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.
Abstract: 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.
© 2017 by the Wound Healing Society.
Publication Date: 2017-04-27 PubMed ID: 28370679DOI: 10.1111/wrr.12515Google Scholar: Lookup
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- Journal Article
Summary
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This study investigates the potential of substances released by equine mesenchymal stromal cells (MSCs) to minimize disorders of skin overgrowth in wound healing, seen in conditions like keloids in humans, and excessive tissue growth in horses. The research found that these substances can moderate the negative effects of a specific cytokine, TGF-β1, and even modify the behavior of fibroblast cells from wound sites with these overgrowth disorders, suggesting a future therapeutic avenue for these conditions.
Overview of the Research Issue
- Cutaneous Fibroproliferative Disorders (CFPDs) are conditions where skin wounds heal with an overgrowth of tissue, contributing to scarring. Prominent among these are keloids and hypertrophic scars in humans, and exuberant granulation tissue in horses. These CFPDs are the result of an imbalance in the wound healing process.
- Key among the factors causing this imbalance is a cytokine named Transforming Growth Factor Beta 1 (TGF-β1) which stimulates excessive growth of the skin’s connective tissue, distorting the normally ordered layering of these cells known as Dermal Fibroblasts (DF).
The Role of Mesenchymal Stromal Cells (MSCs)
- Mesenchymal Stromal Cells (MSCs) secrete a variety of bioactive substances (known collectively as the MSC secretome) that have been found to promote normal wound healing in humans and horses. The prospect of employing these substances to treat CFPDs, however, hasn’t been thoroughly investigated before.
Research Methodology and Results
- This study begins with a laboratory examination of the effects of the equine MSC secretome on equine DFs stimulated by TGF-β1. It was observed that the MSC secretome was able to combat the TGF-induced changes in the DF cells’ structure, growth rate, gene expression, and contraction ability.
- The team isolated primary DF cells from chronic horse wounds to test the effect of the MSC secretome on cells from an actual CFPD environment. The results did not demonstrate significant changes in cell growth or migration. However, it was seen to alter the expression of genes and proteins involved in rebuilding the extracellular matrix, while also affecting contraction.
Conclusion and Future Implications
- The findings of this study decidedly indicate the potential of the MSC secretome in controlling CFPD-related pathologies, justifying future investigations to evaluate its application as a possible therapeutic strategy.
Cite This Article
APA
Harman RM, Bihun IV, Van de Walle GR.
(2017).
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.
Wound Repair Regen, 25(2), 234-247.
https://doi.org/10.1111/wrr.12515 Publication
Researcher Affiliations
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York.
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York.
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York.
MeSH Terms
- Animals
- Blotting, Western
- Cell Proliferation / drug effects
- Cell- and Tissue-Based Therapy
- Culture Media, Conditioned
- Dermis / cytology
- Fibroblasts / drug effects
- Fibroblasts / physiology
- Gene Expression
- Horses
- Mesenchymal Stem Cells / cytology
- Mesenchymal Stem Cells / metabolism
- Models, Animal
- Transforming Growth Factor beta1 / pharmacology
- Translational Research, Biomedical
- Wound Healing / drug effects
- Wounds and Injuries / pathology
- Wounds and Injuries / therapy
Citations
This article has been cited 7 times.- Marx C, Gardner S, Harman RM, Wagner B, Van de Walle GR. Mesenchymal stromal cell-secreted CCL2 promotes antibacterial defense mechanisms through increased antimicrobial peptide expression in keratinocytes.. Stem Cells Transl Med 2021 Dec;10(12):1666-1679.
- Harman RM, Marx C, Van de Walle GR. Translational Animal Models Provide Insight Into Mesenchymal Stromal Cell (MSC) Secretome Therapy.. Front Cell Dev Biol 2021;9:654885.
- Harman RM, Patel RS, Fan JC, Park JE, Rosenberg BR, Van de Walle GR. Single-cell RNA sequencing of equine mesenchymal stromal cells from primary donor-matched tissue sources reveals functional heterogeneity in immune modulation and cell motility.. Stem Cell Res Ther 2020 Dec 4;11(1):524.
- Marx C, Gardner S, Harman RM, Van de Walle GR. The mesenchymal stromal cell secretome impairs methicillin-resistant Staphylococcus aureus biofilms via cysteine protease activity in the equine model.. Stem Cells Transl Med 2020 Jul;9(7):746-757.
- Zhen C, Zhu H, Li Q, Xu W. Protective effects of mesenchymal stem cell cond tional medium against inflammatory injury on human gingival fibroblast.. Int J Clin Exp Pathol 2017;10(8):8263-8269.
- Al Naem M, Bourebaba L, Kucharczyk K, Röcken M, Marycz K. Therapeutic mesenchymal stromal stem cells: Isolation, characterization and role in equine regenerative medicine and metabolic disorders.. Stem Cell Rev Rep 2020 Apr;16(2):301-322.
- Harman RM, Yang S, He MK, Van de Walle GR. Antimicrobial peptides secreted by equine mesenchymal stromal cells inhibit the growth of bacteria commonly found in skin wounds.. Stem Cell Res Ther 2017 Jul 4;8(1):157.
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