scholarly journals Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1095
Author(s):  
Yifan Tai ◽  
Emma L. Woods ◽  
Jordanna Dally ◽  
Deling Kong ◽  
Robert Steadman ◽  
...  
Keyword(s):  
Smooth Muscle Actin ◽  
Multiple Roles ◽  
Cell Phenotype ◽  
Clinical Settings ◽  
Specific Targeting ◽  
Clinical Challenge ◽  
Formation Function ◽  
Molecular Therapies ◽  
Cellular Markers ◽  
Molecular Interventions

Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge. In recent years, myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings. This comprehensive review article describes the myofibroblast cell phenotype, their origins, and their diverse physiological and pathological functionality. Special attention has been given to mechanisms and molecular pathways governing myofibroblast differentiation, and updates in molecular interventions.

Abstract 38: Rbp-j Regulates the Genetic Program of the Myo-epithelioid JG Cell

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ruth M Castellanos Rivera ◽  
Ellen S. Pentz ◽  
Kenneth W. Gross ◽  
Silvia Medrano ◽  
Jing Yu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Fluorescent Protein ◽  
Smooth Muscle Actin ◽  
Artificial Chromosome ◽  
Specific Protein ◽  
Genetic Program ◽  
Cell Phenotype ◽  
Gfp Expression ◽  
Renin Gene

RBP-J , the major downstream effector of Notch signaling, is necessary to maintain the number of juxtaglomerular (JG) cells. In addition, RBP-J regulates the plasticity of arteriolar smooth muscle cells to adopt the renin cell phenotype when homeostasis is threatened. We hypothesized that RBP-J acts as an on/off switch controlling the expression of genes that determine the renin phenotype. To determine whether RBP-J directly affects renin gene expression, we generated mice harboring a bacterial artificial chromosome (BAC) transgene with green fluorescent protein (GFP) under the control of the renin gene carrying a mutation in its RBP-J- binding site (Mut-BAC). Mut-BAC mice had markedly reduced GFP expression to 12.9 % ±0.01 (n=3) of the control (Wt-BAC) and a diminished response to homeostatic challenges: mut-BAC mice had a reduced number of GFP positive JG areas per total number of glomeruli (Wt-BAC: 25.1 % ±3.0, n=3; Mut-BAC: 9.3 % ±1.4, n=2, p<0.02) and no GFP expression along the arterioles. To determine whether the decrease in the number of JG cells in mice lacking RBP-J (cKO) was due to a diminished endowment of renin progenitor cells, we traced the fate of cells derived from the renin lineage by generating mice ( RBP-J fl/fl ; Ren1d +/cre ; R26R +/- ) in which cells lacking RBP-J simultaneously expressed β-galactosidase (β-gal). The pattern of β-gal in cKO and control kidneys was identical, indicating that cells derived from the renin lineage did not die but instead changed their phenotype. Next we investigated the phenotype adopted by the cells derived from the renin lineage. Expression of α-smooth muscle actin and smoothelin (a marker of mature smooth muscle) was significantly decreased to 41 % ±7.0 (n=2) and 44 % ±8.8 (n=2) respectively with respect to controls (p<0.01). In addition, mutant JG cells in vivo did not express genes characteristic of the renin phenotype such as renin, calponin1, Nfat and Akr1b7 expressing instead fibroblast-specific protein 1 indicating the adoption of a fibroblast-like phenotype. Results indicate that RBP-J directly governs a genetic program that controls the dual endocrine-contractile phenotype of the JG cell, which is crucial to maintain blood pressure and fluid-electrolyte homeostasis.

scholarly journals Expression of Cytoskeletal Proteins in Hepatic Stellatecells Isolated from Normal and Cirrhotic Rat Liver

2005 ◽  
Vol 48 (3-4) ◽  
pp. 137-144 ◽  
Author(s):  
Alena Jiroutová ◽  
Lenka Majdiaková ◽  
Martina Čermáková ◽  
Renata Köhlerová ◽  
Jiří Kanta
Keyword(s):  
Smooth Muscle ◽  
Rat Liver ◽  
Smooth Muscle Actin ◽  
Cytoskeletal Proteins ◽  
Cirrhotic Liver ◽  
Cell Phenotype ◽  
Storage Site ◽  
Muscle Actin ◽  
Normal Cells ◽  
Fibrotic Liver

