Therapeutic approaches to control tissue repair and fibrosis: Extracellular matrix as a game changer

Walraven, Maudy; Hinz, Boris

doi:10.1016/j.matbio.2018.02.020

Cited by 155 publications

(130 citation statements)

References 248 publications

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“…3A) [135,136]. Fibrotic lesions can develop in all organs such as scars in skin, fibrosis of lungs, heart, kidneys, and liver [135][136][137]. Fibrosis hampers tissue function and eventually leads to organ failure.…”

Section: Mechanisms Of Matrix Accumulation In Fibrosismentioning

confidence: 99%

The extracellular matrix as a multitasking player in disease

2019

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Extracellular matrices (ECMs) are highly specialized and dynamic three‐dimensional (3D) scaffolds into which cells reside in tissues. ECM is composed of a variety of fibrillar components, such as collagens, fibronectin, and elastin, and non‐fibrillar molecules as proteoglycans, hyaluronan, and glycoproteins including matricellular proteins. These macromolecular components are interconnected forming complex networks that actively communicate with cells through binding to cell surface receptors and/or matrix effectors. ECMs exert diverse roles, either providing tissues with structural integrity and mechanical properties essential for tissue functions or regulating cell phenotype and functions to maintain tissue homeostasis. ECM molecular composition and structure vary among tissues, and is markedly modified during normal tissue repair as well as during the progression of various diseases. Actually, abnormal ECM remodeling occurring in pathologic circumstances drives disease progression by regulating cell–matrix interactions. The importance of matrix molecules to normal tissue functions is also highlighted by mutations in matrix genes that give rise to genetic disorders with diverse clinical phenotypes. In this review, we present critical and emerging issues related to matrix assembly in tissues and the multitasking roles for ECM in diseases such as osteoarthritis, fibrosis, cancer, and genetic diseases. The mechanisms underlying the various matrix‐based diseases are also discussed. Research focused on the highly dynamic 3D ECM networks will help to discover matrix‐related causative abnormalities of diseases as well as novel diagnostic tools and therapeutic targets.

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Section: Mechanisms Of Matrix Accumulation In Fibrosismentioning

confidence: 99%

The extracellular matrix as a multitasking player in disease

2019

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“…Biomaterials are widely used to develop active medical devices capable of promoting tissue regeneration and functional restoration . During these processes, the extracellular matrix (ECM) with its complex and dynamic microenvironment plays a pivotal role in regulating cell adhesion, growth and proliferation . Thus, the direct combination of scaffolds functionalized with simplified ECM proteins is widely studied as a promising approach for a broad range of biomedical applications.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 During these processes, the extracellular matrix (ECM) with its complex and dynamic microenvironment plays a pivotal role in regulating cell adhesion, growth and proliferation. 3,4 Thus, the direct combination of scaffolds functionalized with simplified ECM proteins is widely studied as a promising approach for a broad range of biomedical applications. Biomaterials functionalized with ECM-derived proteins were demonstrated to significantly affect cell behavior.…”

Section: Introductionmentioning

confidence: 99%

Surface modification of chitosan films with a fibronectin fragment–DNA aptamer complex to enhance osteoblastic cell activity: A mass spectrometry approach probing evidence on protein behavior

Saccani

Parisi

Bergonzi

et al. 2019

Rapid Comm Mass Spectrometry

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Rationale Protein dynamics are fundamental for biological activity. Direct surface functionalization with these biomolecules often creates regions presenting non‐homogeneous and altered protein functionality. Aptamers have been shown to be an effective method to enhance the biocompatibility of biomaterials by acting as docking points for biomolecules capable of improving cell responses and the colonization/proliferation processes. Here mass spectrometry (MS) was successfully applied as an analytical approach to study the interactions between a fibronectin fragment (FN) and anti‐fibronectin aptamers in solution and on a chitosan film. Methods A 30 kDa N‐terminal fibronectin fragment, a ssDNA anti‐fibronectin 40 nucleotide long aptamer and chitosan 95/50 (degree of deacetylation 92.6–97.5%; molecular weight 80–220 kDa) were used. First, the dynamics of the FN in aqueous solution, in the presence or absence of anti‐FN‐specific DNA aptamers, were described. Thus, the same study was carried out on 2% (w/w) chitosan‐based films, functionalized with FN alone or through aptamers as selective spacers. Results Amide hydrogen/deuterium exchange mass spectrometry (HDX‐MS) analysis identified the SYRIGDTWSKKDNRGNL and YRVGDTYERPKDSMI, YVVGETWEKPYQGWMM and WERTYLGNAL fragments as presumably involved in the interaction of FN with aptamers. MS findings indicated the improved functionality of FN on chitosan when aptamers were used as selective spacer, and this may explain why cells preferentially attached to aptamer‐bound FN rather than on chitosan‐FN films. Conclusions Aptamers did not affect the amount of adsorbed FN, but influenced its conformation enhancing its biological activity toward adhesion and growth of osteoblasts. HDX‐MS data allowed the identification of the FN/aptamer interaction regions. Differences in FN flexibility on the chitosan film in the presence or absence of the aptamer were established providing insights at the molecular level to better understand the protein biological functionality on cell proliferation.

