scholarly journals Osr1 Is Required for Mesenchymal Derivatives That Produce Collagen in the Bladder

2021 ◽  
Vol 22 (22) ◽  
pp. 12387
Author(s):  
Vasikar Murugapoopathy ◽  
Philippe G. Cammisotto ◽  
Abubakr H. Mossa ◽  
Lysanne Campeau ◽  
Indra R. Gupta
Keyword(s):  
Extracellular Matrix ◽  
Mesenchymal Cell ◽  
Bladder Capacity ◽  
Bladder Function ◽  
Bladder Injury ◽  
Type I ◽  
Mesenchymal Progenitors ◽  
Adult Mice ◽  
Development Proceeds ◽  
Sirius Red

The extracellular matrix of the bladder consists mostly of type I and III collagen, which are required during loading. During bladder injury, there is an accumulation of collagen that impairs bladder function. Little is known about the genes that regulate production of collagens in the bladder. We demonstrate that the transcription factor Odd-skipped related 1 (Osr1) is expressed in the bladder mesenchyme and epithelium at the onset of development. As development proceeds, Osr1 is mainly expressed in mesenchymal progenitors and their derivatives. We hypothesized that Osr1 regulates mesenchymal cell differentiation and production of collagens in the bladder. To test this hypothesis, we examined newborn and adult mice heterozygous for Osr1, Osr1+/−. The bladders of newborn Osr1+/− mice had a decrease in collagen I by western blot analysis and a global decrease in collagens using Sirius red staining. There was also a decrease in the cellularity of the lamina propria, where most collagen is synthesized. This was not due to decreased proliferation or increased apoptosis in this cell population. Surprisingly, the bladders of adult Osr1+/− mice had an increase in collagen that was associated with abnormal bladder function; they also had a decrease in bladder capacity and voided more frequently. The results suggest that Osr1 is important for the differentiation of mesenchymal cells that give rise to collagen-producing cells.

scholarly journals DOP89 Pre-treatment mucosal inflammatory and wound healing gene programmes reveal mechanisms associated with future stricturing behaviour during 5-year follow-up in paediatric Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S127-S127
Author(s):  
Y Haberman Ziv ◽  
P Minar ◽  
R Karns ◽  
P Dexheimer ◽  
S Ghandikota ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Small Molecules ◽  
Gene Signature ◽  
Type I ◽  
Expression Signature ◽  
Fibroblast Activation ◽  
Sirius Red

Abstract Background Stricturing complications account for substantial morbidity in Crohn’s disease (CD). We aimed to define ileal gene programmes present at diagnosis in paediatric CD associated with future stricturing behaviour (B2), and to identify potential small molecules to reverse these gene signatures. Methods Antimicrobial serologies and ileal gene expression (RNASeq) were assessed at diagnosis in 249 CD patients enrolled in a 5-year inception cohort study. These data were used to define genes associated with stricturing behaviour and for model testing to predict stricturing. Sirius Red immuno-histochemistry was utilised to determine the extent of collagen infiltration into the sub-cryptal space. A bioinformatics approach defined small molecules which may reverse the stricturing gene signature. Results Of 249 (8%) patients, 19 developed B2 behaviour during the 5-year follow-up, while 218 remained B1 inflammatory. We defined 518 genes that were differentially expressed in the ileum at diagnosis (FC≥1.5, FDR<0.05) in B1 patients who later developed B2 stricturing complications vs. those who remained B1 throughout. These were notable for baseline up-regulation of OSM implicated in anti-TNF non-response, NCF2 and CSF3R implicated in myeloid cell activation, TGFBI implicated in tissue fibrosis, and a panel of 17 collagen genes in patients who progressed to stricturing. Sirius red staining confirmed an increase in sub-cryptal type I/III collagen in B1 patients at diagnosis who progressed to B2 behaviour. Of these 518 genes, we highlighted an inflammatory OSM co-expression signature that was tightly associated with an extracellular matrix COL1A2 co-expression signature (Pearson r = 0.88, p < 0.0001). Network annotation analyses of those co-expression signatures showed that response to wounding, myeloid dendritic cells, and gp38+ stromal cells signatures are linked to both. Extracellular matrix (ECM) annotation, collagen binding, fibroblasts, and angiogenesis were more specific to the COL1A2 signature, and granulocytes and response to other organisms were more specific to the OSM co-expression signature. We further define small molecules targeting macrophage and fibroblast activation, and angiogenesis, which may reverse the stricturing gene signature including ephrin inhibitors, eicosatetraynoic acid (cyclooxygenase/lipoxygenase inhibitor), orantinib (PDGFR inhibitor), and PT-630 (fibroblast activation inhibitor). Our previous model containing serologies and a refined ECM gene set was significantly associated with stricturing development by year 5 (AUC:0.82) Conclusion An ileal gene program for macrophage and fibroblast activation is linked to future stricturing complications in treatment naïve paediatric CD, and may inform small-molecule therapeutic approaches.

