Adipose Tissue–Derived Stromal Cells Inhibit TGF-β1–Induced Differentiation of Human Dermal Fibroblasts and Keloid Scar–Derived Fibroblasts in a Paracrine Fashion

Spiekman, Maroesjka; Przybyt, Ewa; Plantinga, J.A.; Gibbs, Susan; Lei, Berend van der; Harmsen, Martin C.

doi:10.1097/prs.0000000000000504

Cited by 79 publications

(72 citation statements)

References 41 publications

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“…The comparative C t method (2 −ΔΔ C t ) was used to quantify gene expression levels where ΔΔ C t = Δ C t (sample) – Δ C t (reference). The previously validated reference gene beta‐2‐Microglobulin ( B2M ) was used to normalize samples . Primers to amplify fibronectin 1 ( FN1 ) , smooth muscle actin ( ACTA2 ), collagen type III alpha 1 ( COL3A1 ), collagen type I alpha 2 ( COL1A2 ), matrix metallopeptidase 1 ( MMP1 ), yes‐associated protein 1 ( YAP1 ) , tafazzin ( TAZ ), and plasminogen activator inhibitor 1 ( SERPINE1 ) were designed using Primer3 software, based on horse sequences found in the National Center of Biotechnology Information (NCBI) GenBank.…”

Section: Methodsmentioning

confidence: 99%

Secreted factors from equine mesenchymal stromal cells diminish the effects of TGF‐β1 on equine dermal fibroblasts and alter the phenotype of dermal fibroblasts isolated from cutaneous fibroproliferative wounds

Harman

Bihun

Walle

2017

Wound Repair Regeneration

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The prevalence of cutaneous fibroproliferative disorders (CFPDs) is high and almost exclusively occurs in humans (keloids and hypertrophic scars) and horses (exuberant granulation tissue), making the horse a valuable translational model for studies on prevention and treatment of human CFPDs. CFPDs arise as a result of dysregulated wound healing characterized by persistently high levels of cytokines, such as transforming growth factor beta 1 (TGF-β1), that contribute to excessive extracellular matrix deposition, and the physical disorganization of dermal fibroblasts (DF). The mesenchymal stromal cell (MSC) secretome, consisting of all factors secreted by MSC, has been shown to promote normal wound healing in both humans and horses, but its potential to treat CFPDs remains largely unexplored. Therefore, the objective of this study was to examine the effects of the equine MSC secretome on equine DF influenced by cytokines that contribute to the development of CFPDs. First, primary equine DF were treated with TGF-β1 in vitro in the presence or absence of MSC secreted products. We found that MSC secreted products could block TGF-β1-induced changes in DF morphology, proliferation rate, gene expression, and contractile-capacity. We then isolated primary DF from equine exuberant granulation tissue, to evaluate the potential of the MSC secretome to alter the phenotype of cells derived from a complex CFPD environment. These results showed that MSC secreted factors did not change proliferation or migration of these cells, but did lead to changes in expression of genes and proteins involved in extracellular matrix remodeling and did affect contractile capacity. These results warrant future studies designed to evaluate the potential of the MSC secretome to minimize the pathologies associated with CFPD in vivo.

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Section: Methodsmentioning

confidence: 99%

Secreted factors from equine mesenchymal stromal cells diminish the effects of TGF‐β1 on equine dermal fibroblasts and alter the phenotype of dermal fibroblasts isolated from cutaneous fibroproliferative wounds

Harman

Bihun

Walle

2017

Wound Repair Regeneration

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“…43,44 Previous research in our laboratory showed that ASC secrete paracrine factors that abrogate TGF-β-induced differentiation of dermal fibroblasts to myofibroblasts which is a mesenchymal transition too. 45 In general, ASC and their secreted bioactive factors harbour pro-regenerative [46][47][48] and anti-inflammatory potential. 49,50 In addition, ASC promote angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Adipose tissue–derived stromal cells’ conditioned medium modulates endothelial‐mesenchymal transition induced by IL‐1β/TGF‐β2 but does not restore endothelial function

