FNDC5/Irisin improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells for myocardial infarction

Abstract

Background: The beneficial functions of bone marrow mesenchymal stem cells (BM-MSCs) decline with decreased cells survival, limiting their therapeutic efficacy for myocardial infarction (MI). Irisin, a novel myokine which is cleaved from its precursor fibronectin type III domain-containing protein 5 (FNDC5), is believed involved in a cardioprotective effect but little was known on injured BM-MSCs and MI repair yet. Here, we investigated whether FNDC5 or irisin could improve the low viability of transplanted BM-MSCs and increase their therapeutic efficacy after MI. Methods: BM-MSCs, isolated from dual-reporter firefly luciferase and enhanced green fluorescent protein positive (Fluc+– eGFP+) transgenic mice, were exposed to normoxic condition and hypoxic stress for 12 h, 24 h, and 48 h, respectively. In addition, BM-MSCs were treated with irisin (20 nmol/L) and overexpression of FNDC5 (FNDC5-OV) in serum deprivation (H/SD) injury. Furthermore, BM-MSCs were engrafted into infarcted hearts with or without FNDC5-OV. Results: Hypoxic stress contributed to increased apoptosis, decreased cells viability and paracrine effects of BM-MSCs while irisin or FNDC5-OV alleviated these injuries. Longitudinal in vivo bioluminescence imaging and immunofluorescence results illustrated that BM-MSCs with overexpression of FNDC5 treatment (FNDC5-MSCs) improved the survival of transplanted BM-MSCs, which ameliorated the increased apoptosis and decreased angiogenesis of BM-MSCs in vivo. Interestingly, FNDC5-OV elevated the secretion of exosomes in BM-MSCs. Furthermore, FNDC5-MSCs therapy significantly reduced fibrosis and alleviated injured heart function. Conclusions: The present study indicated that irisin or FNDC5 improved BM-MSCs engraftment and paracrine effects in infarcted hearts, which might provide a potential therapeutic target for MI.

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

“…Future work is required to determine the molecular and cellular mechanisms underlying the catch-up and facilitation, which were well correlated with IL-35 promotion of macrophage survival and improvement of wound healing after myocardial infarction ( 85 ). In addition, differences between the IL-35 roles in angiogenesis in HLI and myocardial infarction may also result from potential functions of cardiokines ( 86 ) and myokines ( 87 ).…”

“…Of note, the stronger protection of IL-35 in the cardiac muscle than in the skeletal muscle may be due to tissue specificity. In addition, differences between the IL-35 roles in angiogenesis in HLI and myocardial infarction may also result from potential functions of cardiokines ( 86 ) and myokines ( 87 ). These findings provide a novel insight on the future therapeutic potential of IL-35 in suppressing ischemia/inflammation-triggered inflammatory angiogenesis at the early phase but sparing regenerative angiogenesis at the late phase, which is similar to our recent report that IL-35 inhibits human aortic endothelial cell activation triggered by proatherogenic lipids but spare trained immunity pathway ( 8 ).…”

An Insight on Multicentric Signaling of Angiotensin II in Cardiovascular system: A Recent Update

“…Bone marrow MSCs derived conditioned medium could prevent aneurysm growth through macrophage polarization regulation (Zhou et al, 2019). In addition, precursor fibronectin type III domain-containing protein 5 or irisin, a novel myokine has the potential to improve bone marrow MSC mediated paracrine effect and engraftments in infarcted hearts (Deng et al, 2020). Previous studies have shown that MSC-derived exosomes have distinct properties, including immunomodulation, angiogenesis, and paracrine effect that protect organ functions in animal studies.…”

Exosomes secreted by FNDC5-BMMSCs protect myocardial infarction by anti-inflammation and macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis

“…Apart from this, its expression and role in various other conditions such as in ammation, cardiovascular diseases, aging and other metabolic conditions have been reported [18][19][20]. In addition, our previous study showed that FNDC5 pre-treatment BMMSCs improved MI repair [21]. Interestingly, we also found that BMMSCs with overexpression of FNDC5 secreted more exosomes compared ordinary BMMSCs.…”