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JAM-A Overexpression in Human Umbilical Cord-Derived Mesenchymal Stem Cells Accelerated the Angiogenesis of Diabetic Wound By Enhancing Both Paracrine Function and Survival of Mesenchymal Stem Cells

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Abstract

Mesenchymal stem cells (MSCs) is promising in promoting wound healing mainly due to their paracrine function. Nonetheless, the transplanted MSCs presented poor survival with cell dysfunction and paracrine problem in diabetic environment, thus limiting their therapeutic efficacy and clinical application. JAM-A, an adhesion molecule, has been reported to play multi-functional roles in diverse cells. We therefore investigated the potential effect of JAM-A on MSCs under diabetic environment and explored the underlying mechanism. Indeed, high-glucose condition inhibited MSCs viability and JAM-A expression. However, JAM-A abnormality was rescued by lentivirus transfection and JAM-A overexpression promoted MSCs proliferation, migration and adhesion under hyperglycemia. Moreover, JAM-A overexpression attenuated high-glucose-induced ROS production and MSCs apoptosis. The bio-effects of JAM-A on MSCs under hyperglycemia were confirmed by RNA-seq with enrichment analyses. Moreover, Luminex chip results showed JAM-A overexpression dramatically upregulated PDGF-BB and VEGF in the supernatant of MSCs, which was verified by RT-qPCR and western blotting. The supernatant was further found to facilitate HUVECs proliferation, migration and angiogenesis under hyperglycemia. In vivo experiments revealed JAM-A overexpression significantly enhanced MSCs survival, promoted wound angiogenesis, and thus accelerated diabetic wound closure, partially by enhancing PDGF-BB and VEGF expression. This study firstly demonstrated that JAM-A expression of MSCs was inhibited upon high-glucose stimulation. JAM-A overexpression alleviated high-glucose-induced MSCs dysfunction, enhanced their anti-oxidative capability, protected MSCs from hyperglycemia-induced apoptosis and improved their survival, thus strengthening MSCs paracrine function to promote angiogenesis and significantly accelerating diabetic wound healing, which offers a promising strategy to maximize MSCs-based therapy in diabetic wound.

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Data Availability

The data and materials used to support the findings of this study are available from the corresponding author upon request.

Code Availability

Not applicable.

Abbreviations

DM :

Diabetes mellitus

MSCs :

mesenchymal stem cells, multipotent stromal cells, or mesenchymal stromal cells

ROS :

reactive oxygen species

JAM-A :

junction adhesion molecule A

HUVECs :

human umbilical vein endothelial cells

GFP :

green fluorescent protein

JAM-A MSCs :

JAM-A overexpressing MSCs

VEC MSCs :

the vector control MSCs

DCFH-DA :

2,7-dichlorodihydrofluorescein diacetate

CCK8 :

cell counting kit-8

RNA-Seq :

RNA Sequencing

GO :

Gene Ontology

KEGG :

Kyoto Encyclopedia of Genes and Genomes

GSEA :

gene set enrichment analysis

DEGs :

differentially expressed genes

MSCs-CM :

MSCs-Conditioned Medium

VEGF :

vascular endothelial growth factor

PDGF-BB :

platelet-derived growth factor-BB

MSCs :

mesenchymal stem cells, multipotent stromal cells, or mesenchymal stromal cells

ROS :

reactive oxygen species

JAM-A :

junction adhesion molecule A

HUVECs :

human umbilical vein endothelial cells

GFP :

green fluorescent protein

JAM-A MSCs :

JAM-A overexpressing MSCs

VEC MSCs :

the vector control MSCs

DCFH-DA :

2,7-dichlorodihydrofluorescein diacetate

CCK8 :

cell counting kit-8

RNA-Seq :

RNA Sequencing

GO :

Gene Ontology

KEGG :

Kyoto Encyclopedia of Genes and Genomes

GSEA :

gene set enrichment analysis

DEGs :

differentially expressed genes

MSCs-CM :

MSCs-Conditioned Medium

VEGF :

vascular endothelial growth factor

PDGF-BB :

platelet-derived growth factor-BB

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Funding

This work was supported by the National Key R&D Program of China (2019YFA0110503); the National Nature Science Foundation of China (81772076, 81930057, 82072170, 81871559, and 82172201); CAMS Innovation Fund for Medical Sciences (2019-I2M-5–076), Achievements Supportive Fund (2018-CGPZ-B03); Shanghai Rising Star Program (22QA1411700); the Youth Incubation Plan of the Military Medical Science and Technology Project (20QNPY035).

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  1. Futing Shu, Jianyu Lu and Wei Zhang these authors contributed equally to this article.

Authors and Affiliations

  1. Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People’s Republic of China

    Futing Shu, Jianyu Lu, Wei Zhang, Hongchao Huang, Jiezhi Lin, Luofeng Jiang, Wenzhang Liu, Tianyi Liu, Shichu Xiao, Yongjun Zheng & Zhaofan Xia

  2. Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, 200433, People’s Republic of China

    Zhaofan Xia

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Contributions

XZF, ZYJ and XSC contributed to the conception and design. SFT LJY and ZW contributed to the data, analysis and interpretation. SFT contributed to the manuscript writing. SFT, LJY, ZW and HHC contributed to the animal experiments. XZF and ZYJ contributed to the manuscript revision. LJZ, JLF, LWZ and LTY provided the study materials. XZF, ZYJ and XSC contributed to the conception and design, financial support, and final approval of the manuscript. The authors read and approved the final manuscript.

Corresponding authors

Correspondence to Shichu Xiao, Yongjun Zheng or Zhaofan Xia.

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The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Changhai Hospital, Shanghai, China. All experimental procedures were approved by the animal use and care committee of Changhai Hospital, Shanghai, China.

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Supplementary Fig. 1

Cluster heatmaps of all genes in the gene sets. The heatmaps showed the clustered genes in the gene sets of the KEGG terms CELL CYCLE (A), ADHERENS JUNCTION (B), APOPTOSIS (C), and NF-κB SIGNALING PATHWAY (D). Red represented highly expressed genes, and blue represented genes with low expression. JAM-A MSCs+HG vs. VEC MSCs+HG. JAM-A MSCs, JAM-A overexpressing MSCs; VEC MSCs, the vector control MSCs. HG, high glucose. n = 3 biological replicates. (PNG 16700 kb)

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Shu, F., Lu, J., Zhang, W. et al. JAM-A Overexpression in Human Umbilical Cord-Derived Mesenchymal Stem Cells Accelerated the Angiogenesis of Diabetic Wound By Enhancing Both Paracrine Function and Survival of Mesenchymal Stem Cells. Stem Cell Rev and Rep 19, 1554–1575 (2023). https://doi.org/10.1007/s12015-023-10518-0

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