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Stem Cell Therapy: Wound Healing and Skin Regeneration

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (1 December 2020) | Viewed by 39216

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Special Issue Editors

Dr. Markus H. Frank

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Guest Editor

Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Interests: dermal stem cells; skin immunity; ABC transporters; ABCB5
Special Issues, Collections and Topics in MDPI journals

Dr. Natasha Y. Frank

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Guest Editor

Brigham and Women’s Hospital, Harvard Medical School, Boston, TX, USA
Interests: epithelial stem cells; skin development; genetic mouse models, genetic skin disorders, ABCB5

Special Issue Information

Dear Colleagues,

Skin regenerative self-renewal and repair following wounding are thought to be driven by adult stem cells that continuously replenish the epidermis, dermis, and skin appendages. Stem cell loss or dysfunction likely contributes to age-related or inflammatory skin disorders, including declines of skin elasticity and barrier function, hair loss, dysregulation of immune homeostasis, and impaired wound healing. Nonhealing wounds pose a significant health problem in older patients who often also suffer from chronic systemic disorders. While stem cell transplantation carries great promise in the field of regenerative medicine, the precise contributions of stem cell dysfunction to skin aging and inflammation, and hence the potential therapeutic role of stem cells for aging prevention and/or the treatment of wound healing disorders, are currently only beginning to be explored. Additionally, current limitations in isolation of molecularly defined, pure stem cell populations with established roles in skin homeostasis and regeneration represent significant barriers to the design of rational cell-based strategies for skin regenerative disorders. This Special Issue is aimed at presenting cutting-edge research in the fields of skin regeneration, wound healing and stem cells therapy.

We cordially invite you to contribute your original research to this exciting Special Issue of Cells.

Sincerely,

Dr. Markus H. Frank
Dr. Natasha Y. Frank
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Skin regeneration
Stem cell therapy
Dermal stem cells
Epithelial stem cells
Skin immunity
Skin development
Skin aging

Published Papers (7 papers)

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Research

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21 pages, 2966 KiB

Open AccessArticle

Migration Inhibitory Factor in Conditioned Medium from Human Umbilical Cord Blood-Derived Mesenchymal Stromal Cells Stimulates Hair Growth

by Hyun Ah Oh, Jihye Kwak, Beom Joon Kim, Hye Jin Jin, Won Seok Park, Soo Jin Choi, Wonil Oh and Soyoun Um

Cells 2020, 9(6), 1344; https://doi.org/10.3390/cells9061344 - 28 May 2020

Cited by 21 | Viewed by 3802

Abstract

Conventional therapeutic applications of mesenchymal stromal cells (MSCs) focus on cell replacement and differentiation; however, increasing evidence suggests that most of their therapeutic effects are carried out by their various secretions. This study investigated the application of conditioned medium (CM) from human umbilical cord blood-derived MSCs (hUCB-MSCs) to improve hair growth and developed a method to reliably produce this optimized CM. Primed MSC-derived CM (P-CM) with combinations of TGF-β1 and LiCl was optimized by comparing its effects on the cell viability of dermal papilla cells (DPCs). P-CM significantly increased the viability of DPCs compared to CM. The secretion of vascular endothelial growth factor (VEGF) in DPCs was regulated by the macrophage migration inhibitory factor (MIF) in the P-CM secreted by MSCs. These findings suggest that P-CM can improve the efficacy in hair growth via a paracrine mechanism and that MIF in P-CM exerts hair growth-promoting effects via a VEGF-related β-catenin and p-GSK-3β [SER9] signaling pathway. Furthermore, clinical trials have shown that 5% P-CM improved androgenetic alopecia through producing an increased hair density, thickness, and growth rate, suggesting that this topical agent may be a novel and effective treatment option for patients with androgenetic alopecia. Full article

(This article belongs to the Special Issue Stem Cell Therapy: Wound Healing and Skin Regeneration)

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17 pages, 2939 KiB

Open AccessArticle

Cellular Response to Vitamin C-Enriched Chitosan/Agarose Film with Potential Application as Artificial Skin Substitute for Chronic Wound Treatment

by Vladyslav Vivcharenko, Michal Wojcik and Agata Przekora

Cells 2020, 9(5), 1185; https://doi.org/10.3390/cells9051185 - 10 May 2020

Cited by 24 | Viewed by 4193

Abstract

The treatment of chronic wounds is still a meaningful challenge to physicians. The aim of this work was to produce vitamin C-enriched chitosan/agarose (CHN/A) film that could serve as potential artificial skin substitute for chronic wound treatment. The biomaterial was fabricated by a newly developed and simplified method via mixing acidic chitosan solution with alkaline agarose solution that allowed to obtain slightly acidic pH (5.97) of the resultant material, which is known to support skin regeneration. Vitamin C was immobilized within the matrix of the film by entrapment method during production process. Produced films (CHN/A and CHN/A + vit C) were subjected to comprehensive evaluation of cellular response with the use of human skin fibroblasts, epidermal keratinocytes, and macrophages. It was demonstrated that novel biomaterials support adhesion and growth of human skin fibroblasts and keratinocytes, have ability to slightly reduce transforming growth factor-beta 1 (TGF-β1) (known to be present at augmented levels in the epidermis of chronic wounds), and increase platelet-derived growth factor-BB (PDGF-BB) secretion by the cells. Nevertheless, addition of vitamin C to the biomaterial formulation does not significantly improve its biological properties due to burst vitamin release profile. Obtained results clearly demonstrated that produced CHN/A film has great potential to be used as cellular dermal, epidermal, or dermo-epidermal graft pre-seeded with human skin cells for chronic wound treatment. Full article