scholarly journals Targeting the Extracellular Matrix in Abdominal Aortic Aneurysms Using Molecular Imaging Insights

2021 ◽  
Vol 22 (5) ◽  
pp. 2685
Author(s):  
Lisa Adams ◽  
Julia Brangsch ◽  
Bernd Hamm ◽  
Marcus R. Makowski ◽  
Sarah Keller
Keyword(s):  
Extracellular Matrix ◽  
Molecular Imaging ◽  
Molecular Targets ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Type I ◽  
Target Tissue ◽  
Pharmacologic Treatment ◽  
Abdominal Aortic

This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be discussed and results from animal studies will be contrasted with clinical trials. Abdominal aortic aneurysm (AAA) is an often fatal disease without non-invasive pharmacologic treatment options. The ECM, with collagen type I and elastin as major components, is the key structural component of the aortic wall and is recognized as a target tissue for both initiation and the progression of AAA. Molecular imaging allows in vivo measurement and characterization of biological processes at the cellular and molecular level and sets forth to visualize molecular abnormalities at an early stage of disease, facilitating novel diagnostic and therapeutic pathways. By providing surrogate criteria for the in vivo evaluation of the effects of pharmacological therapies, molecular imaging techniques targeting the ECM can facilitate pharmacological drug development. In addition, molecular targets can also be used in theranostic approaches that have the potential for timely diagnosis and concurrent medical therapy. Recent successes in preclinical studies suggest future opportunities for clinical translation. However, further clinical studies are needed to validate the most promising molecular targets for human application.

scholarly journals The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1046
Author(s):  
Jorge Martinez ◽  
Patricio C. Smith
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Cell Metabolism ◽  
Breast Tumors ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Desmoplastic Reaction ◽  
The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

scholarly journals 14 Characterization of adipose tissue extracellular matrix component mRNA expression during porcine adipogenesis using real-time PCR

2020 ◽  
Vol 98 (Supplement_2) ◽  
pp. 35-35
Author(s):  
Maegan A Reeves ◽  
Courtney E Charlton ◽  
Terry D Brandebourg
Keyword(s):  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Mrna Expression ◽  
Real Time ◽  
Real Time Pcr ◽  
Collagen Type ◽  
Primary Cultures ◽  
Collagen Type I ◽  
Type I ◽  
Matrix Metallopeptidase

Abstract Given adipose tissue is histologically classified as connective tissue, we hypothesized expression of extracellular matrix (ECM) components are significantly altered during adipogenesis. However, little is known about the regulation of the ECM during adipose tissue development in the pig. Therefore, the objective of this study was to characterize expression of ECM components during porcine adipogenesis. Primary cultures of adipose tissue stromal-vascular cells were harvested from 3-day-old neonatal pigs (n=6) and preadipocytes induced to differentiate in vitro for 8 days in the presence of insulin, hydrocortisone, and rosiglitazone. Total RNA was extracted from these cultures on days 0 and 8 post-induction. Real-time PCR was then utilized to determine changes in mRNA expression for collagen type I alpha 1 chain (COL1A), collagen type I alpha 2 chain (COL2A), collagen type I alpha 3 chain (COL3A), collagen type I alpha 4 chain (COL4A), collagen type I alpha 6 chain (COL6A), biglycan, fibronectin, laminin, nitogen-1 (NID1), matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9), metallopeptidase inhibitor 3 (TIMP3). The mRNA abundances of COL1A, COL3A and MMP2 were significantly downregulated 2.86-fold (P < 0.05), 16.7-fold (P < 0.01) and 3.1-fold (P < 0.05) respectively in day 8 (differentiated) compared to day 0 (undifferentiated) cultures. Meanwhile, mRNA abundances were significantly upregulated during adipogenesis for the COL2A (2.82-fold; P < 0.05), COL4A (2.01-fold; P < 0.05), COL6A (2.8-fold; P < 0.05), biglycan (49.9- fold; P < 0.001), fibronectin (452-fold; P < 0.001), laminin (6.1-fold; P < 0.05), NID1(47.4-fold; P < 0.01), MMP9 (76.8- fold; P < 0.01), and TIMP3(3.04-fold; P < 0.05) genes. These data support the hypothesis that significant changes in ECM components occur during porcine adipogenesis. Modulating adipose tissue ECM remodeling might be a novel strategy to manipulate adiposity in the pig.

