Fibroblast and myofibroblast activation in normal tissue repair and fibrosis

Younesi, Fereshteh Sadat; Miller, Andrew E.; Barker, Thomas H.; Rossi, Fabio M. V.; Hinz, Boris

doi:10.1038/s41580-024-00716-0

Cited by 57 publications

(7 citation statements)

References 325 publications

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“…Fibrotic skin conditions such as pathological scarring and systemic sclerosis mainly manifest with fibroblast proliferation and differentiation into a profibrotic myofibroblast phenotype, causing an exaggerated and prolonged wound healing response that leads to dermal ECM hyperplasia [ 1 , 2 , 11 , 13 , 15 , 16 , 18 ]. Currently, the pathogenesis of these diseases has not been fully elucidated, and remarkably high medical needs and poor treatment possibilities still represent major burdens [ 1 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Despite different etiologies and disease-specific pathophysiologic processes, especially immune, autoimmune, and inflammatory mechanisms, that lead to cutaneous fibrosis, the abnormal and excessive accumulation of extracellular matrix (ECM) constituents in the skin is universally governed by proliferation, chronic activation, and transition of fibroblasts toward a myofibroblast phenotype [ 13 , 14 , 15 ]. Indeed, at variance with physiologic wound healing in which α-smooth muscle actin (α-SMA)-expressing myofibroblasts undergo apoptosis after wound contraction, the aberrant persistence of myofibroblasts results in the formation of a scar tissue consisting in a hyperplastic, disorganized, and stiff ECM particularly rich in collagens, hyaluronan, and fibronectin [ 11 , 13 , 14 , 15 , 16 , 17 , 18 ]. In such a scenario, ECM stiffness and myofibroblast-ECM interactions have emerged as prominent mechanical cues that drive skin fibrosis progression by perpetuating myofibroblast differentiation and evasion of apoptosis in a kind of vicious circle [ 13 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Blockade of Sialylation with Decrease in Polysialic Acid Levels Counteracts Transforming Growth Factor β1-Induced Skin Fibroblast-to-Myofibroblast Transition

Fioretto,

Rosa,

Tani

et al. 2024

Cells

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Aberrant sialylation with overexpression of the homopolymeric glycan polysialic acid (polySia) was recently reported in fibroblasts from fibrotic skin lesions. Yet, whether such a rise in polySia levels or sialylation in general may be functionally implicated in profibrotic activation of fibroblasts and their transition to myofibroblasts remains unknown. Therefore, we herein explored whether inhibition of sialylation could interfere with the process of skin fibroblast-to-myofibroblast transition induced by the master profibrotic mediator transforming growth factor β1 (TGFβ1). Adult human skin fibroblasts were pretreated with the competitive pan-sialyltransferase inhibitor 3-Fax-peracetyl-Neu5Ac (3-Fax) before stimulation with recombinant human TGFβ1, and then analyzed for polySia expression, cell viability, proliferation, migratory ability, and acquisition of myofibroblast-like morphofunctional features. Skin fibroblast stimulation with TGFβ1 resulted in overexpression of polySia, which was effectively blunted by 3-Fax pre-administration. Pretreatment with 3-Fax efficiently lessened TGFβ1-induced skin fibroblast proliferation, migration, changes in cell morphology, and phenotypic and functional differentiation into myofibroblasts, as testified by a significant reduction in FAP, ACTA2, COL1A1, COL1A2, and FN1 gene expression, and α-smooth muscle actin, N-cadherin, COL1A1, and FN-EDA protein levels, as well as a reduced contractile capability. Moreover, skin fibroblasts pre-administered with 3-Fax displayed a significant decrease in Smad3-dependent canonical TGFβ1 signaling. Collectively, our in vitro findings demonstrate for the first time that aberrant sialylation with increased polySia levels has a functional role in skin fibroblast-to-myofibroblast transition and suggest that competitive sialyltransferase inhibition might offer new therapeutic opportunities against skin fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blockade of Sialylation with Decrease in Polysialic Acid Levels Counteracts Transforming Growth Factor β1-Induced Skin Fibroblast-to-Myofibroblast Transition

Fioretto,

Rosa,

Tani

et al. 2024

Cells

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“…Myofibroblasts are vital in wound healing and repair, although constitutive overactivation of these cells may lead to fibrosis and other disease phenotypes. 7 , 8 …”

