Heat-Killed Lactobacilli Preparations Promote Healing in the Experimental Cutaneous Wounds

Probiotics are defined as microorganisms with beneficial health effects when consumed by humans, being applied mainly to improve allergic or intestinal diseases. Due to the increasing resistance of pathogens to antibiotics, the abuse of antibiotics becomes inefficient in the skin and in systemic infections, and probiotics may also provide the protective effect for repairing the healing of infected cutaneous wounds. Here we selected two Lactobacillus strains, L. plantarum GMNL-6 and L. paracasei GMNL-653, in heat-killed format to examine the beneficial effect in skin wound repair through the selection by promoting collagen synthesis in Hs68 fibroblast cells. The coverage of gels containing heat-killed GMNL-6 or GMNL-653 on the mouse tail with experimental wounds displayed healing promoting effects with promoting of metalloproteinase-1 expression at the early phase and reduced excessive fibrosis accumulation and deposition in the later tail-skin recovery stage. More importantly, lipoteichoic acid, the major component of Lactobacillus cell wall, from GMNL-6/GMNL-653 could achieve the anti-fibrogenic benefit similar to the heat-killed bacteria cells in the TGF-β stimulated Hs68 fibroblast cell model. Our study offers a new therapeutic potential of the heat-killed format of Lactobacillus as an alternative approach to treating skin healing disorders.

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Phagocytosis of Wnt inhibitor SFRP4 by late wound macrophages drives chronic Wnt activity for fibrotic skin healing

Science Advances ◽

10.1126/sciadv.aay3704 ◽

2020 ◽

Vol 6 (12) ◽

pp. eaay3704 ◽

Cited By ~ 5

Author(s):

Denise Gay ◽

Giulia Ghinatti ◽

Christian F. Guerrero-Juarez ◽

Rubén A. Ferrer ◽

Federica Ferri ◽

...

Keyword(s):

Hidradenitis Suppurativa ◽

Wound Repair ◽

Skin Condition ◽

Skin Wound ◽

Skin Wound Healing ◽

Single Cell Rna Sequencing ◽

Wnt Inhibitor ◽

Skin Healing ◽

Skin Wounding ◽

Regenerative Repair

Human and murine skin wounding commonly results in fibrotic scarring, but the murine wounding model wound-induced hair neogenesis (WIHN) can frequently result in a regenerative repair response. Here, we show in single-cell RNA sequencing comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.

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The Role of MSC in Wound Healing, Scarring and Regeneration

Cells ◽

10.3390/cells10071729 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1729

Author(s):

Raquel Guillamat-Prats

Keyword(s):

Wound Healing ◽

Wound Repair ◽

Therapeutic Potential ◽

Healing Process ◽

Repair Process ◽

Skin Wound ◽

Wound Healing Process ◽

Matrix Remodeling ◽

Skin Wound Healing ◽

Tissue Repair And Regeneration

Tissue repair and regeneration after damage is not completely understood, and current therapies to support this process are limited. The wound healing process is associated with cell migration and proliferation, extracellular matrix remodeling, angiogenesis and re-epithelialization. In normal conditions, a wound will lead to healing, resulting in reparation of the tissue. Several risk factors, chronic inflammation, and some diseases lead to a deficient wound closure, producing a scar that can finish with a pathological fibrosis. Mesenchymal stem/stromal cells (MSCs) are widely used for their regenerative capacity and their possible therapeutically potential. Derived products of MSCs, such as exosomes or extravesicles, have shown a therapeutic potential similar to MSCs, and these cell-free products may be interesting in clinics. MSCs or their derivative products have shown paracrine beneficial effects, regulating inflammation, modifying the fibroblast activation and production of collagen and promoting neovascularization and re-epithelialization. This review describes the effects of MSCs and their derived products in each step of the wound repair process. As well, it reviews the pre-clinical and clinical use of MSCs to benefit in skin wound healing in diabetic associated wounds and in pathophysiological fibrosis.