scholarly journals Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Wei Dai ◽  
Shenglan Liu ◽  
Shubo Wang ◽  
Li Zhao ◽  
Xiao Yang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Uveal Melanoma ◽  
Specific Inhibitor ◽  
Type I ◽  
Matrix Remodeling ◽  
Metastatic Colonization ◽  
Tgf Β1

AbstractColonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.

The extracellular matrix of hybrids between melanoma cells and normal fibroblasts

1988 ◽  
Vol 91 (2) ◽  
pp. 281-286
Author(s):  
M.C. Copeman ◽  
H. Harris
Keyword(s):  
Extracellular Matrix ◽  
Protease Activity ◽  
Malignant Tumour ◽  
Melanoma Cells ◽  
Chromosome Loss ◽  
Type I ◽  
Chromosome 4 ◽  
Hybrid Cells

It has been shown that when malignant tumour cells are fused with normal fibroblasts the suppression of malignancy in the hybrids is linked to their ability to produce a collagenous extracellular matrix in vivo. When, as a consequence of chromosome loss, segregants arise that reacquire malignancy, these do not produce any detectable matrix. In this paper we examine the main components of the extracellular matrix produced in vitro by hybrids between malignant mouse melanoma cells and normal mouse fibroblasts. Hybrids in which malignancy is suppressed synthesize about ten times as much type 1 procollagen as the malignant segregants derived from them; they also retain more fibronectin in the cell layer and release less protease activity into the medium. Malignant segregants more closely resemble the parental melanoma cells in producing fibronectin and mainly types IV and V procollagen. When hybrid cells in which malignancy is initially suppressed are grown continuously in vitro, the production of type I procollagen declines, and the production of type V procollagen and the release of protease activity into the medium increase. These changes, which are associated with the loss from the hybrid cells of both copies of the chromosome 4 derived from the parental fibroblast, predict the reacquisition of malignancy when the cells are inoculated into mice. It is possible that one gene or set of genes located on chromosome 4 determines both the execution of the fibroblast differentiation programme and the suppression of malignancy.

Long Noncoding RNA MIAT Modulates the Extracellular Matrix Deposition in Leiomyomas by Sponging MiR-29 Family

Endocrinology ◽  
2021 ◽  
Vol 162 (11) ◽  
Author(s):  
Tsai-Der Chuang ◽  
Derek Quintanilla ◽  
Drake Boos ◽  
Omid Khorram
Keyword(s):  
Extracellular Matrix ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Luciferase Reporter ◽  
Cycle Phase ◽  
Type I ◽  
Matrix Deposition

Abstract The objective of this study was to determine the expression and functional role of a long noncoding RNA (lncRNA) MIAT (myocardial infarction–associated transcript) in leiomyoma pathogenesis. Leiomyoma compared with myometrium (n = 66) expressed significantly more MIAT that was independent of race/ethnicity and menstrual cycle phase but dependent on MED12 (mediator complex subunit 12) mutation status. Leiomyomas bearing the MED12 mutation expressed higher levels of MIAT and lower levels of microRNA 29 family (miR-29a, -b, and -c) compared with MED12 wild-type leiomyomas. Using luciferase reporter activity and RNA immunoprecipitation analysis, MIAT was shown to sponge the miR-29 family. In a 3-dimensional spheroid culture system, transient transfection of MIAT siRNA in leiomyoma smooth muscle cell (LSMC) spheroids resulted in upregulation of miR-29 family and downregulation of miR-29 targets, collagen type I (COL1A1), collagen type III (COL3A1), and TGF-β3 (transforming growth factor β-3). Treatment of LSMC spheroids with TGF-β3 induced COL1A1, COL3A1, and MIAT levels, but repressed miR-29 family expression. Knockdown of MIAT in LSMC spheroids blocked the effects of TGF-β3 on the induction of COL1A1 and COL3A1 expression. Collectively, these results underscore the physiological significance of MIAT in extracellular matrix accumulation in leiomyoma.

