GDF11 restores the impaired function of EPCs-MA by promoting autophagy: GDF11 ameliorates endothelial progenitor cell aging by promoting autophagy

Abstract

Objective Our study aimed to assess the effects of Growth and differentiation factor 11 (GDF11) on the function of endothelial progenitor cells in middle-age individuals (EPCs-MA) isolated from mouse bone marrow and to explore the mechanistic relationship between GDF11 and age-related ALP impairment. Methods Bone marrow-derived EPCs were isolated, culture and GDF11 treatment. In vivo, the mice model of myocardial ischemia (MI) was induced by permanent ligation of the left anterior descending coronary artery (LAD) and mice were randomly divided into MI group and EPCs transplantation group (EPCs-Y, EPCs-MA, EPCs-MA/GDF11). The positive effect of GDF11 treatment of EPCs-MA on MI was verified by echocardiography and the average ratio of fibrotic area to left ventricular (LV) area. In vitro, the effect of GDF11 on ameliorating EPCs aging by promoting autophagy was confirmed by transwell assay, immunofluorescence staining, characterization of EPCs ultrastructure through transmission electron microscope (TEM), lysosome imaging and Western blot. Result Our findings demonstrate that GDF11 enhances the migration capacity of EPCs-MA and improves recovery of impaired cardiac function after myocardial infarction (MI) in mice, with EPCs isolated from young mice (EPCs-Y) as controls. Moreover, GDF11 restored functional phenotypes of EPCs-MA to levels akin to EPCs-Y, promoting the expression of CD31, endogenous NO synthase, and the restoration of von Willebrand factor (vWF) and CDH5 expression patterns, as well as the formation of Weibel-Palade bodies—key organelles for storage and secretion in endothelial cells and EPCs. Furthermore, GDF11 significantly enhanced the autophagic clearance capability of EPCs-MA by promoting ALP. Conclusions Our results suggest that GDF11 ameliorates cardiac function impairment by restoring the activities of EPCs from aging mice through enhanced ALP. These findings suggest that GDF11 may hold therapeutic potential for improving aging-related conditions associated with declined autophagy.

Keywords

GDF11 / endothelial progenitor cells / autophagy lysosome pathway / aging

Acknowledgement

Not Applicable.

Author contributions

Liu D H: Experimental studies, Validation, Formal analysis, Writing-Original Draft, Funding, Statistical analysis; Zhang Y: Supervision, Funding; Liu X: Literature search, Experimental studies; data acquisition, Formal analysis, Validation; Huang Q H: Experimental studies; Zhang X F: Experimental studies; Yang R: Experimental studies; Zhao Y: Experimental studies; Li P H: Experimental studies; He J Y: Experimental studies; Zhang K X: Experimental studies; Pan Z W: Conceptualization, Resources, Supervision, Project administration, Funding, Experimental studies; Liu H W: Writing-Review and Editing, Supervision; Yang B F: Project administration, Funding, Conceptualization, Supervision, Resources, Writing-Review and Editing

Source of funding

Creative Research Groups of the National Natural Science Foundation of China (81421063); China Postdoctoral Science Foundation (2016M591556); Natural Science Foundation of Heilongjiang Province of China (H2016008); Postdoctoral Science Foundation of Heilongjiang Province of China (LBHZ15146); Research Project of the Health and Family Planning Commission of Heilongjiang Province (2016-166).

Ethical approval

Healthy male C57BL/6 mice aged 2 to 8 months were used for animal studies (Animal Experimental Ethical Inspection Protocol Np. HMUIRB3021619). Use of animals was approved by Ethic Committees of Harbin Medical University and confirmed to the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No.85-23, revised 1996).

Informed consent

Not Applicable.

Conflict of interest

Yang B F is the editor-in-chief of Frigid Zone Medicine. This ariticle was subject to journal's standard procedures, while peer review handled independently of this Membr and his research groups.

Data availability statement

All data are available from the corresponding authors upon reasonable request.

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