The Role of Myofibroblasts in Physiological and Pathological Tissue Repair

Schuster, Ronen; Younesi, Fereshteh; Ezzo, Maya; Hinz, Boris

doi:10.1101/cshperspect.a041231

Cited by 77 publications

(35 citation statements)

References 386 publications

(462 reference statements)

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“…Although the pathogenesis of HS is not yet fully understood, an increasing number of evidences indicated that the dermal myofibroblasts, mainly from activated fibroblasts, are the key effector cells in the progression of HS. [ 25 ] Histomorphologically, HS is characterized with aberrant ECM deposition, especially type I collagen (Col‐I) and type III collagen (Col‐III). [ 26 ] Alpha‐smooth muscle actin (α‐SMA), a differentiating marker to identify pathologic fibroblasts, is abundantly expressed in dermal myofibroblasts.…”

Section: Resultsmentioning

confidence: 99%

Ferroptosis‐Mediated Synergistic Therapy of Hypertrophic Scarring Based on Metal–Organic Framework Microneedle Patch

Zhao

Guo

Zhou

et al. 2023

Adv Funct Materials

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Hypertrophic scarring, an abnormal fibroproliferative wound-healing disease, has brought tremendous burden for global healthcare systems. To date, no satisfactory treatment of hypertrophic scarring is available yet. Ferroptosis, an iron-dependent form of cell death, has attracted much attention recently for the therapy of diseases featuring iron addiction. Intriguingly, myofibroblasts derived from hypertrophic scarring are found to exhibit a high iron state which appears to be sensitive to trigger ferroptosis for scarring treatment. Accordingly, in this study, a pH responsive self-assembly nanoplatform is designed by encapsulating silver nanoclusters (AgNCs) and Chinese herbal medicine trigonelline (TRG) into zeolitic imidazolate framework-8 (ZIF-8) for synergistic ferroptosis therapy against hypertrophic scarring. The fabricated AgNC/TRG/ZIF-8 composites exhibit good biocompatibility and pH responsive-degradation inside myofibroblasts. The ZIF-8 precursors can increase the generation of lipid reactive oxygen species and deplete intracellular glutathione (GSH). Also, AgNCs have the capability to consume GSH, while TRG can inhibit the activity of glutathione peroxidase. Consequently, the synergistic ferroptosis anti-scarring therapy can be effectively achieved. Furthermore, AgNC/TRG/ZIF-8-loaded microneedle patches made of gelatin methacrylate show remarkable therapeutic effect against hypertrophic scarring on a rabbit ear model. This study suggests the great potential of ferroptosis-mediated strategy for treating fibrotic skin diseases in future clinical application.

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Section: Resultsmentioning

confidence: 99%

Ferroptosis‐Mediated Synergistic Therapy of Hypertrophic Scarring Based on Metal–Organic Framework Microneedle Patch

Zhao

Guo

Zhou

et al. 2023

Adv Funct Materials

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“…Since it has been established that culture on nonfibrous soft elastomers can suppress myofibroblast activation from various precursor cells, [ 38 ] we next measured α‐SMA expression to assess the potential of soft EKGelMA to reduce myofibroblast activation of mouse lung fibroblasts. Such an effect would render the EKGelMA hydrogels suitable scaffolds to deliver fibroblasts without activating them into scar myofibroblast, [ 38c,39 ] which would be a desired feature in, e.g., skin restoration therapies. [ 40 ] Indeed, fibroblasts grown for 4 days on low‐stiffness EKGelMA hydrogel exhibited 1.3‐ and 1.6‐fold lower α‐SMA expression than fibroblasts grown on medium‐ and high‐stiffness gels, respectively (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

“…These results are consistent with a threshold of ≈15 kPa, below which myofibroblasts are not activated on substrates with tuned stiffness. [ 38b,39b ] In contrast to the elastic substrates used in these earlier studies, EKGelMA hydrogels are fibrous and biocompatible and, thus, potentially suitable as scaffolds for tissue repair cell therapies.…”

Section: Discussionmentioning

confidence: 99%

Intrafibrillar Crosslinking Enables Decoupling of Mechanical Properties and Structure of a Composite Fibrous Hydrogel