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“…A critical event in the development of myocardial fibrosis is the activation of FBs into MFBs [12]. Here, to establish an in vitro model that mimics tissue-level aspects of atrial fibrosis, we used Ang II to induce FB activation to contractile MFBs characterized by de novo expression of α-SMA and increased expres- sion of extracellular matrix proteins (fibronectin and collagen) and matricellular proteins (CTGF/CCN2 and osteopontin) [20][21][22]. It is noteworthy that the non-Ang II-treated FBs also expressed some microfilament proteins, which might be attributed to stiff culture substrates and suggested that these FBs could be referred to as proto-MFBs [23].…”

Section: Discussionmentioning

confidence: 99%

Myofibroblast-Derived Exosomes Contribute to Development of a Susceptible Substrate for Atrial Fibrillation

Gao

Liu

et al. 2020

Cardiology

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Objective: Atrial fibrosis plays a critical role in atrial fibrillation (AF). A key event in the pathogenesis of fibrosis is the activation of fibroblasts (FBs) into myofibroblasts (MFBs). Paracrine factors released from MFBs lead to ion channel expression changes in cardiomyocytes (CMs). Downregulation of L-type calcium channel Ca v 1.2 expression is a hallmark of AF-associated ionic remodeling. However, whether exosome (Exo)-mediated crosstalk between MFBs and CMs regulates Ca v 1.2 expression remains unknown. Methods: Atrial FBs and CMs were isolated and cultured from neonatal rats by enzymatic digestion. The activation of FBs into MFBs was induced by angiotensin II. Co-culture assay and in vitro Exo treatment were used to determine the effect of MFB-derived Exos on Ca v 1.2 expression. Confocal Ca 2+ imaging was performed to examine the adrenergic stimulation-elicited Ca 2+ influx signals. The levels of potential Ca v 1.2-inhibitory mi-croRNAs (miRNAs) were measured by qRT-PCR. Results: Untreated FBs expressed limited amounts of alpha smooth muscle actin (α-SMA), while angiotensin II induced a signifi-cant upregulation of α-SMA-expressing MFBs. Co-cultures of MFBs and CMs resulted in downregulation of Ca v 1.2 expression in CMs, which was largely abolished by pretreatment of MFBs with exosomal inhibitor GW4869. More importantly, treatment with MFB-derived Exos caused repression of Ca v 1.2 expression in CMs. Additionally, the adrenergic receptor agonist-elicited Ca 2+ influx signals in CMs were remarkably attenuated by pretreatment with MFB-derived Exos, corresponding to the paralleled change in Ca v 1.2 expression. Finally, miR-21-3p, a potential Ca v 1.2-inhibitory miRNA, was enriched in MFB-derived Exos and upregulated in CMs in response to MFB-derived Exos. Conclusion: We uncover an Exo-mediated crosstalk between MFBs and CMs, contributing to increased vulnerability to AF by reducing the expression of Ca v 1.2 in CMs.

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Therapeutic approaches to control tissue repair and fibrosis: Extracellular matrix as a game changer

Cited by 155 publications

References 248 publications

The extracellular matrix as a multitasking player in disease

The extracellular matrix as a multitasking player in disease

Surface modification of chitosan films with a fibronectin fragment–DNA aptamer complex to enhance osteoblastic cell activity: A mass spectrometry approach probing evidence on protein behavior

Myofibroblast-Derived Exosomes Contribute to Development of a Susceptible Substrate for Atrial Fibrillation

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