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In vitro antimicrobial activity and cytotoxicity of nickel(II) complexes with different diamine ligands

Journal of the Serbian Chemical Society ◽

10.2298/jsc170113026d ◽

2017 ◽

Vol 82 (4) ◽

pp. 389-398 ◽

Cited By ~ 1

Author(s):

Nenad Draskovic ◽

Biljana Glisic ◽

Sandra Vojnovic ◽

Jasmina Nikodinovic-Runic ◽

Milos Djuran

Keyword(s):

Cell Line ◽

Therapeutic Potential ◽

Fibroblast Cell ◽

Skin Wound ◽

Significant Activity ◽

Bacterial Strains ◽

Negative Effects ◽

Human Lung Fibroblast ◽

Diamine Ligands

Three diamines, 1,3-propanediamine (1,3-pd), 2,2-dimethyl-1,3-propanediamine (2,2-diMe-1,3-pd) and (?)-1,3-pentanediamine (1,3-pnd), were used for the synthesis of nickel(II) complexes 1?3, respectively, of the general formula [Ni(L)2(H2O)2]Cl2. The stoichiometries of the complexes were confirmed by elemental microanalysis, and their structures were elucidated by spectroscopic (UV?Vis and IR) and molar conductivity measurements. The complexes 1?3, along with NiCl2?6H2O and the diamine ligands, were evaluated against a panel of microbial strains that are associated with skin, wound, urinary tract and nosocomial infections. The obtained results revealed no significant activity of 1?3 against the investigated bacterial strains. On the other hand, they showed good antifungal activity against pathogenic Candida strains, with minimum inhibitory concentration (MIC) values in the range from 15.6 to 62.5 ?g mL-1. The best anti-Candida activity was observed for complex 2 against C. parapsilosis, while the least susceptible to the effect of the complexes was C. krusei. The antiproliferative effect on normal human lung fibroblast cell line MRC-5 was also evaluated in order to determine the therapeutic potential of nickel(II) complexes 1?3. These complexes showed lower negative effects on the viability of the MRC-5 cell line than the clinically used nystatin and comparable selectivity indexes to that of this antifungal drug.

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Mesenchymal Stromal Cells and Cutaneous Wound Healing: A Comprehensive Review of the Background, Role, and Therapeutic Potential

Stem Cells International ◽

10.1155/2018/6901983 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 40

Author(s):

Michael S. Hu ◽

Mimi R. Borrelli ◽

H. Peter Lorenz ◽

Michael T. Longaker ◽

Derrick C. Wan

Keyword(s):

Wound Healing ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Wound Repair ◽

Therapeutic Potential ◽

Skin Wound ◽

Skin Wound Healing ◽

Differentiation Potential ◽

Cutaneous Wound ◽

Aging Populations

Cutaneous wound repair is a highly coordinated cascade of cellular responses to injury which restores the epidermal integrity and its barrier functions. Even under optimal healing conditions, normal wound repair of adult human skin is imperfect and delayed healing and scarring are frequent occurrences. Dysregulated wound healing is a major concern for global healthcare, and, given the rise in diabetic and aging populations, this medicoeconomic disease burden will continue to rise. Therapies to reliably improve nonhealing wounds and reduce scarring are currently unavailable. Mesenchymal stromal cells (MSCs) have emerged as a powerful technique to improve skin wound healing. Their differentiation potential, ease of harvest, low immunogenicity, and integral role in native wound healing physiology make MSCs an attractive therapeutic remedy. MSCs promote cell migration, angiogenesis, epithelialization, and granulation tissue formation, which result in accelerated wound closure. MSCs encourage a regenerative, rather than fibrotic, wound healing microenvironment. Recent translational research efforts using modern bioengineering approaches have made progress in creating novel techniques for stromal cell delivery into healing wounds. This paper discusses experimental applications of various stromal cells to promote wound healing and discusses the novel methods used to increase MSC delivery and efficacy.

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A Self-Healing Hierarchical Fiber Hydrogel That Mimics ECM Structure

Materials ◽

10.3390/ma13225277 ◽

2020 ◽

Vol 13 (22) ◽

pp. 5277

Author(s):

Kai Li ◽

Yuting Zhu ◽

Qiang Zhang ◽

Xiaoli Shi ◽

Feng Liang ◽

...