Hepatic stellate cells (HSC) are located in Disse spaces of normal rat liver. In their quiescent state they serve as a storage site for vitamin A. In fibrotic liver they become activated, proliferate and they undergo transdifferentiation into myofibroblast-like cells. Changes in the cell phenotype are accompanied by changes in the cellular cytoskeleton. We have studied the expression of α-smooth muscle actin and intermediate filament proteins vimentin, desmin and glial fibrillary acidic protein (GFAP) by immunocytochemistry in HSC cultured for 2 or 7 days after isolation. Normal or cirrhotic rat liver was perfused with solutions of pronase and collagenase and HSC were isolated by density gradient centrifugation of the resulting cell suspension. Liver cirrhosis was produced in rats by repeated carbon tetrachloride administration. Vimentin was detected in all cells from normal and cirrhotic liver. The concentration of desmin in the cells from cirrhotic liver was slightly higher than that in normal cells and it increased with time in culture. GFAP could be detected only in normal cells 2 days after their isolation. In contrast, alpha smooth muscle actin (α-SMA) was absent from normal cells at this time but its expression was pronouced later. In most cells from cirrhotic liver this antigen was already present on the second day of culture and its expression further increased.

Abstract 57: The Epigenetic Enzyme Kdm6b Controls the Pro-Fibrotic Transcriptome Signature of Foam Cells

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Annette E Neele ◽  
Koen H Prange ◽  
Marten A Hoeksema ◽  
Saskia van der Velden ◽  
Tina Lucas ◽  
...  
Keyword(s):  
Foam Cell ◽  
Smooth Muscle Actin ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Cell Phenotype ◽  
Sequencing Analysis ◽  
Dependent Manner ◽  
Alpha Smooth Muscle Actin

Aim: Foam cells are a key hallmark of atherosclerotic lesion formation. Within the atherosclerotic lesion macrophages scavenge modified lipoproteins and thereby acquire their foam cell characteristics. Besides their foam cell phenotype, macrophages can have specific inflammation regulatory functions in atherosclerotic lesions. Epigenetic pathways are crucial for monocyte to macrophage differentiation and activation. The H3K27 demethylase Kdm6b (also known as Jmjd3) is regulated in response to various triggers and regulates several modes of macrophage activation. Given the crucial role of macrophage foam cells in atherosclerosis, we here studied Kdm6b in peritoneal foam cells in order to identify regulated pathways. Material and Methods: A myeloid deficient Kdm6b mice (LysMCre-Kdm6b fl/fl ) was generated and bone marrow of Kdm6b wt or Kdm6b del mice was transplanted to irradiated Ldlr -/- mice which were fed a high fat diet for 9 weeks to induce foam cell formation. Peritoneal foam cells from Kdm6b del or Kdm6b wt mice were isolated and used for RNA-sequencing analysis. Results: Among the list of downregulated genes many genes involving fibrosis were affected in Kdm6b deficient foam cells including Collagen genes ( Col1a1 , Col1a2 ), Alpha smooth muscle actin ( Acta2 ) and Fibronectin-1 ( Fn1 ). Pathway analysis on downregulated genes ( P -value < 0.05) indicated that pathways involved in epithelial to mesenchymaltransition (EMT) ( q- value=10 -13 ) and extracellular matrix organization ( q- value=10 -4 ) were significantly downregulated. Pro-fibrotic pathways were thus strongly suppressed in Kdm6b deleted foam cells. Analysis of published datasets of foam cells showed that foam cell formation induces these pro-fibrotic characteristics. Overlay of both data sets indicated that fibrotic genes which are induced upon foam cell formation, are reduced in the absence of Kdm6b. These data suggest that foam cell formation induces a pro-fibrotic gene signature in a Kdm6b-dependent manner. Conclusion: We identified Kdm6b as a novel regulator of the pro-fibrotic signature of peritoneal foam cells.

