Myofibroblasts contribute to but are not necessary for wound contraction

Ibrahim, Mohamed M.; Chen, Lei; Bond, Jennifer; Medina, Manuel A.; Ren, Lixia; Kokosis, George; Selim, Angelica; Levinson, Howard

doi:10.1038/labinvest.2015.116

Cited by 67 publications

(37 citation statements)

References 32 publications

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“…In a model of cutaneous injury, mice with global loss of α-SMA had delayed contraction and immature organization of cutaneous wounds [59]. Whether these defects result from impaired myofibroblast transdifferentiation, or reflect actions of α-SMA in vascular cells and wound angiogenesis or vascular maturation remains unknown.…”

Section: Discussionmentioning

confidence: 99%

The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling

Shinde

Humeres

Frangogiannis

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

384

257

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Cardiac myofibroblasts play an important role in myocardial remodeling. Although α-smooth muscle actin (α-SMA) expression is the hallmark of mature myofibroblasts, its role in regulating fibroblast function remains poorly understood. We explore the effects of the matrix environment in modulating cardiac fibroblast phenotype, and we investigate the role of α-SMA in fibroblast function using loss- and gain-of-function approaches. In murine myocardial infarction, infiltration of the infarct border zone with abundant α-SMA-positive myofibroblasts was associated with scar contraction. Isolated cardiac fibroblasts cultured in plates showed high α-SMA expression localized in stress fibers, exhibited activation of focal adhesion kinase (FAK), and synthesized large amounts of extracellular matrix proteins. In contrast, when these cells were cultured in collagen lattices, they exhibited marked reduction of α-SMA expression, negligible FAK activation, attenuated collagen synthesis, and increased transcription of genes associated with matrix metabolism. Transforming Growth Factor-βl-mediated contraction of fibroblast-populated collagen pads was associated with accentuated α-SMA synthesis. In contrast, serum- and basic Fibroblast Growth Factor-induced collagen pad contraction was associated with reduced α-SMA expression. α-SMA siRNA knockdown attenuated contraction of collagen pads populated with serum-stimulated cells. Surprisingly, α-SMA overexpression also reduced collagen pad contraction, suggesting that α-SMA is not sufficient to promote contraction of the matrix. Reduced contraction by α-SMA-overexpressing cells was associated with attenuated proliferative activity, in the absence of any effects on apoptosis. α-SMA may be implicated in contraction and remodeling of the extracellular matrix, but is not sufficient to induce contraction. α-SMA expression may modulate cellular functions, beyond its effects on contractility.

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Section: Discussionmentioning

confidence: 99%

The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling

Shinde

Humeres

Frangogiannis

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

384

257

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“…Myofibroblasts also have a contractile phenotype, which enables them to close the wound gap and further restore tissue integrity (38–43). Both experimental and computational studies of fibrosis have explored these mechanisms in detail (38–42, 44–58). Granulomas, however, are different than traditional wounds because they involve a highly dense organized structure that serves to wall off the infection rather than to restore damaged lung tissue architecture.…”

Section: Introductionmentioning

confidence: 99%

Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection

Warsinske

DiFazio

Linderman

et al. 2017

Journal of Theoretical Biology

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Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a pulmonary pathogen of major global concern. A key feature of Mtb infection in primates is the formation of granulomas, dense cellular structures surrounding infected lung tissue. These structures serve as the main site of host-pathogen interaction in TB, and thus to effectively treat TB we must clarify mechanisms of granuloma formation and their function in disease. Fibrotic granulomas are associated with both good and bad disease outcomes. Fibrosis can serve to isolate infected tissue from healthy tissue, but it can also cause difficulty breathing as it leaves scars. Little is known about fibrosis in TB, and data from non-human primates is just beginning to clarify the picture. This work focuses on constructing a hybrid multi-scale model of fibrotic granuloma formation, in order to identify mechanisms driving development of fibrosis in Mtb infected lungs. We combine dynamics of molecular, cellular, and tissue scale models from previously published studies to characterize the formation of two common sub-types of fibrotic granulomas: peripherally fibrotic, with a cuff of collagen surrounding granulomas, and centrally fibrotic, with collagen throughout granulomas. Uncertainty and sensitivity analysis, along with large simulation sets, enable us to identify mechanisms differentiating centrally vs. peripherally fibrotic granulomas. These findings suggest that heterogeneous cytokine environments exist within granulomas and may be responsible for driving tissue scale morphologies. Using this model we are primed to better understand the complex structure of granulomas, a necessity for developing successful treatments for TB.

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“…Hematoxylin and eosin (HE) staining, Masson's Trichrome staining, and Toluidine blue staining were performed following the manufacturer's (Sigma) standardized protocols. Immunohistochemistry (IHC) Ki67 and NM95 staining was proceeded using established methods 33. Measurements of epidermal thickness 34, collagen index 35, and microvessels, hair follicles and cell counting 36-38 in high-power field (HPF) were performed with ImageJ software.…”

Section: Methodsmentioning

confidence: 99%

Pre-vascularization Enhances Therapeutic Effects of Human Mesenchymal Stem Cell Sheets in Full Thickness Skin Wound Repair

et al. 2017

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Split thickness skin graft (STSG) implantation is one of the standard therapies for full thickness wound repair when full thickness autologous skin grafts (FTG) or skin flap transplants are inapplicable. Combined transplantation of STSG with dermal substitute could enhance its therapeutic effects but the results remain unsatisfactory due to insufficient blood supply at early stages, which causes graft necrosis and fibrosis. Human mesenchymal stem cell (hMSC) sheets are capable of accelerating the wound healing process. We hypothesized that pre-vascularized hMSC sheets would further improve regeneration by providing more versatile angiogenic factors and pre-formed microvessels. In this work, in vitro cultured hMSC cell sheets (HCS) and pre-vascularized hMSC cell sheets (PHCS) were implanted in a rat full thickness skin wound model covered with an autologous STSG. Results demonstrated that the HCS and the PHCS implantations significantly reduced skin contraction and improved cosmetic appearance relative to the STSG control group. The PHCS group experienced the least hemorrhage and necrosis, and lowest inflammatory cell infiltration. It also induced the highest neovascularization in early stages, which established a robust blood micro-circulation to support grafts survival and tissue regeneration. Moreover, the PHCS grafts preserved the largest amount of skin appendages, including hair follicles and sebaceous glands, and developed the smallest epidermal thickness. The superior therapeutic effects seen in PHCS groups were attributed to the elevated presence of growth factors and cytokines in the pre-vascularized cell sheet, which exerted a beneficial paracrine signaling during wound repair. Hence, the strategy of combining STSG with PHCS implantation appears to be a promising approach in regenerative treatment of full thickness skin wounds.

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Myofibroblasts contribute to but are not necessary for wound contraction

Cited by 67 publications

References 32 publications

The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling

The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling

Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection

Pre-vascularization Enhances Therapeutic Effects of Human Mesenchymal Stem Cell Sheets in Full Thickness Skin Wound Repair

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