Chen,

Ezzo,

Zondag

et al. 2023

Advanced Materials

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The fibrous network of an extracellular matrix (ECM) possesses mechanical properties that convey critical biological functions in cell mechanotransduction. Engineered fibrous hydrogels show promise in emulating key aspects of ECM structure and functions, however, varying hydrogel mechanics without changing its architecture remains a challenge. We developed a composite fibrous hydrogel to vary gel stiffness without affecting structure by controlling intrafibrillar crosslinking. The hydrogel was formed from aldehyde‐modified cellulose nanocrystals and gelatin methacryloyl (GelMA) that provided the capability of intrafibrillar photocrosslinking. By varying the degree of gelatin functionalization with methacryloyl groups and/or photoirradiation time, we changed the hydrogel's elastic modulus by more than an order of magnitude, while preserving the fiber diameter and pore size. The hydrogel was used to seed primary mouse lung fibroblasts and test the role of ECM stiffness on fibroblast contraction and activation. Increasing hydrogel stiffness by stronger intrafibrillar crosslinking resulted in enhanced fibroblast activation and increased fibroblast contraction force, yet at reduced contraction speed. The developed approach enables the fabrication of biomimetic hydrogels with decoupled structural and mechanical properties, facilitating studies of the influence of tissue‐like ECM mechanics on tissue development and disease progression.This article is protected by copyright. All rights reserved

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“…[ 12 ] Myofibroblasts can produce and organize a massive collagen/extracellular matrix (ECM), resulting in dermal microenvironment disruption and skin appendage loss. [ 13 ] Dermal papilla cells (DPC) are the dermal cell population located at the root of a hair follicle, which contributes to hair follicle development, growth, and regeneration, and they are developmentally originated from SRY‐box transcription factor 2 (SOX2) + fibroblasts. [ 14 ] Thus, regulation of fibroblast fate and activation of DPC programs may achieve scar‐free in situ HF regeneration.…”

Section: Introductionmentioning

confidence: 99%

Cocktail Cell‐Reprogrammed Hydrogel Microspheres Achieving Scarless Hair Follicle Regeneration

Ji,

Li,

Xiang

et al. 2024

Advanced Science

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The scar repair inevitably causes damage of skin function and loss of skin appendages such as hair follicles (HF). It is of great challenge in wound repair that how to intervene in scar formation while simultaneously remodeling HF niche and inducing in situ HF regeneration. Here, chemical reprogramming techniques are used to identify a clinically chemical cocktail (Tideglusib and Tamibarotene) that can drive fibroblasts toward dermal papilla cell (DPC) fate. Considering the advantage of biomaterials in tissue repair and their regulation in cell behavior that may contributes to cellular reprogramming, the artificial HF seeding (AHFS) hydrogel microspheres, inspired by the natural processes of “seeding and harvest”, are constructed via using a combination of liposome nanoparticle drug delivery system, photoresponsive hydrogel shell, positively charged polyamide modification, microfluidic and photocrosslinking techniques. The identified chemical cocktail is as the core nucleus of AHFS. In vitro and in vivo studies show that AHFS can regulate fibroblast fate, induce fibroblast‐to‐DPC reprogramming by activating the PI3K/AKT pathway, finally promoting wound healing and in situ HF regeneration while inhibiting scar formation in a two‐pronged translational approach. In conclusion, AHFS provides a new and effective strategy for functional repair of skin wounds.

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The Role of Myofibroblasts in Physiological and Pathological Tissue Repair

Cited by 77 publications

References 386 publications

Ferroptosis‐Mediated Synergistic Therapy of Hypertrophic Scarring Based on Metal–Organic Framework Microneedle Patch

Ferroptosis‐Mediated Synergistic Therapy of Hypertrophic Scarring Based on Metal–Organic Framework Microneedle Patch

Intrafibrillar Crosslinking Enables Decoupling of Mechanical Properties and Structure of a Composite Fibrous Hydrogel

Cocktail Cell‐Reprogrammed Hydrogel Microspheres Achieving Scarless Hair Follicle Regeneration

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