Biomechanical and Optical Characteristics of a Corneal Stromal Equivalent1

2003 ◽  
Vol 125 (4) ◽  
pp. 439-444 ◽  
Author(s):  
Elizabeth J. Orwin ◽  
Melinda L. Borene ◽  
Allison Hubel
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Collagen Matrix ◽  
Matrix Composition ◽  
Cell Phenotype ◽  
Matrix Remodeling ◽  
Muscle Actin ◽  
Stromal Fibroblasts ◽  
The Matrix ◽  
Actin Expression

Cell matrix interactions are important in understanding the healing characteristics of the cornea after refractive surgery or transplantation. The purpose of this study was to characterize in more detail the evolution of biomechanical and optical properties of a stromal equivalent (stromal fibroblasts cultured in a collagen matrix). Human corneal stromal fibroblasts were cultured in a collagen matrix. Compaction and modulus were determined for the stromal equivalent as a function of time in culture and matrix composition. The corneal stromal fibroblasts were stained for α-smooth muscle actin expression as an indicator of myofibroblast phenotype. The nominal modulus of the collagen matrix was 364±41 Pa initial and decreased initially with time in culture and then slowly increased to 177±75 Pa after 21 days. The addition of chondroitin sulfate decreased the contraction of the matrix and enhanced its transparency. Cell phenotype studies showed dynamic changes in the expression of α-smooth muscle actin with time in culture. These results indicate that the contractile behavior of corneal stromal cells can be influenced by both matrix composition and time in culture. Changes in contractile phenotype after completion of the contraction process also indicate that significant cellular changes persist beyond the initial matrix-remodeling phase.

scholarly journals HIVAN phenotype: consequence of epithelial mesenchymal transdifferentiation

2010 ◽  
Vol 298 (3) ◽  
pp. F734-F744 ◽  
Author(s):  
Anju Yadav ◽  
Sridevi Vallabu ◽  
Dileep Kumar ◽  
Guohua Ding ◽  
Douglas N. Charney ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
De Novo ◽  
Smooth Muscle Actin ◽  
Tissue Expression ◽  
Renal Tissue ◽  
Specific Protein ◽  
Cell Phenotype ◽  
Renal Epithelial Cell

Human immunodeficiency virus (HIV)-1-associated nephropathy (HIVAN) is characterized by proliferation of glomerular and tubular epithelial cells. We studied the role of epithelial mesenchymal transdifferentiation (EMT) in the development of HIVAN phenotype. Renal cortical sections from six FVB/N (control) and six Tg26 (HIVAN) mice were immunolabeled for PCNA, α-smooth muscle actin (α-SMA), fibroblast-specific protein-1 (FSP1), CD3, and F4/80. Since periglomerular cells (PGCs) and peritubular cells (PTCs) did not show any labeling for CD3 and F4/80 but showed labeling for α-SMA or FSP1, it appears that these were myofibroblasts that migrated from either glomerular or tubular sites, respectively. Occurrence of EMT was also supported by diminished expression of E-cadherin by renal epithelial cells in Tg26 mice. Interestingly, Tg26 mice also showed enhanced renal tissue expression of ZEB2; henceforth, it appears that transcription of molecules required for maintenance of de novo renal epithelial cell phenotype was suppressed. To evaluate the role of ANG II, Tg26 mice in groups of three were administered either normal saline or telmisartan (an AT1 receptor blocker) for 2 wk, followed by evaluation for renal cell EMT. Renal cortical section of Tg26 mice showed a sevenfold increase ( P < 0.001) in parietal epithelial cell (PEC)-PGC and a threefold increase ( P < 0.01) in tubular cell (TC)-PTC proliferation (PCNA-positive cells). Similarly, both PECs-PGCs and TCs-PTCs in Tg26 mice showed enhanced expression of α-SMA and FSP1. Both PECs and podocytes contributed to the glomerular proliferative phenotype, but the contribution of PECs was much greater. Telmisartan-receiving Tg26 mice (TRM) showed attenuated number of proliferating PECs-PGCs and TCs-PTCs compared with saline-receiving Tg26 mice (SRM). Similarly, TRM showed diminished expression of α-SMA and FSP1 by both PECs-PGCs and TCs-PTCs compared with SRM. We conclude that EMT contributes to the manifestation of the proliferative phenotype in HIVAN mice.

