ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers

Abstract Background Adipose-derived mesenchymal stem cells (ADSCs) are an important focus in regenerative medicine. However, the biological function of ADSCs in the wound repair of diabetic foot ulcers (DFUs) remains unclear. This study aimed to determine the underlying mechanisms of ADSCs involved...

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Autores principales:	Jie Zhou, Tianhong Wei, Zhiyou He
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	ADSCs Wound healing DFU Therapeutics. Pharmacology RM1-950 Biochemistry QD415-436
Acceso en línea:	https://doaj.org/article/075a1e8b5f1f40e484996f68bb7373d4
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spelling	oai:doaj.org-article:075a1e8b5f1f40e484996f68bb7373d42021-11-14T12:12:04ZADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers10.1186/s10020-021-00406-z1076-15511528-3658https://doaj.org/article/075a1e8b5f1f40e484996f68bb7373d42021-11-01T00:00:00Zhttps://doi.org/10.1186/s10020-021-00406-zhttps://doaj.org/toc/1076-1551https://doaj.org/toc/1528-3658Abstract Background Adipose-derived mesenchymal stem cells (ADSCs) are an important focus in regenerative medicine. However, the biological function of ADSCs in the wound repair of diabetic foot ulcers (DFUs) remains unclear. This study aimed to determine the underlying mechanisms of ADSCs involved in the wound healing of DFUs. Methods The cell surface markers cluster of differentiation 34 (CD34), stromal cell antigen 1 (Stro-1), cluster of differentiation 90 (CD90) and cluster of differentiation 105 (CD105) on ADSCs were identified by flow cytometry. Oil Red O staining and Alizarin Red S staining were performed to identify the multipotential differentiation of ADSCs into adipocytes and bone. The levels of Methyltransferase-like 3 (METTL3), vascular endothelial growth factor C (VEGF-C) and insulin-like growth factor 2 binding protein 2 (IGF2BP2) were assessed by RT-qPCR. CCK-8, Transwell and tubule formation assays were conducted to assess lymphatic endothelial cell (LEC) viability, migration and tubule formation ability, respectively. RIP and RNA pulldown assays were conducted to assess the interaction between IGF2BP2 and VEGF-C. The levels of VEGF-C, VEGFR3, LYVE-1 and IGF2BP2 proteins were assessed by Western blotting. The levels of VEGF-C in LECs were measured by ELISA. Results Our findings illustrated that ADSCs accelerate LEC proliferation, migration and lymphangiogenesis via the METTL3 pathway and regulate VEGF-C expression via the METTL3/IGF2BP2-m6A pathway VEGF-C-mediated lymphangiogenesis via the METTL3/IGF2BP2-m6A pathway in DFU mice. Conclusion ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing in DFUs, indicating that ADSCs may be regarded as a promising therapeutic strategy to promote wound healing in DFUs.Jie ZhouTianhong WeiZhiyou HeBMCarticleADSCsWound healingDFUTherapeutics. PharmacologyRM1-950BiochemistryQD415-436ENMolecular Medicine, Vol 27, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ADSCs Wound healing DFU Therapeutics. Pharmacology RM1-950 Biochemistry QD415-436
spellingShingle	ADSCs Wound healing DFU Therapeutics. Pharmacology RM1-950 Biochemistry QD415-436 Jie Zhou Tianhong Wei Zhiyou He ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers
description	Abstract Background Adipose-derived mesenchymal stem cells (ADSCs) are an important focus in regenerative medicine. However, the biological function of ADSCs in the wound repair of diabetic foot ulcers (DFUs) remains unclear. This study aimed to determine the underlying mechanisms of ADSCs involved in the wound healing of DFUs. Methods The cell surface markers cluster of differentiation 34 (CD34), stromal cell antigen 1 (Stro-1), cluster of differentiation 90 (CD90) and cluster of differentiation 105 (CD105) on ADSCs were identified by flow cytometry. Oil Red O staining and Alizarin Red S staining were performed to identify the multipotential differentiation of ADSCs into adipocytes and bone. The levels of Methyltransferase-like 3 (METTL3), vascular endothelial growth factor C (VEGF-C) and insulin-like growth factor 2 binding protein 2 (IGF2BP2) were assessed by RT-qPCR. CCK-8, Transwell and tubule formation assays were conducted to assess lymphatic endothelial cell (LEC) viability, migration and tubule formation ability, respectively. RIP and RNA pulldown assays were conducted to assess the interaction between IGF2BP2 and VEGF-C. The levels of VEGF-C, VEGFR3, LYVE-1 and IGF2BP2 proteins were assessed by Western blotting. The levels of VEGF-C in LECs were measured by ELISA. Results Our findings illustrated that ADSCs accelerate LEC proliferation, migration and lymphangiogenesis via the METTL3 pathway and regulate VEGF-C expression via the METTL3/IGF2BP2-m6A pathway VEGF-C-mediated lymphangiogenesis via the METTL3/IGF2BP2-m6A pathway in DFU mice. Conclusion ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing in DFUs, indicating that ADSCs may be regarded as a promising therapeutic strategy to promote wound healing in DFUs.
format	article
author	Jie Zhou Tianhong Wei Zhiyou He
author_facet	Jie Zhou Tianhong Wei Zhiyou He
author_sort	Jie Zhou
title	ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers
title_short	ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers
title_full	ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers
title_fullStr	ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers
title_full_unstemmed	ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers
title_sort	adscs enhance vegfr3-mediated lymphangiogenesis via mettl3-mediated vegf-c m6a modification to improve wound healing of diabetic foot ulcers
publisher	BMC
publishDate	2021
url	https://doaj.org/article/075a1e8b5f1f40e484996f68bb7373d4
work_keys_str_mv	AT jiezhou adscsenhancevegfr3mediatedlymphangiogenesisviamettl3mediatedvegfcm6amodificationtoimprovewoundhealingofdiabeticfootulcers AT tianhongwei adscsenhancevegfr3mediatedlymphangiogenesisviamettl3mediatedvegfcm6amodificationtoimprovewoundhealingofdiabeticfootulcers AT zhiyouhe adscsenhancevegfr3mediatedlymphangiogenesisviamettl3mediatedvegfcm6amodificationtoimprovewoundhealingofdiabeticfootulcers
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ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers

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