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In this study, for feature extraction of seismic- and nonlinear trend terms of the nonlinear and nonstationary high-rate Global Navigation Satellite System (GNSS) seismic displacements, we present an adaptive complete ensemble empirical mode decomposition (CEEMD) method based on correlation coefficient. We also introduce an improved CEEMD (ICEEMD) based on multiway principal component analysis (MPCA), hereafter, ICEEMD-MPCA, denoising method for boosting the high-rate GNSS seismic displacements with/without nonlinear trend. The results show that the proposed method is suitable for extracting features of nonlinear and nonstationary high-rate GNSS seismic displacements. The ICEEMD-MPCA denoising method is able to obviously eliminate white noise at high frequencies, remove systematic errors, and effectively preserve the earthquake wave signals. The denoising method reflects that high-rate GNSS has millimeter-level accuracy in the vertical component and submillimeter-level accuracy in the horizontal component. To verify the performance characteristics of the feature extraction and denoising method, the focal mechanism inversion for the 2010 El Mayor–Cucapah earthquake is estimated using the high-rate GNSS data (5 Hz) and collocated strong motion data (50 and 200 Hz). The focal mechanism of the earthquake estimated using the denoised high-rate GNSS with/without nonlinear trend are more consistent with the teleseismic estimates than those estimated using the raw high-rate GNSS and strong motion data. For the GNSS observations, the inversion results are more affected by errors in low-frequency, which accumulate over time and display their signatures as trend in coseismic displacements. It can be concluded that with the adaptive CEEMD method and the ICEEMD-MPCA denoising method, high-rate GNSS at near-field stations only or combined with GNSS/strong-motion records can be applied to yield better information regarding the earthquake focal mechanism inversion, the lower bounds of earthquake magnitudes, and earthquake rupture parameters for small to moderate earthquakes.

Angiogenesis is essential for vascular development. The roles of regulatory long noncoding RNAs (lncRNAs) in mediating angiogenesis remain under‐explored. Human embryonic stem cell‐derived mesenchymal stem cells (hES‐MSCs) are shown to exert more potent cardioprotective effects against cardiac ischemia than human bone marrow‐derived MSCs (hBM‐MSCs), associated with enhanced neovascularization. The purpose of this study is to search for angiogenic lncRNAs enriched in hES‐MSCs, and investigate their roles and mechanisms. AC103746.1 is one of the most highly expressed intergenic lncRNAs detected in hES‐MSCs versus hBM‐MSCs, and named as SCDAL (stem cell‐derived angiogenic lncRNA). SCDAL knockdown significantly reduce the angiogenic potential and reparative effects of hES‐MSCs in the infarcted hearts, while overexpression of SCDAL in either hES‐MSCs or hBM‐MSCs exhibits augmented angiogenesis and cardiac function recovery. Mechanistically, SCDAL induces growth differentiation factor 6 (GDF6) expression via direct interaction with SNF5 at GDF6 promoter. Secreted GDF6 promotes endothelial angiogenesis via non‐canonical vascular endothelial growth factor receptor 2 activation. Furthermore, SCDAL‐GDF6 is expressed in human endothelial cells, and directly enhances endothelial angiogenesis in vitro and in vivo. Thus, these findings uncover a previously unknown lncRNA‐dependent regulatory circuit for angiogenesis. Targeted intervention of the SCDAL‐GDF6 pathway has potential as a therapy for ischemic heart diseases., Long noncoding RNA (lncRNA) SCDAL (stem cell‐derived angiogenic lncRNA) is identified as a critical regulator for angiogenic actions of human embryonic stem cell‐derived mesenchymal stem cells (hES‐MSCs) in ischemic hearts. SCDALinitiates growth differentiation factor 6 (GDF6) expression by recruiting SNF5 to GDF6 promoter. Secreted GDF6 promotes endothelial angiogenesis through vascular endothelial growth factor receptor 2 pathway.

Bone marrow mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been widely used for treating myocardial infarction (MI). However, low retention and short-lived therapeutic effects are still significant challenges. This study aimed to determine whether incorporation of MSC-derived sEVs in alginate hydrogel increases their retention in the heart thereby improving therapeutic effects. Methods: The optimal sodium alginate hydrogel incorporating sEVs system was determined by its release ability of sEVs and rheology of hydrogel. Ex vivo fluorescence imaging was utilized to evaluate the retention of sEVs in the heart. Immunoregulation and effects of sEVs on angiogenesis were analyzed by immunofluorescence staining. Echocardiography and Masson's trichrome staining were used to estimate cardiac function and infarct size. Results: The delivery of sEVs incorporated in alginate hydrogel (sEVs-Gel) enhanced their retention in the heart. Compared with sEVs only treatment (sEVs), sEVs-Gel treatment significantly decreased cardiac cell apoptosis and promoted the polarization of macrophages at day 3 after MI. sEVs-Gel treatment also increased scar thickness and angiogenesis at four weeks post-infarction. Measurement of cardiac function and infarct size were significantly better in the sEVs-Gel group than in the group treated with sEVs only. Conclusion: Delivery of sEVs incorporated in alginate hydrogel provides a novel approach of cell-free therapy and optimizes the therapeutic effect of sEVs for MI.

