Implications of lymphatic alterations in the pathogenesis and treatment of inflammatory bowel disease

Zhang, Lu; Ocansey, Dickson Kofi Wiredu; Liu, Lianqin; Olovo, Chinasa Valerie; Zhang, Xu; Qian, Hui; Xu, Wenrong; Mao, Fei

doi:10.1016/j.biopha.2021.111752

Cited by 25 publications

(26 citation statements)

References 121 publications

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“…In previous studies, researchers paid little attention to the role of lymphatics in the pathophysiology of CD. The intestinal and mesenteric lymphatic vessels conduct functional and morphological changes in CD patients, which negatively influence intestinal immune homeostasis, stable faecal microbiota, and epithelial barrier integrity [ 22 ]. VEGF-C, as the main ligand of VEGFR-3, is necessary for regulating functional lymphatic vessel networks [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…The intestinal lymphatic vascular system serves as an essential modality in resolving tissue oedema, leucocyte transportation, inflammatory chemokines and bacterial clearance [ 20 , 21 ]. Increased pathological hyperplasia of lymphatic vessels and lymphatic vascular dysfunction are visible in active CD [ 22 ]. The main molecular mechanism that drives lymphangiogenesis is the VEGF-C/VEGFR-3 signalling axis.…”

Section: Introductionmentioning

confidence: 99%

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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

Wang

et al. 2022

Stem Cell Res Ther

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2022

Stem Cell Res Ther

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“…The lymphatic vasculature is critical to the transport of intestinal immune and inflammatory cells, and interactions between LECs and leukocytes have been demonstrated to influence immune cell migration, thus modulating the immune response. Thus, dysfunction in the lymphatics can lead to alterations of immune cell trafficking [ 3 , 7 , 9 ]. Lymphatic endothelial cells also appear to have roles in prenatal lymphatic patterning and post-natal control of formation of new lymphatics, or lymphangiogenesis [ 1 , 10 , 11 , 12 ].…”

Section: Overview Of the Intestinal Lymphatic Vasculaturementioning

confidence: 99%

“…Lymphatic endothelial cells also appear to have roles in prenatal lymphatic patterning and post-natal control of formation of new lymphatics, or lymphangiogenesis [ 1 , 10 , 11 , 12 ]. Finally, the intestinal lymphatic vasculature is influenced by and an influencer of gut microbiota health, epithelial integrity and barrier function [ 9 ].…”

Section: Overview Of the Intestinal Lymphatic Vasculaturementioning

confidence: 99%

Pathophysiology, Diagnosis, and Management of Canine Intestinal Lymphangiectasia: A Comparative Review

Jablonski

2022

Animals

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Intestinal lymphangiectasia was first described in the dog over 50 years ago. Despite this, canine IL remains poorly understood and challenging to manage. Intestinal lymphangiectasia is characterized by variable intestinal lymphatic dilation, lymphatic obstruction, and/or lymphangitis, and is a common cause of protein-losing enteropathy in the dog. Breed predispositions are suggestive of a genetic cause, but IL can also occur as a secondary process. Similarly, both primary and secondary IL have been described in humans. Intestinal lymphangiectasia is definitively diagnosed via intestinal histopathology, but other diagnostic results can be suggestive of IL. Advanced imaging techniques are frequently utilized to aid in the diagnosis of IL in humans but have not been thoroughly investigated in the dog. Management strategies differ between humans and dogs. Dietary modification is the mainstay of therapy in humans with additional pharmacological therapies occasionally employed, and immunosuppressives are rarely used due to the lack of a recognized immune pathogenesis. In contrast, corticosteroid and immunosuppressive therapies are more commonly utilized in canine IL. This review aims toward a better understanding of canine IL with an emphasis on recent discoveries, comparative aspects, and necessary future investigations.

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“…Considering the discovery of increased LV density in certain pathologies, such as inflammatory bowel disease ( Zhang et al, 2021 ), where LV regression could be therapeutic, in addition to the identification of decreased lymphatic clearance in other pathologies, such as Alzheimer’s disease ( Tarasoff-Conway et al, 2015 ; Petrova and Koh, 2020 ), a clear understanding of the mechanisms underlying LV regression is urgently needed. Herein, we summarize what is known about LV regression, extend insights from the prolific field of BV regression to shed light on LV regression, discuss the implications of the newly identified roles of lymphatics in a variety of pathologies, and describe research models and modalities that can be utilized to further advance the understudied field of LV regression.…”

Section: Introductionmentioning

confidence: 99%

Lymphatic Vessel Regression and Its Therapeutic Applications: Learning From Principles of Blood Vessel Regression

et al. 2022

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Aberrant lymphatic system function has been increasingly implicated in pathologies such as lymphedema, organ transplant rejection, cardiovascular disease, obesity, and neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. While some pathologies are exacerbated by lymphatic vessel regression and dysfunction, induced lymphatic regression could be therapeutically beneficial in others. Despite its importance, our understanding of lymphatic vessel regression is far behind that of blood vessel regression. Herein, we review the current understanding of blood vessel regression to identify several hallmarks of this phenomenon that can be extended to further our understanding of lymphatic vessel regression. We also summarize current research on lymphatic vessel regression and an array of research tools and models that can be utilized to advance this field. Additionally, we discuss the roles of lymphatic vessel regression and dysfunction in select pathologies, highlighting how an improved understanding of lymphatic vessel regression may yield therapeutic insights for these disease states.

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Implications of lymphatic alterations in the pathogenesis and treatment of inflammatory bowel disease

Cited by 25 publications

References 121 publications

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

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

Pathophysiology, Diagnosis, and Management of Canine Intestinal Lymphangiectasia: A Comparative Review

Lymphatic Vessel Regression and Its Therapeutic Applications: Learning From Principles of Blood Vessel Regression

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