Abstract 222: Dkk1 and Msx2-Wnt7b Signaling Reciprocally Regulate the Endothelial-Mesenchymal Transition in Aortic Endothelial Cells

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Su-Li Cheng ◽  
Jian-su Shao ◽  
Abraham Behrmann ◽  
Karen Krchma ◽  
Dwight A Towler
Keyword(s):  
Endothelial Cells ◽  
Mesenchymal Cell ◽  
Type I ◽  
Cuboidal Cell ◽  
Aortic Endothelial Cells ◽  
Mesenchymal Transition ◽  
Cell Responses ◽  
The Impact ◽  
Endothelial Mesenchymal Transition ◽  
Aortic Endothelial

Objective Endothelial cells (ECs) can undergo an endothelial-mesenchymal transition (EndMT) during tissue fibrosis. Wnt- and Msx2-regulated signals participate in arteriosclerotic calcification and fibrosis. We studied the impact of Wnt7, Msx2, and Dkk1 (Wnt7 antagonist) on EndMT in primary aortic endothelial cells (AoECs). Methods and Results Transduction of AoECs with vectors expressing Dkk1 suppressed EC differentiation and induced a mineralizing myofibroblast phenotype. Dkk1 suppressed claudin 5, PECAM, cadherin 5 (Cdh5), Tie1 and Tie2. Dkk1 converted the cuboidal cell monolayer into a spindle-shaped multilayer and inhibited EC cord formation. Myofibrogenic and osteogenic markers - e.g., SM22, type I collagen, Osx, Runx2, alkaline phosphatase – were upregulated by Dkk1 via activin-like kinase / Smad pathways. Dkk1 increased fibrosis and mineralization of AoECs cultured under osteogenic conditions - the opposite of mesenchymal cell responses. Msx2 and Wnt7b maintained the “cobblestone” morphology of differentiated ECs and promoted EC marker expression. Deleting EC Wnt7b with the Cdh5-Cre transgene in Wnt7b(fl/fl);LDLR-/- mice upregulated aortic osteogenic genes (Osx, Sox9, Runx2, Msx2) and nuclear pSmad1/5, and increased collagen accumulation. Conclusions Dkk1 enhances EndMT in AoECs, while Msx2-Wnt7 signals stabilize EC phenotype. EC responses to Dkk1, Wnt7b, and Msx2 are the opposite of mesenchymal cell responses, coupling EC phenotypic stability with osteofibrogenic predilection during arteriosclerosis.

scholarly journals Precision-Cut Kidney Slices as a Tool to Understand the Dynamics of Extracellular Matrix Remodeling in Renal Fibrosis

2016 ◽  
Vol 11 ◽  
pp. BMI.S38439 ◽  
Author(s):  
Federica Genovese ◽  
Zsolt S. Kàrpàti ◽  
Signe H. Nielsen ◽  
Morten A. Karsdal
Keyword(s):  
Extracellular Matrix ◽  
Collagen Type ◽  
Interstitial Fibrosis ◽  
Ex Vivo ◽  
Collagen Type I ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Renal Interstitial Fibrosis ◽  
Ex Vivo Model

The aim of this study was to set up an ex vivo model for renal interstitial fibrosis in order to investigate the extracellular matrix (ECM) turnover profile in the fibrotic kidney. We induced kidney fibrosis in fourteen 12-week-old male Sprague Dawley rats by unilateral ureteral obstruction (UUO) surgery of the right ureter. The left kidney (contralateral) was used as internal control. Six rats were sham operated and used as the control group. Rats were terminated two weeks after the surgery; the kidneys were excised and precision-cut kidney slices (PCKSs) were cultured for five days in serum-free medium. Markers of collagen type I formation (P1NP), collagen type I and III degradation (C1M and C3M), and α-smooth muscle actin (αSMA) were measured in the PCKS supernatants by enzyme-linked immunosorbent assay. P1NP, C1M, C3M, and α-SMA were increased up to 2- to 13-fold in supernatants of tissue slices from the UUO-ligated kidneys compared with the contralateral kidneys ( P < 0.001) and with the kidneys of sham-operated animals ( P < 0.0001). The markers could also reflect the level of fibrosis in different animals. The UUO PCKS ex vivo model provides a valuable translational tool for investigating the extracellular matrix remodeling associated with renal interstitial fibrosis.

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