Keyword(s):

Wound Repair ◽

Structural Similarity ◽

Skin Wound ◽

Good Effect ◽

Self Healing ◽

Rat Skin ◽

Simple Strategy ◽

High Structural Similarity ◽

Good Biocompatibility ◽

Skin Healing

Although there have been many studies on using hydrogels as substitutes for natural extracellular matrices (ECMs), hydrogels that mimic the structure and properties of ECM remain a contentious topic in current research. Herein, a hierarchical biomimetic fiber hydrogel was prepared using a simple strategy, with a structure highly similar to that of the ECM. Cell viability experiments showed that the hydrogel not only has good biocompatibility but also promotes cell proliferation and growth. It was also observed that cells adhere to the fibers in the hydrogel, mimicking the state of cells in the ECM. Lastly, through a rat skin wound repair experiment, we demonstrated that this hydrogel has a good effect on promoting rat skin healing. Its high structural similarity to the ECM and good biocompatibility make this hydrogel a good candidate for prospective applications in the field of tissue engineering.

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A pulsatile release platform based on photo-induced imine-crosslinking hydrogel promotes scarless wound healing

Nature Communications ◽

10.1038/s41467-021-21964-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jian Zhang ◽

Yongjun Zheng ◽

Jimmy Lee ◽

Jieyu Hua ◽

Shilong Li ◽

...

Keyword(s):

Wound Healing ◽

Wound Repair ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Skin Wound ◽

Large Animal ◽

Skin Wounds ◽

Tgfβ Signaling ◽

Pulsatile Release ◽

Ecm Extracellular Matrix

AbstractEffective healing of skin wounds is essential for our survival. Although skin has strong regenerative potential, dysfunctional and disfiguring scars can result from aberrant wound repair. Skin scarring involves excessive deposition and misalignment of ECM (extracellular matrix), increased cellularity, and chronic inflammation. Transforming growth factor-β (TGFβ) signaling exerts pleiotropic effects on wound healing by regulating cell proliferation, migration, ECM production, and the immune response. Although blocking TGFβ signaling can reduce tissue fibrosis and scarring, systemic inhibition of TGFβ can lead to significant side effects and inhibit wound re-epithelization. In this study, we develop a wound dressing material based on an integrated photo-crosslinking strategy and a microcapsule platform with pulsatile release of TGF-β inhibitor to achieve spatiotemporal specificity for skin wounds. The material enhances skin wound closure while effectively suppressing scar formation in murine skin wounds and large animal preclinical models. Our study presents a strategy for scarless wound repair.

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Current knowledge of immunomodulation strategies for chronic skin wound repair

Journal of Biomedical Materials Research Part B Applied Biomaterials ◽

10.1002/jbm.b.34921 ◽

2021 ◽

Author(s):

Parisa Heydari ◽

Mahshid Kharaziha ◽

Jaleh Varshosaz ◽

Shaghayegh Haghjooy Javanmard

Keyword(s):

Wound Repair ◽

Current Knowledge ◽

Skin Wound ◽

Chronic Skin

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A Novel Xenograft Model Demonstrates Human Fibroblast Behavior During Skin Wound Repair and Fibrosis

Advances in Wound Care ◽

10.1089/wound.2020.1392 ◽

2021 ◽

Author(s):

Mimi Borrelli ◽

Abra H Shen ◽

Michelle Griffin ◽

Shamik Mascharak ◽

Sandeep Adem ◽

...