Liguori

Moreira

et al. 2019

Cell Proliferation

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Objectives Endothelial cells undergo TGF‐β–driven endothelial‐mesenchymal transition (EndMT), representing up to 25% of cardiac myofibroblasts in ischaemic hearts. Previous research showed that conditioned medium of adipose tissue–derived stromal cells (ASC‐CMed) blocks the activation of fibroblasts into fibrotic myofibroblasts. We tested the hypothesis that ASC‐CMed abrogates EndMT and prevents the formation of adverse myofibroblasts. Materials and methods Human umbilical vein endothelial cells (HUVEC) were treated with IL‐1β and TGF‐β2 to induce EndMT, and the influence of ASC‐CMed was assessed. As controls, non‐treated HUVEC or HUVEC treated only with IL‐1β in the absence or presence of ASC‐CMed were used. Gene expression of inflammatory, endothelial, mesenchymal and extracellular matrix markers, transcription factors and cell receptors was analysed by RT‐qPCR. The protein expression of endothelial and mesenchymal markers was evaluated by immunofluorescence microscopy and immunoblotting. Endothelial cell function was measured by sprouting assay. Results IL‐1β/TGF‐β2 treatment induced EndMT, as evidenced by the change in HUVEC morphology and an increase in mesenchymal markers. ASC‐CMed blocked the EndMT‐related fibrotic processes, as observed by reduced expression of mesenchymal markers TAGLN (P = 0.0008) and CNN1 (P = 0.0573), as well as SM22α (P = 0.0501). The angiogenesis potential was impaired in HUVEC undergoing EndMT and could not be restored by ASC‐CMed. Conclusions We demonstrated that ASC‐CMed reduces IL‐1β/TGF‐β2‐induced EndMT as observed by the loss of mesenchymal markers. The present study supports the anti‐fibrotic effects of ASC‐CMed through the modulation of the EndMT process.

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“…Studies done with full thickness wounds have shown that the knockdown of YAP and TAZ significantly delays the rate of wound closure and reduces the amount of TGF‐β1 expression in fibroblast cells . These factors also modulate the expression of TGF‐β1 signaling pathway components, such as Smad2 and Smad7 . Specifically, YAP is capable of interacting with Smad7 to enhance its ability to inhibit the TGF‐β pathway .…”

Section: Hypertrophic Scar Developmentmentioning

confidence: 99%

“…While the role of exposed fat tissue and inherent MSCs/ADSCs in burn wound healing is not yet completely understood, therapy with exogenous stem cells has been explored as a new promising modality of fibrosis/scarring/contracture prevention and treatment . MSCs are defined as self‐renewing multipotent stem cells that can differentiate into various lineages of mesenchymal origin .…”

Section: Hypertrophic Scar Developmentmentioning

confidence: 99%

Current concepts related to hypertrophic scarring in burn injuries

Chiang

Borovikova

King

et al. 2016

Wound Repair Regeneration

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Scarring following burn injury and its accompanying aesthetic and functional sequelae still pose major challenges. Hypertrophic scarring (HTS) can greatly impact patients’ quality of life related to appearance, pain, pruritus and even loss of function of the injured body region. The identification of molecular events occurring in the evolution of the burn scar has increased our knowledge; however, this information has not yet translated into effective treatment modalities. Although many of the pathophysiologic pathways that bring about exaggerated scarring have been identified, certain nuances in burn scar formation are starting to be recognized. These include the effects of neurogenic inflammation, mechanotransduction, and the unique interactions of burn wound fluid with fat tissue in the deeper dermal layers, all of which may influence scarring outcome. Tension on the healing scar, pruritus, and pain all induce signaling pathways that ultimately result in increased collagen formation and myofibroblast phenotypic changes. Exposure of the fat domes in the deep dermis is associated with increased HTS, possibly on the basis of altered interaction of adipose-derived stem cells and the deep burn exudate. These pathophysiologic patterns related to stem cell-cytokine interactions, mechanotransduction, and neurogenic inflammation can provide new avenues of exploration for possible therapeutic interventions.

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Adipose Tissue–Derived Stromal Cells Inhibit TGF-β1–Induced Differentiation of Human Dermal Fibroblasts and Keloid Scar–Derived Fibroblasts in a Paracrine Fashion

Abstract: The authors show that adipose tissue-derived stromal cells inhibit TGF-β1-induced adverse differentiation and function of adult human dermal fibroblasts and TGF-β1-induced contraction in keloid scar-derived fibroblasts, in a paracrine fashion.

Cited by 79 publications

References 41 publications

Secreted factors from equine mesenchymal stromal cells diminish the effects of TGF‐β1 on equine dermal fibroblasts and alter the phenotype of dermal fibroblasts isolated from cutaneous fibroproliferative wounds

Secreted factors from equine mesenchymal stromal cells diminish the effects of TGF‐β1 on equine dermal fibroblasts and alter the phenotype of dermal fibroblasts isolated from cutaneous fibroproliferative wounds

Adipose tissue–derived stromal cells’ conditioned medium modulates endothelial‐mesenchymal transition induced by IL‐1β/TGF‐β2 but does not restore endothelial function

Current concepts related to hypertrophic scarring in burn injuries

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