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, H 2 O 2 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 H 2 O 2-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.

The Antisenescence Effect of Exosomes from Human Adipose-Derived Stem Cells on Skin Fibroblasts

“…Previous studies have reported that ADSCs can improve photoaging wrinkles and promote collagen production in photoaged fibroblasts in vitro [ 5 , 6 ]. Despite the tremendous achievements of stem cell therapy, there are still some challenges in clinical application, especially the low survival rate after transplantation [ 10 , 11 ]. So, there is an urgent need to find better ways to use stem cells in the clinic.…”

[Retracted] Mesenchymal Stem Cell‐Derived Exosomes and Their Potential Agents in Hematological Diseases

“…It uncovered more than 1000 clinical trials when we searched the keywords "mesenchymal stem cell" or "mesenchymal stromal cell" in the ClinicalTrials.gov database (http://www.clinicaltrials.gov/, accessed on June 2021). Despite the tremendous achievements made in MSCs therapy [3,[7][8][9][10][11], there are several limitations toward their clinical translation, such as invasive cell collection procedures, orchestrated engraftment steps, low posttransplantation cell viability, poor homing, and multiple doses to maintain the therapeutic effects [12][13][14][15]. Promisingly, accumulating experimental and clinical studies reveal that the powerful therapeutic agents of MSCs are mainly exerted by their paracrine effects, in particularly by exosomes [13,[16][17][18][19].…”

Tripeptidyl Peptidase 1 Regulates Human Trophoblast Cell Proliferation Implying a Role in Placentation

“…MRE11 has been recently identified as a TPP1 downstream target [ 15 ]. In addition to enhancing DNA repair and improving cell survival [ 15 ], MRE11 is also required for cell proliferation [ 16 ].…”

“…MRE11 has been recently identified as a TPP1 downstream target [ 15 ]. In addition to enhancing DNA repair and improving cell survival [ 15 ], MRE11 is also required for cell proliferation [ 16 ]. In human breast cancer cells, MRE11 regulates cell proliferation via signal transducer and activator of transcription 3 (STAT3) [ 17 ].…”