Keyword(s):

Human Fibroblast ◽

Wound Repair ◽

Xenograft Model ◽

Skin Wound

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Abstract 13373: Exercise Improves Angiogenic Function of Circulating Exosomes in Type 2 Diabetes: Role of Extracellular SOD

Circulation ◽

10.1161/circ.142.suppl_3.13373 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Kareem Abdelsaid ◽

Sudhahar Varadarajan ◽

Archita Das ◽

Yutao Liu ◽

Xuexiu Fang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Wound Healing ◽

Endothelial Dysfunction ◽

Wound Repair ◽

Cell Communication ◽

Tube Formation ◽

Skin Wound ◽

Skin Wound Healing

Background: Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) have detrimental effects. Exercise not only improves endothelial dysfunction and angiogenesis in T2DM but also induces secretion of exosomes into circulation. Extracellular superoxide dismutase (ecSOD) is a major secretory Cu containing antioxidant enzyme that catalyzes dismutation of O 2 •- to H 2 O 2 and its full activity requires Cu transporter ATP7A. We reported that ecSOD-derived H 2 O 2 in endothelial cells (ECs) enhances angiogenesis while impaired ATP7A-ecSOD axis in diabetes induces endothelial dysfunction. Here we examined whether exercise-derived exosomes (Exe-Exo) may have pro-angiogenic effects via regulating ATP7A-ecSOD axis in T2DM. Results: Two weeks of voluntary wheel exercise of control C57Bl6 mice increased plasma exosome levels (6.2-fold) characterized by Nanosight, TEM and exosome markers (CD63, CD81, Tsg101). Treatment of HUVECs with equal number of exosomes revealed that angiogenic responses such as EC migration (1.8-fold) and tube formation (1.7-fold) were significantly enhanced by Exe-Exo compared to sedentary-derived exosomes (Sed-Exo). This was associated with increased ATP7A (2.9-fold) and ecSOD (1.4-fold) expression in Exe-Exo. Sed-Exo from high fat-induced T2DM mice significantly decreased EC migration (40%) and tube formation (10%) as well as ATP7A expression (28%) compared to Sed-Exo from control mice, which were restored by T2DM Exe-Exo, but not by T2DM/ecSOD KO Exe-Exo. Furthermore, exosomes overexpressing ecSOD (ecSOD-Exo) which mimic exercise increased angiogenesis and H2O2 levels in ECs, which were inhibited by overexpression of catalase. In vivo, skin wound healing model showed that direct application of T2DM Sed-Exo delayed while T2DM Exe-Exo enhanced wound healing of control mice. Furthermore, defective wound healing in T2DM mice or ecSOD KO mice were rescued by ecSOD-Exo application. Conclusion: Exercise training improves pro-angiogenic function of circulating exosomes in T2DM via increasing ATP7A-ecSOD axis, which may provide an effective therapy for promoting angiogenesis and wound repair in metabolic and cardiovascular diseases.

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Adipose-derived stromal/stem cells improve epidermal homeostasis

Scientific Reports ◽

10.1038/s41598-019-54797-5 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Mariko Moriyama ◽

Shunya Sahara ◽

Kaori Zaiki ◽

Ayumi Ueno ◽

Koichi Nakaoji ◽

...

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Culture System ◽

Wound Repair ◽

Cell Types ◽

Skin Wound ◽

Epidermal Keratinocytes ◽

Stromal Stem Cells ◽

Collagen Vitrigel

AbstractWound healing is regulated by complex interactions between the keratinocytes and other cell types including fibroblasts. Recently, adipose-derived mesenchymal stromal/stem cells (ASCs) have been reported to influence wound healing positively via paracrine involvement. However, their roles in keratinocytes are still obscure. Therefore, investigation of the precise effects of ASCs on keratinocytes in an in vitro culture system is required. Our recent data indicate that the epidermal equivalents became thicker on a collagen vitrigel membrane co-cultured with human ASCs (hASCs). Co-culturing the human primary epidermal keratinocytes (HPEK) with hASCs on a collagen vitrigel membrane enhanced their abilities for cell proliferation and adhesion to the membrane but suppressed their differentiation suggesting that hASCs could maintain the undifferentiated status of HPEK. Contrarily, the effects of co-culture using polyethylene terephthalate or polycarbonate membranes for HPEK were completely opposite. These differences may depend on the protein permeability and/or structure of the membrane. Taken together, our data demonstrate that hASCs could be used as a substitute for fibroblasts in skin wound repair, aesthetic medicine, or tissue engineering. It is also important to note that a co-culture system using the collagen vitrigel membrane allows better understanding of the interactions between the keratinocytes and ASCs.

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