ADSCs stimulated by VEGF-C alleviate intestinal inflammation via dual mechanisms of enhancing lymphatic drainage by a VEGF-C/VEGFR-3-dependent mechanism and inhibiting the NF-κB pathway by the secretome

doi:10.1186/s13287-022-03132-3

	ADSCs stimulated by VEGF-C alleviate intestinal inflammation via dual mechanisms of enhancing lymphatic drainage by a VEGF-C/VEGFR-3-dependent mechanism and inhibiting the NF-κB pathway by the secretome
	Zhang, Lei 1; Ye, Chen 2; Li, Peng3 ; Li, Chuanding 1; Shu, Weigang 1; Zhao, Yujie 1; Wang, Xiaolei 1
	2022-09-05
发表期刊	STEM CELL RESEARCH AND THERAPY
EISSN	1757-6512
卷号	13 期号:1
发表状态	已发表
DOI	10.1186/s13287-022-03132-3
摘要	Background: Adipose-derived stem cells (ADSCs) have provided promising applications for Crohn’s disease (CD). However, the practical efficacy of ADSCs remains controversial, and their mechanism is still unclear. Based on the pathogenesis of dysregulated immune responses and abnormal lymphatic alterations in CD, vascular endothelial growth factor-C (VEGF-C) is thought to be a favourable growth factor to optimize ADSCs. We aimed to investigate the efficacy of VEGF-C-stimulated ADSCs and their dual mechanisms in both inhibiting inflammation “IN” and promoting inflammation “OUT” in the intestine. Methods: Human stem cells isolated from adipose tissues were identified, pretreated with or without 100 ng/ml VEGF-C and analysed for the secretion of cell culture supernatants in vitro. Lymphatic endothelial cells (LECs) were treated with ADSCs-conditioned medium or co-cultured with ADSCs and VEGF-C stimulated ADSCs. Changes in LECs transmigration, and VEGF-C/VEGFR-3 mRNA levels were assessed by transwell chamber assay and qRT–PCR. ADSCs and VEGF-C-stimulated ADSCs were intraperitoneally injected into mice with TNBS-induced chronic colitis. ADSCs homing and lymphatic vessel density (LVD) were evaluated by immunofluorescence staining. Lymphatic drainage was assessed using Evans blue. Cytokines and growth factors expression was detected respectively by ELISA and qRT–PCR. The protein levels of VEGF-C/VEGFR-3-mediated downstream signals and the NF-κB pathway were assayed by western blot. Faecal microbiota was measured by 16S rRNA sequencing. Results: ADSCs stimulated with VEGF-C released higher levels of growth factors (VEGF-C, TGF-β1, and FGF-2) and lower expression of cytokines (IFN-γ and IL-6) in cell supernatants than ADSCs in vitro (all P < 0.05). Secretome released by VEGF-C stimulated ADSCs exhibited a stronger LEC migratory capability and led to elevated VEGF-C/VEGFR-3 expression, but these effects were markedly attenuated by VEGFR-3 inhibitor. VEGF-C-stimulated ADSCs homing to the inflamed colon and mesenteric lymph nodes (MLNs) can exert stronger efficacy in improving colitis symptoms, reducing inflammatory cell infiltration, and significantly enhancing lymphatic drainage. The mRNA levels and protein concentrations of anti-inflammatory cytokines and growth factors were markedly increased with decreased proinflammatory cytokines in the mice treated with VEGF-C-stimulated ADSCs. Systemic administration of VEGF-C-stimulated ADSCs upregulated the colonic VEGF-C/VEGFR-3 pathway and activated downstream AKT and ERK phosphorylation signalling, accompanied by decreased NF-κB p65 expression. A higher abundance of faecal p-Bacteroidetes and lower p-Firmicutes were detected in mice treated with VEGF-C-stimulated ADSCs (all P < 0.05). Conclusion: VEGF-C-stimulated ADSCs improve chronic intestinal inflammation by promoting lymphatic drainage and enhancing paracrine signalling via activation of VEGF-C/VEGFR-3-mediated signalling and inhibition of the NF-κB pathway. Our study may provide a new insight into optimizing ADSCs treatment and investigating potential mechanisms in CD.
关键词	Adipose derived-stem cells Chronic colitis Faecal microbiota Lymphatic drainage Paracrine Vascular endothelial growth factor C
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收录类别	SCIE
语种	英语
Scopus 记录号	2-s2.0-85137254765
来源库	Scopus
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/235581
专题	免疫化学研究所_特聘教授组_范国平组
通讯作者	Zhao, Yujie; Wang, Xiaolei
作者单位	1.Department of Gastroenterology,Shanghai Tenth People’s Hospital,Tongji University School of Medicine,Shanghai,200072,China 2.Medical College of Soochow University,Suzhou,Jiangsu Province,215000,China 3.Shanghai Institute for Advanced Immunochemical Studies,ShanghaiTech University,Shanghai,201210,China
推荐引用方式 GB/T 7714	Zhang, Lei,Ye, Chen,Li, Peng,et al. ADSCs stimulated by VEGF-C alleviate intestinal inflammation via dual mechanisms of enhancing lymphatic drainage by a VEGF-C/VEGFR-3-dependent mechanism and inhibiting the NF-κB pathway by the secretome[J]. STEM CELL RESEARCH AND THERAPY,2022,13(1).
APA	Zhang, Lei.,Ye, Chen.,Li, Peng.,Li, Chuanding.,Shu, Weigang.,...&Wang, Xiaolei.(2022).ADSCs stimulated by VEGF-C alleviate intestinal inflammation via dual mechanisms of enhancing lymphatic drainage by a VEGF-C/VEGFR-3-dependent mechanism and inhibiting the NF-κB pathway by the secretome.STEM CELL RESEARCH AND THERAPY,13(1).
MLA	Zhang, Lei,et al."ADSCs stimulated by VEGF-C alleviate intestinal inflammation via dual mechanisms of enhancing lymphatic drainage by a VEGF-C/VEGFR-3-dependent mechanism and inhibiting the NF-κB pathway by the secretome".STEM CELL RESEARCH AND THERAPY 13.1(2022).