A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions

Liu, Chenghao; Teo, Melissa Hui Yen; Pek, Sharon Li Ting; Wu, Xiaoting; Leong, Mei Ling; Tay, Hui Min; Hou, Han Wei; Ruedl, Christiane; Moss, Stephen E.; Greenwood, John; Tavintharan, Subramaniam; Hong, Wanjin

doi:10.2337/db20-0585

Cited by 50 publications

(53 citation statements)

References 47 publications

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“…And Kumagai et al [22] have revealed that LRG1 is produced from heart-infiltrating myeloid cells in MI hearts and that LRG1 ameliorates cardiac remodeling with angiogenesis in the subacute phase after MI. Liu et al [27] have found that the angiogenic effect of LRG1 is required for normal wound healing and LRG1 is predominantly produced by the wound-infiltrating CD11b + myeloid cells. In line with these findings, our previous [24] and present study showed that LRG1 was mainly located at renal tubules and some inflammatory cells in kidney including CD4 + , CD11b + , and CD11c + cells.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, LRG1 has different roles in different conditions. Liu et al [27] has found that LRG1 is significantly increased at the inflammation stage of murine wound healing, and LRG1 deletion causes impaired immune cell infiltration, re-epithelialization, and angiogenesis, leading to delayed wound healing. But on the other hand, LRG1 was markedly induced in diabetic wounds in both humans and mice, and LRG1-deficient mice were resistant to diabetes-induced delay in wound repair.…”

Section: Discussionmentioning

confidence: 99%

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LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines

et al. 2021

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Introduction: Increasing evidence has demonstrated that loss of peritubular capillaries plays a critical role in renal interstitial fibrosis. Leucine-rich α2-glycoprotein-1 (LRG1) has been observed promoting angiogenesis in the ocular disease mouse model and myocardial infarction model. We aimed to explore the role of LRG1 in renal interstitial fibrosis. Methods: We analyzed the expression of LRG1 in the plasma and kidney of CKD patients by ELISA and immunohistochemistry. Relationships between the expression of LRG1 in plasma and kidney and renal fibrosis and inflammation were analyzed. Tube formation assay was used to detect the angiogenesis in the human umbilical vein endothelial cell lines (HUVECs). And real-time PCR was used to detect the mRNA expression of LRG1, inflammatory factors, renal tubular injury indicators, pro-fibrotic cytokines, and CD31. We examined the effects of genetic ablation of LRG1 on renal fibrosis induced by unilateral ureteral obstruction (UUO) mice model at day 7. Results: We demonstrated that the expression of LRG1 in renal tissues and plasma samples was upregulated in CKD patients. And the expression of LRG1 was elevated in human renal tubular epithelial cell line (HK-2) cells in response to the stimulation of TNF-α in vitro, and in kidney after UUO in vivo. The deficiency of the LRG1 gene aggravated renal fibrosis, inflammatory cells infiltration, and capillary rarefaction after UUO. In vitro, LRG1 promoted the tube formation of HUVEC cells. LRG1 inhibits fibronectin secretion induced by TGF-β1 in HK-2 and overexpression of LRG1 in HK-2 cells decreased fibronectin secretion. Conclusion: LRG1 may prevent renal fibrosis by inhibiting the secretion of inflammatory and pro-fibrotic cytokines and promoting angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines

et al. 2021

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“…In this study we provide new insight into the cause of dysfunctional vessel growth in tumors and show that LRG1 is a significant angiopathic factor capable of disrupting the normal angiogenic process and contributing to the pro-oncogenic microenvironment of primary tumors. Under normal conditions the principal source of LRG1 is the liver where it may serve as an acute phase protein ( 39 ) involved in wound healing ( 40 ). In many diseases, however, LRG1 is induced locally in tissue lesions by the vascular endothelia and, in the case of cancer, by surrounding tumor cells.…”

Section: Discussionmentioning

confidence: 99%

LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency

O’Connor

Kallenberg

Jackstadt

et al. 2020

Preprint

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Vascular dysfunction contributes to the pro-oncogenic tumor microenvironment and impedes the delivery of therapeutics. Normalizing of the tumor vasculature has therefore become a potential therapeutic objective. We previously reported that the secreted glycoprotein, leucine-rich α-2-glycoprotein 1 (LRG1), contributes to the formation of pathogenic neovascularization. Here we show that in mouse models of cancer, Lrg1 is induced in tumor endothelial cells. We demonstrate that the expression of LRG1 impacts on tumor progression as Lrg1 deletion or treatment with a LRG1 function-blocking antibody inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function resulting in significantly enhanced efficacy of cisplatin chemotherapy, adoptive T-cell therapy and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent (cold) to immune active (hot). LRG1 therefore drives vascular abnormalization and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics.

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“…In endothelial cells (EC), LRG1 promotes angiogenesis by tipping the balance of TGFβ1 signalling toward the ALK1/Smad1,5,8 pathway, which is dependent on the presence of the type III TGF β1 receptor endoglin [7]. Besides its role in retinal angiogenesis [7], LRG1 has been linked to abnormal angiogenesis in glomerular [8], ischemic brain [9], cornea [10], and diabetic wounds [11]. Neovascularization plays an essential role in tumour expansion [12] and tumour vasculature provides a route of transportation for tumour cell dissemination [13].…”

Section: Introductionmentioning

confidence: 99%

LRG1 Promotes Metastatic Dissemination of Melanoma through Regulating EGFR/STAT3 Signalling

Kwan

Teo

Lim

et al. 2021

Cancers

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Although less common, melanoma is the deadliest form of skin cancer largely due to its highly metastatic nature. Currently, there are limited treatment options for metastatic melanoma and many of them could cause serious side effects. A better understanding of the molecular mechanisms underlying the complex disease pathophysiology of metastatic melanoma may lead to the identification of novel therapeutic targets and facilitate the development of targeted therapeutics. In this study, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in melanoma development and progression. We first established the association between LRG1 and melanoma in both human patient biopsies and mouse melanoma cell lines and revealed a significant induction of LRG1 expression in metastatic melanoma cells. We then showed no change in tumour cell growth, proliferation, and angiogenesis in the absence of the host Lrg1. On the other hand, there was reduced melanoma cell metastasis to the lungs in Lrg1-deficient mice. This observation was supported by the promoting effect of LRG1 in melanoma cell migration, invasion, and adhesion. Mechanistically, LRG1 mediates melanoma cell invasiveness in an EGFR/STAT3-dependent manner. Taken together, our studies provided compelling evidence that LRG1 is required for melanoma metastasis but not growth. Targeting LRG1 may offer an alternative strategy to control malignant melanoma.

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A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions

Cited by 50 publications

References 47 publications

LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines

LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines

LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency

LRG1 Promotes Metastatic Dissemination of Melanoma through Regulating EGFR/STAT3 Signalling

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