scholarly journals Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis

2013 ◽  
Vol 304 (10) ◽  
pp. G876-G884 ◽  
Author(s):  
Dimitrios C. Ziogas ◽  
Beatriz Gras-Miralles ◽  
Sarah Mustafa ◽  
Brenda M. Geiger ◽  
Robert M. Najarian ◽  
...  
Keyword(s):  
Biological Effects ◽  
Smooth Muscle Actin ◽  
Major Complication ◽  
Experimental Colitis ◽  
Hormone Treatment ◽  
Blocking Antibody ◽  
Clinical Challenge ◽  
Mouse Tissues ◽  
Melanin Concentrating Hormone ◽  
Inflammatory Bowel

Fibrosis represents a major complication of several chronic diseases, including inflammatory bowel disease (IBD). Treatment of IBD remains a clinical challenge despite several recent therapeutic advances. Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide shown to regulate appetite and energy balance. However, accumulating evidence suggests that MCH has additional biological effects, including modulation of inflammation. In the present study, we examined the efficacy of an MCH-blocking antibody in treating established, dextran sodium sulfate-induced experimental colitis. Histological and molecular analysis of mouse tissues revealed that mice receiving anti-MCH had accelerated mucosal restitution and lower colonic expression of several proinflammatory cytokines, as well as fibrogenic genes, including COL1A1. In parallel, they spared collagen deposits seen in the untreated mice, suggesting attenuated fibrosis. These findings raised the possibility of perhaps direct effects of MCH on myofibroblasts. Indeed, in biopsies from patients with IBD, we demonstrate expression of the MCH receptor MCHR1 in α-smooth muscle actin(+) subepithelial cells. CCD-18Co cells, a primary human colonic myofibroblast cell line, were also positive for MCHR1. In these cells, MCH acted as a profibrotic modulator by potentiating the effects of IGF-1 and TGF-β on proliferation and collagen production. Thus, by virtue of combined anti-inflammatory and anti-fibrotic effects, blocking MCH might represent a compelling approach for treating IBD.

scholarly journals Molecular characterization of perivascular drainage pathways in the murine brain

2017 ◽  
Vol 38 (4) ◽  
pp. 669-686 ◽  
Author(s):  
Melanie-Jane Hannocks ◽  
Michelle E Pizzo ◽  
Jula Huppert ◽  
Tushar Deshpande ◽  
N Joan Abbott ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Fluid Flow ◽  
Molecular Characterization ◽  
Immune Cell ◽  
Smooth Muscle Actin ◽  
Cell Trafficking ◽  
Cellular Markers ◽  
Waste Transfer ◽  
The Brain

Perivascular compartments surrounding central nervous system (CNS) vessels have been proposed to serve key roles in facilitating cerebrospinal fluid flow into the brain, CNS waste transfer, and immune cell trafficking. Traditionally, these compartments were identified by electron microscopy with limited molecular characterization. Using cellular markers and knowledge on cellular sources of basement membrane laminins, we here describe molecularly distinct compartments surrounding different vessel types and provide a comprehensive characterization of the arachnoid and pial compartments and their connection to CNS vessels and perivascular pathways. We show that differential expression of plectin, E-cadherin and laminins α1, α2, and α5 distinguishes pial and arachnoid layers at the brain surface, while endothelial and smooth muscle laminins α4 and α5 and smooth muscle actin differentiate between arterioles and venules. Tracer studies reveal that interconnected perivascular compartments exist from arterioles through to veins, potentially providing a route for fluid flow as well as the transport of large and small molecules.

