Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways

Abstract

The age‐related functional exhaustion limits potential efficacy of mesenchymal stem cells (MSC) in treating cardiovascular disease. Therefore, rejuvenation of aged MSC in the elderly population is of great interest. We have previously reported that Erb‐B2 receptor tyrosine kinase 4 (ERBB4) plays a critical role in regulating MSC survival under hypoxia. The aim of this study was to investigate whether ERBB4 rejuvenates aged MSC and how ERBB4 enhances therapeutic efficacy of aged MSC in treating myocardial infarction (MI). Compared with vector aged MSC (aged‐MSC), ERBB4‐engineered aged MSC (ER4‐aged‐MSC) conferred resistance to oxidative stress‐induced cell death and ameliorated the senescent phenotype in vitro. Four weeks after MI, the ER4‐aged‐MSC group exhibited enhanced blood vessel density, reduced cardiac remodeling and apoptosis with improved heart function compared with the aged‐MSC group. Overexpression of ERBB4 caused an increase in phosphorylated v‐akt murine thymoma viral oncogene homolog 1 (AKT), and phosphorylated ERK expression under hypoxia. ER4‐aged‐MSC secreted higher levels of angiopoietin, epithelial neutrophil activating peptide 78, VEGF, and fibroblast growth factor 2, and enhanced tube formation in HUVEC. The impact of ERBB4 on protein expression, proangiogenesis, cell behavior, and cytokine secretion was abolished by inhibiting PI3K/AKT and MAPK/ERK signaling pathway.—Liang, X., Ding, Y., Lin, F., Zhang, Y., Zhou, X., Meng, Q., Lu, X., Jiang, G., Zhu, H., Chen, Y., Lian, Q., Fan, H., Liu, Z. Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways. FASEB J. 33, 4559–4570 (2019). http://www.fasebj.org

Haemin pre‐treatment augments the cardiac protection of mesenchymal stem cells by inhibiting mitochondrial fission and improving survival

“…Among the various types of stem cells currently used in pre-clinical and clinical trials, MSCs have been considered a favourable cell source for MI treatment because of their unique advantages, such as easy isolation, low immunogenicity and multipotent differentiation capacity. 20,22 However, most MSCs died within 3 days after transplantation in the harsh environment of the injured heart, thus limiting therapeutic efficacy. 23 Recently, accumulating evidence has demonstrated pharmacological pre-treatment as a novel strategy to promote the survival of transplanted BM-MSCs in the ischaemic heart.…”

“…Female C57/B6J mice, 6‐8 weeks old, were purchased from the Shanghai Laboratory Animal Research Center (Shanghai, China). An MI model in mice was developed as previously described . After ligation of the left anterior descending artery (LAD) 2 mm from the aorta, randomly chosen mice received an intramyocardial injection of 30 µL of PBS (MI group, n = 15), 3.0 × 10 5 BM‐MSCs in 30 μL PBS (BM‐MSC group, n = 13) or 3.0 × 10 5 haemin‐pretreated BM‐MSCs in 30 μL PBS (haemin‐BM‐MSC group, n = 12) at four sites on the surrounding border of the infarct area.…”

miR‐155‐5p inhibition rejuvenates aged mesenchymal stem cells and enhances cardioprotection following infarction

“…We also observed that transplantation of AMSCs had a lower therapeutic efficacy for MI in mice compared with transplantation of YMSCs. Indeed, rejuvenating aged MSCs to increase their therapeutic efficacy for cardiovascular diseases has attracted a lot of attention, and several novel strategies have been explored to rejuvenate aged MSCs, including gene modification (Liang et al, 2019; Song et al, 2017) and pharmacological pretreatment (Fang et al, 2018). However, the potential mechanisms underlying MSC senescence remain unclear.…”

“…Human YMSCs and AMSCs were isolated from the bone marrow of young and aged volunteer donors, respectively, as previously described (Liang et al, 2019). Written informed consent was obtained from all donors.…”

“…The plasmid contained an expression cassette consisting of a CMV promoter followed by cDNA encoding eGFP and an anti‐miR155‐5p sequence (Figure ). The lentivirus was packaged as previously reported (Liang et al, 2019). For stable transduction, AMSCs at a confluence of 70%–80% were infected by lentivirus at a multiplicity of infection of 10 with polybrene (8 μg/ml).…”