Key result
iPS-MSCdOex-mIRs outperforms iPS-MSC therapy in preserving LVEF in a rat model of doxorubicin-induced cardiomyopathy.
Why the study?
This study tested whether double overexpression of miR-19a and miR-20a in human induced pluripotent stem cell-derived mesenchymal stem cells effectively preserves LVEF in doxorubicin-induced dilated cardiomyopathy.
Does double overexpression of miR-19a and miR-20a in iPS-MSCs improve LVEF and reduce myocardial damage in a rat model of dilated cardiomyopathy?
Does double overexpression of miR-19a and miR-20a in iPS-MSCs improve LVEF and reduce myocardial damage in a rat model of dilated cardiomyopathy?
p-value: p=<0.0001
Double overexpression of miR-19a and miR-20a in iPS-MSCs provides superior preservation of left ventricular function compared to standard iPS-MSCs in a rat model of doxorubicin-induced dilated cardiomyopathy.
Background: This study tested the hypothesis that double overexpression of miR-19a & miR-20a (dOex-mIRs) in human induced pluripotent stem cell (iPS)-derived mesenchymal stem cells (MSCs) effectively preserved left-ventricular-ejection-fraction (LVEF) in dilated cardiomyopathy (DCM) (i.e., induced by doxorubicin) rat. Methods and Results: In vitro study was categorized into groups G1 (iPS-MSC), G2 (iPS-MSC dOex-mIRs ), G3 (iPS-MSC + H 2 O 2 /100uM), and G4 (iPS-MSC dOex-mIRs + H 2 O 2 /100uM). The in vitro results showed the cell viability was significantly lower in G3 than in G1 and G2, and that was reversed in G4 but it showed no difference between G1/G2 at time points of 6h/24h/48h, whereas the flow cytometry of intra-cellular/mitochondrial oxidative stress (DCFA/mitoSOX) and protein expressions of mitochondrial-damaged (cytosolic-cytochrome-C/DRP1/Cyclophilin-D), oxidative-stress (NOX-1/NOX2), apoptotic (cleaved-caspase-3/PARP), fibrotic (p-Smad3/TGF-ß) and autophagic (ratio of LC3B-II/LC3BI) biomarkers exhibited an opposite pattern of cell-proliferation rate (all p<0.001). Adult-male SD rats (n=32) were equally divided into groups 1 (sham-operated control), 2 (DCM), 3 (DCM + iPS-MSCs/1.2 x 10 6 cells/administered by post-28 day’s DCM induction) and 4 (DCM + iPS-MSC dOex-mIRs /1.2 x 10 6 cells) and euthanized by day 60 after DCM induction. LV myocardium protein expressions of oxidative-stress signaling (p22-phox/NOX-1/NOX-2/ASK1/p-MMK4,7/p-JNK1,2/p-cJUN), upstream (TLR-4/MAL/MyD88/TRIF/TRAM/ TFRA6/IKK α/ß /NF-κB) and downstream (TNF-α/IL-1ß/MMP-9) inflammatory signalings, apoptotic (cleaved-PARP/mitochondrial-Bax), fibrotic (Smad3/TGF-ß), mitochondrial-damaged (cytosolic-cytochrome-C/DRP1/cyclophilin-D) and autophagic (beclin1/Atg5) biomarkers were highest in group 2, lowest in group 1 and significantly lower in group 4 than in group 3, whereas the LVEF exhibited an opposite pattern of oxidative stress (all p<0.0001). Conclusion: iPS-MSC dOex-mIRs therapy was superior to iPS-MSC therapy for preserving LV function in DCM rat.
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Sheu et al. (2021) studied Dilated cardiomyopathy (n=32). iPS-MSCdOex-mIRs (double overexpression of miR-19a & miR-20a in iPS-derived MSCs) vs. iPS-MSCs, DCM only, and sham control was evaluated on Left ventricular ejection fraction (LVEF) (p=<0.0001). Treatment with iPS-MSCdOex-mIRs was superior to iPS-MSC therapy for preserving left ventricular ejection fraction in a rat model of doxorubicin-induced dilated cardiomyopathy.
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