Early cell changes and TGFβ pathway alterations in the aortopathy associated with bicuspid aortic valve stenosis

2012 ◽  
Vol 124 (2) ◽  
pp. 97-108 ◽  
Author(s):  
Amalia Forte ◽  
Alessandro Della Corte ◽  
Mario Grossi ◽  
Ciro Bancone ◽  
Raffaela Provenzano ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Cell Phenotype ◽  
Tgfβ Receptor ◽  
Lesser Curvature ◽  
Tgfβ Pathway

Previous studies on BAV (bicuspid aortic valve)-related aortopathy, whose aetiology is still debated, have focused mainly on severe dilatations. In the present study, we aimed to detect earlier signs of aortopathy. Specimens were collected from the ‘concavity’ (lesser curvature) and the ‘convexity’ (greater curvature) of mildly dilated AAs (ascending aortas; diameter ≤4 cm) with stenotic TAV (tricuspid aortic valve) or BAV and from donor normal aortas. Specimens were submitted to morphometry, immunohistochemistry and differential gene-expression analysis, focusing on SMC (smooth muscle cell) phenotype, remodelling, MF (myofibroblast) differentiation and TGFβ (transforming growth factor β) pathway. Smoothelin and myocardin mRNAs decreased in all the samples from patients, with the exception of those from BAV convexity, where a change in orientation of smoothelin-positive SMCs and an increase of α-SMA (α-smooth muscle actin) mRNA occurred. Dilated aortas from BAV and TAV patients showed both shared and distinct alterations concerning the TGFβ pathway, including an increased TGFβ and TGFβR2 (TGFβ receptor 2) expression in both groups and a decreased TGFβR1 expression in BAV samples only. Despite a decrease of the mRNA coding for the ED-A (extra domain-A) isoform of FN (fibronectin) in the BAV convexity, the onset of the expression of the corresponding protein in the media was observed in dilated aortas, whereas the normal media from donors was negative for this isoform. This discrepancy could be related to modifications in the intima, normally expressing ED-A FN and showing an altered structure in mild aortic dilatations in comparison with donor aorta. Our results suggest that changes in SMC phenotype and, likely, MF differentiation, occur early in the aortopathy associated with valve stenosis. The defective expression of TGFβR1 in BAV might be a constitutive feature, while other changes we reported could be influenced by haemodynamics.

scholarly journals EndMT: New findings on the mechanism underlying fibrosis of intrauterine adhesions

2021 ◽  
Author(s):  
Chengcheng Xu ◽  
Meng Bao ◽  
Xiaorong Fan ◽  
Jin Huang ◽  
Changhong Zhu ◽  
...  
Keyword(s):  
Smooth Muscle Actin ◽  
High Recurrence Rate ◽  
Alpha Smooth Muscle Actin ◽  
Double Positive ◽  
Intrauterine Adhesions ◽  
Mesenchymal Transition ◽  
Intrauterine Adhesion ◽  
Clinical Challenge ◽  
New Findings ◽  
Endothelial To Mesenchymal Transition

Abstract BackgroundIntrauterine adhesion (IUA) is one of the leading causes of infertility and the main clinical challenge is the high recurrence rate. The key to solving this dilemma lies in elucidating the mechanisms of endometrial fibrosis. The aim of our team is to study the mechanism underlying intrauterine adhesion fibrosis and the origin of fibroblasts in the repair of endometrial fibrosis.MethodsOur experimental study involving an animal model of intrauterine adhesion and detection of fibrosis-related molecules. The levels of molecular factors related to the endothelial-to-mesenchymal transition (EndMT) were examined in a rat model of intrauterine adhesion using immunofluorescence, immunohistochemistry, qPCR and Western blot analyses. Main outcome measures are levels of the endothelial marker CD31 and the mesenchymal markers alpha-smooth muscle actin (α-SMA) and vimentin.ResultsImmunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium. Decreased CD31 levels and increased α-SMA and vimentin levels indicate that EndMT is involved in intrauterine adhesion fibrosis.ConclusionsEndothelial cells promote the emergence of fibroblasts via the EndMT during the endometrial fibrosis of intrauterine adhesions.Trial registrationNot applicable.

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