wangxing W Gao Chenyang C Liu Feng F Chen Jinyong J Qian Yi Y Xu Dilin D Zhao Jing J Liu Xianbao X Wang Jian'an J

Frontiers in cell and developmental biology 20201029

<h4>Background</h4>Poor 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 <i>in vivo</i> and <i>in vitro</i>.<h4>Methods</h4>Aged mouse MSCs ...[more]

PMID: 33195247

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Project description:BackgroundMesenchymal stem cells (MSCs) have been recently demonstrated as a promising stem cell type to rescue damaged myocardium after acute infarction. One of the most important mechanisms underlying their therapeutic effects is the secretion of paracrine factors. However, the expression profile of paracrine factors of MSCs in infarcted hearts, especially at single cell level, is poorly defined.Methods and resultsWe aimed to depict the transcriptional profile of paracrine factors secreted by MSCs in vivo, with particular interest in the comparison between normal and infarcted hearts. Bone marrow mesenchymal stem cells were isolated and injected into mice hearts immediately after infarction surgery. Bioluminescence imaging (BLI) indicated a proportion of cells still alive even up to 10 days post surgery. Paralleled with survived cells, cardiac function was significantly improved after MSC injection compared to that in PBS-injected mice, indicated by MRI and histology. Despite increased number of vessels in MSC-injected hearts, endothelial cells and cardiomyocytes transdifferentiation were not observed in infarcted hearts 5 days after infarction. Furthermore, laser capture microdissection (LCM) followed by high through-put real time PCR was employed in our study, uncovering that the injected MSCs, compared to local cardiomyocytes, displayed elevated levels of secreted factors. To further investigate the regulation of those factors, we performed single cell analysis to dissect the gene expression profile of MSCs at single cell level in infarcted and normal hearts, respectively. Consistent with the in vivo observation, a similar regulation pattern of those factors was detected in cultured MSCs under hypoxia.ConclusionsOur study, for the first time, elucidated gene expression profiles, as well as regulation of paracrine factors, of MSCs at single cell level in vivo, indicating that paracrine factors from MSCs account for the improvement of cardiac function after infarction.

Dataset Information

TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway.

Publications

TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway.

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