Sequential transplantation of exosomes and mesenchymal stem cells pretreated with a combination of hypoxia and Tongxinluo efficiently facilitates cardiac repair

Abstract

Background Bone marrow-derived mesenchymal stem cells (MSCs), which possess immunomodulatory characteristic, are promising candidates for the treatment of acute myocardial infarction (AMI). However, the low retention and survival rate of MSCs in the ischemic heart limit their therapeutic efficacy. Strategies either modifying MSCs or alleviating the inflammatory environment, which facilitates the recruitment and survival of the engrafted MSCs, may solve the problem. Thus, we aimed to explore the therapeutic efficacy of sequential transplantation of exosomes and combinatorial pretreated MSCs in the treatment of AMI. Methods Exosomes derived from MSCs were delivered to infarcted hearts through intramyocardial injection followed by the intravenous infusion of differentially pretreated MSCs on Day 3 post-AMI. Enzyme linked immunosorbent assay (ELISA) was performed to evaluate the inflammation level as well as the SDF-1 levels in the infarcted border zone of the heart. Echocardiography and histological analysis were performed to assess cardiac function, infarct size, collagen area and angiogenesis. Results Sequential transplantation of exosomes and the combinatorial pretreated MSCs significantly facilitated cardiac repair compared to AMI rats treated with exosomes alone. Notably, compared to the other three methods of cotransplantation, combinatorial pretreatment with hypoxia and Tongxinluo (TXL) markedly enhanced the CXCR4 level of MSCs and promoted recruitment, which resulted in better cardiac function, smaller infarct size and enhanced angiogenesis. We further demonstrated that exosomes effectively reduced apoptosis in MSCs in vitro. Conclusion Sequential delivery of exosomes and pretreated MSCs facilitated cardiac repair post-AMI, and combined pretreatment with hypoxia and TXL better enhanced the cardioprotective effects. This method provides new insight into the clinical translation of stem cell-based therapy for AMI.

Hypoxia Induced Changes of Exosome Cargo and Subsequent Biological Effects

“…There were large amounts of studies that investigated exosomes derived from mesenchymal stem cells, such exosomes exhibited protective effects in cardiac injury and many miRNAs were reported to be encapsulated in exosome cargo. Especially, exosomes derived from hypoxia pretreated bone marrow-derived mesenchymal stem cells (BMSCs) were able to improve the cardiac function, reduce the infarct size and enhance the angiogenesis of the infarcted hearts ( 141 ). miR-98-5p was upregulated by hypoxia in exosomes derived from BMSCs and injection of such exosomes to rats with myocardial ischemia-reperfusion injury improved the cardiac function by targeting TRL4 and activating PI3K/AKT signaling pathway ( 149 ).…”

Ginsenoside Rh2 Inhibits NLRP3 Inflammasome Activation and Improves Exosomes to Alleviate Hypoxia-Induced Myocardial Injury

“…However, the harsh microenvironments, such as calcium overload, acidosis, and reactive oxygen species production in the injured myocardium, significantly dampen the survival rate of the transplanted exosomes and undermine the incidence of homing to the injured tissue, posing great limits on their clinical application as cell-free therapies ( 34 ). The injection of exosomes into myocardial tissue at the early stage of MI can effectively reduce inflammation, inhibit apoptosis, and increase SDF-1 expression ( 35 ). Additionally, pre-hypoxic treatment of stem cell-derived exosomes in cardiomyocytes can significantly promote angiogenesis, reduce cardiac fibrosis, and improve cardiac function ( 36 ).…”

Extracellular vesicles mediate biological information delivery: A double-edged sword in cardiac remodeling after myocardial infarction

“…Transplantation of exogenous vesicles into the ischemic heart within 30 min of MI significantly modulates the ischemic environment, including decreasing inflammatory IL-6 and TNFα, enhancing SDF-1 expression and MSC survival. Additionally, several studies have demonstrated that combined pretreatment with hypoxia and the herbal compound Tongxinluo can effectively achieve better performance in facilitating cardiac repair through increasing CXCR4 expression, which provides new insights into stem cell therapy for cardiac rehabilitation (Xiong et al, 2022). Furthermore, Ruan et al suggested that Suxiao Jiuxin pills modulate myocardial MSC-Exos, causing structural genetic chromatin remodeling in recipient cardiomyocytes and accelerating cardiomyocyte propagation (Ruan et al, 2018).…”