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in adults. The cellular mechanisms of CAVD are still unknown, but accumulating evidence has revealed that osteogenic differentiation of human valve interstitial cells (hVICs) plays an important role in CAVD. Thus, we aimed to investigate the function of estrogen-related receptor α (ERRα) in the osteogenic differentiation of hVICs. We found that the level of ERRα was significantly increased in CAVD samples compared to normal controls. In addition, ERRα was significantly upregulated during hVIC osteogenic differentiation in vitro. Gain- and loss-of-function experiments were performed to identify the function of ERRα in hVIC calcification in vitro. Inhibition of endogenous ERRα attenuated hVIC calcification, whereas overexpression of ERRα in hVICs promoted this process. RNA sequencing results suggested that heme oxygenase-1 (Hmox1) was a downstream target of ERRα, which was further confirmed by western blotting. Additionally, we also found that downregulation of Hmox1 by shHmox1 efficiently reversed the inhibition of calcification induced by ERRα shRNA in hVICs. ChIP-qPCR and luciferase assays indicated that Hmox1 was negatively regulated by ERRα. We found that overexpression of Hmox1 or its substrates significantly inhibited hVIC calcification in vitro. In conclusion, we found that knockdown of ERRα can inhibit hVIC calcification through upregulating Hmox1 and that ERRα and Hmox1 are potential targets for the treatment of CAVD.

Stem cell-derived small extracellular vesicles (sEVs) promote angiogenesis after myocardial infarction (MI). However, the components of sEVs that contribute to these effects and the safety and efficiency of engineered sEV treatment for MI remain unresolved. Here, we observed improved cardiac function, enhanced vascular density, and smaller infarct size in mice treated with the sEVs from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) (HP-sEVs) than in mice treated with normoxia-preconditioned (N) MSCs (N-sEVs). MicroRNA profiling revealed a higher abundance of miR-486-5p in HP-sEVs than in N-sEVs, and miR-486-5p inactivation abolished the benefit of HP-sEV treatment, whereas miR-486-5p up-regulation enhanced the benefit of N-sEV treatment. Matrix metalloproteinase 19 (MMP19) abundance was lower in HP-sEV-treated than N-sEV-treated mouse hearts but was enriched in cardiac fibroblasts (CFs), and Mmp19 was identified as one of the target genes of miR-486-5p. Conditioned medium from CFs that overexpressed miR-486-5p or silenced MMP19 increased the angiogenic activity of endothelial cells; however, medium from CFs that simultaneously overexpressed Mmp19 and miR-486-5p abolished this effect. Mmp19 silencing in CFs reduced the cleavage of extracellular vascular endothelial growth factor (VEGF). Furthermore, miR-486-5p-overexpressing N-sEV treatment promoted angiogenesis and cardiac recovery without increasing arrhythmia complications in a nonhuman primate (NHP) MI model. Collectively, this study highlights the key role of sEV miR-486-5p in promoting cardiac angiogenesis via fibroblastic MMP19-VEGFA cleavage signaling. Delivery of miR-486-5p-engineered sEVs safely enhanced angiogenesis and cardiac function in an NHP MI model and may promote cardiac repair.

Rationale : Autophagy can preserve cell viability under conditions of mild ischemic stress by degrading damaged organelles for ATP production, but under conditions of severe ischemia, it can promote cell death and worsen cardiac performance. Mesenchymal stem cells (MSCs) are cardioprotective when tested in animal models of myocardial infarction, but whether these benefits occur through the regulation of autophagy is unknown. Objective: To determine whether transplanted MSCs reduce the rate of autophagic degradation (autophagic flux) in infarcted hearts and if so, to characterize the mechanisms involved. Methods and Results: Treatment with transplanted MSCs improved cardiac function and infarct size while reducing apoptosis and measures of autophagic flux (bafilomycin A1-induced LC3-II [microtubule-associated protein 1 light chain 3] accumulation and autophagosome/autolysosome prevalence) in infarcted mouse hearts. In hypoxia and serum deprivation–cultured neonatal mouse cardiomyocytes, autophagic flux and cell death, as well as p53-Bnip3 (B-cell lymphoma 2–interacting protein 3) signaling, declined when the cells were cultured with MSCs or MSC-secreted exosomes (MSC-exo), but the changes associated with MSC-exo were largely abolished by pretreatment with the exosomal inhibitor GW4869. Furthermore, a mimic of the exosomal oligonucleotide miR-125b reduced, whereas an anti-miR-125b oligonucleotide increased, autophagic flux and cell death, via modulating p53-Bnip3 signaling in hypoxia and serum deprivation–cultured neonatal mouse cardiomyocytes. In the in vivo mouse myocardial infarction model, MSC-exo, but not the exosomes obtained from MSCs pretreated with the anti-miR-125b oligonucleotide (MSC-exo anti-miR-125b ), recapitulated the same results as the in vitro experiments. Moreover, measurements of infarct size and cardiac function were significantly better in groups that were treated with MSC-exo than the MSC-exo anti-miR-125b group. Conclusions: The beneficial effects offered by MSC transplantation after myocardial infarction are at least partially because of improved autophagic flux through excreted exosome containing mainly miR-125b-5p.