February 7, 2022Stem Cell Research & Therapy41 citationsOpen Access

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

YXYuyan XiongUnion Hospital RTRuijie TangNanjing University of Chinese Medicine JXJunyan XuMinistry of Education

Structured PICO

Does sequential transplantation of exosomes and MSCs pretreated with hypoxia and Tongxinluo improve cardiac repair in a rat model of acute myocardial infarction?

Population

Female Sprague-Dawley (SD) rats (200-220 g) with induced acute myocardial infarction (AMI) via left anterior descending (LAD) coronary artery ligation.

Intervention

Sequential transplantation of MSC-derived exosomes (20 μg in 100 μL PBS via intramyocardial injection 30 min post-AMI) and MSCs pretreated with hypoxia (1% O2) and Tongxinluo (400 μg/mL) (2×10^6 cells via intravenous infusion on Day 3 post-AMI).

Comparator

Sham surgery, AMI with PBS alone (100 μL intramyocardial), exosomes alone, MSCs alone, or exosomes combined with MSCs pretreated with either hypoxia alone or Tongxinluo alone.

Outcome

Cardiac function (LVEF, LVFS, LVEDV, LVESV) assessed by echocardiography at 4 weeks post-AMI.surrogate

Sequential delivery of exosomes and MSCs pretreated with hypoxia and Tongxinluo significantly facilitates cardiac repair post-AMI, offering a novel strategy to enhance stem cell therapy efficacy.

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.

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