Section: Dermatopontin ( Dpt + ) Fib...mentioning

confidence: 99%

Essential growth factor receptors for fibroblast homeostasis and activation: Fibroblast Growth Factor Receptor (FGFR), Platelet Derived Growth Factor Receptor (PDGFR), and Transforming Growth Factor β Receptor (TGFβR)

Cheng,

Abdullah,

Buechler

2024

F1000Res

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Fibroblasts are cells of mesenchymal origin that are found throughout the body. While these cells have several functions, their integral roles include maintaining tissue architecture through the production of key extracellular matrix components, and participation in wound healing after injury. Fibroblasts are also key mediators in disease progression during fibrosis, cancer, and other inflammatory diseases. Under these perturbed states, fibroblasts can activate into inflammatory fibroblasts or contractile myofibroblasts. Fibroblasts require various growth factors and mitogenic molecules for survival, proliferation, and differentiation. While the activity of mitogenic growth factors on fibroblasts in vitro was characterized as early as the 1970s, the proliferation and differentiation effects of growth factors on these cells in vivo are unclear. Recent work exploring the heterogeneity of fibroblasts raises questions as to whether all fibroblast cell states exhibit the same growth factor requirements. Here, we will examine and review existing studies on the influence of fibroblast growth factor receptors (FGFRs), platelet-derived growth factor receptors (PDGFRs), and transforming growth factor β receptor (TGFβR) on fibroblast cell states.

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“…A hallmark and widely used indicator of myofibroblast activation is the presence of discrete αSMA stress fibers 10 . Traditionally, researchers and pathologists have used immunostaining of tissue sections or fibroblast cultures to visualize αSMA; however, grading the severity and discreteness of the fibers has remained largely subjective.…”

Section: Introductionmentioning

confidence: 99%

“…Due to their pivotal role in fibrosis, fibroblasts and their activation to myofibroblasts have been extensively studied in virtually every organ system [6][7][8][9] . A hallmark and widely used indicator of myofibroblast activation is the presence of discrete ⍺SMA stress fibers 10 . Traditionally, researchers and pathologists have used immunostaining of tissue sections or fibroblast cultures to visualize ⍺SMA; however, grading the severity and discreteness of the fibers has remained largely subjective.…”

mentioning

confidence: 99%

Automated Prediction of Fibroblast Phenotypes Using Mathematical Descriptors of Cellular Features

Khang,

Barmore,

Tseropoulos

et al. 2024

Preprint

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Fibrosis is caused by pathological activation of resident fibroblasts to myofibroblasts that leads to aberrant tissue stiffening and diminished function of affected organs with limited pharmacological interventions. Despite the prevalence of myofibroblasts in fibrotic tissue, existing methods to grade fibroblast phenotypes are typically subjective and qualitative, yet important for screening of new therapeutics. Here, we develop mathematical descriptors of cell morphology and intracellular structures to identify quantitative and interpretable cell features that capture the fibroblast-to-myofibroblast phenotypic transition in immunostained images. We train and validate models on features extracted from over 2,500 primary heart valve interstitial cells (VICs) and test their predictive performance on VICs treated with the small molecule drug 5-azacytidine, which inhibited myofibroblast activation. Collectively, this work introduces an analytical framework that unveils key features associated with distinct fibroblast phenotypes via quantitative image analysis and is broadly applicable for high-throughput screening assays of candidate treatments for fibrotic diseases.

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Fibroblast and myofibroblast activation in normal tissue repair and fibrosis

Cited by 57 publications

References 325 publications

Blockade of Sialylation with Decrease in Polysialic Acid Levels Counteracts Transforming Growth Factor β1-Induced Skin Fibroblast-to-Myofibroblast Transition

Blockade of Sialylation with Decrease in Polysialic Acid Levels Counteracts Transforming Growth Factor β1-Induced Skin Fibroblast-to-Myofibroblast Transition

Essential growth factor receptors for fibroblast homeostasis and activation: Fibroblast Growth Factor Receptor (FGFR), Platelet Derived Growth Factor Receptor (PDGFR), and Transforming Growth Factor β Receptor (TGFβR)

Automated Prediction of Fibroblast Phenotypes Using Mathematical Descriptors of Cellular Features

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