(This article belongs to the Special Issue Stem Cell Therapy: Wound Healing and Skin Regeneration)

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23 pages, 5246 KiB

Open AccessArticle

Homing and Engraftment of Intravenously Administered Equine Cord Blood-Derived Multipotent Mesenchymal Stromal Cells to Surgically Created Cutaneous Wound in Horses: A Pilot Project

by Suzanne J. K. Mund, Eiko Kawamura, Awang Hazmi Awang-Junaidi, John Campbell, Bruce Wobeser, Daniel J. MacPhee, Ali Honaramooz and Spencer Barber

Cells 2020, 9(5), 1162; https://doi.org/10.3390/cells9051162 - 08 May 2020

Cited by 10 | Viewed by 3249

Abstract

Limb wounds on horses are often slow to heal and are prone to developing exuberant granulation tissue (EGT) and close primarily through epithelialization, which results in a cosmetically inferior and non-durable repair. In contrast, wounds on the body heal rapidly and primarily through contraction and rarely develop EGT. Intravenous (IV) multipotent mesenchymal stromal cells (MSCs) are promising. They home and engraft to cutaneous wounds and promote healing in laboratory animals, but this has not been demonstrated in horses. Furthermore, the clinical safety of administering >1.00 × 10⁸ allogeneic MSCs IV to a horse has not been determined. A proof-of-principle pilot project was performed with two horses that were administered 1.02 × 10⁸ fluorescently labeled allogeneic cord blood-derived MSCs (CB-MSCs) following wound creation on the forelimb and thorax. Wounds and contralateral non-wounded skin were sequentially biopsied on days 0, 1, 2, 7, 14, and 33 and evaluated with confocal microscopy to determine presence of homing and engraftment. Results confirmed preferential homing and engraftment to wounds with persistence of CB-MSCs at 33 days following wound creation, without clinically adverse reactions to the infusion. The absence of overt adverse reactions allows further studies to determine effects of IV CB-MSCs on equine wound healing. Full article

(This article belongs to the Special Issue Stem Cell Therapy: Wound Healing and Skin Regeneration)

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20 pages, 6920 KiB

Open AccessArticle

A Dense Fibrillar Collagen Scaffold Differentially Modulates Secretory Function of iPSC-Derived Vascular Smooth Muscle Cells to Promote Wound Healing

by Biraja C. Dash, Ocean Setia, Jolanta Gorecka, Hassan Peyvandi, Kaiti Duan, Lara Lopes, James Nie, Francois Berthiaume, Alan Dardik and Henry C. Hsia

Cells 2020, 9(4), 966; https://doi.org/10.3390/cells9040966 - 14 Apr 2020

Cited by 19 | Viewed by 3691

Abstract

The application of human-induced pluripotent stem cells (hiPSCs) to generate vascular smooth muscle cells (hiPSC-VSMCs) in abundance is a promising strategy for vascular regeneration. While hiPSC-VSMCs have already been utilized for tissue-engineered vascular grafts and disease modeling, there is a lack of investigations exploring their therapeutic secretory factors. The objective of this manuscript was to understand how the biophysical property of a collagen-based scaffold dictates changes in the secretory function of hiPSC-VSMCs while developing hiPSC-VSMC-based therapy for durable regenerative wound healing. We investigated the effect of collagen fibrillar density (CFD) on hiPSC-VSMC’s paracrine secretion and cytokines via the construction of varying density of collagen scaffolds. Our study demonstrated that CFD is a key scaffold property that modulates the secretory function of hiPSC-VSMCs. This study lays the foundation for developing collagen-based scaffold materials for the delivery of hiPSC-VSMCs to promote regenerative healing through guiding paracrine signaling pathways. Full article

(This article belongs to the Special Issue Stem Cell Therapy: Wound Healing and Skin Regeneration)

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17 pages, 14143 KiB

Open AccessArticle

Inflammation Alters the Secretome and Immunomodulatory Properties of Human Skin-Derived Precursor Cells

by Joery De Kock, Robim Marcelino Rodrigues, Steven Branson, Lieven Verhoye, Haaike Colemonts-Vroninks, Matthias Rombaut, Joost Boeckmans, Jessie Neuckermans, Sien Lequeue, Karolien Buyl, Makram Merimi, Douaa Moussa Agha, Veerle De Boe, Laurence Lagneaux, Philip Meuleman, Tamara Vanhaecke and Mehdi Najar

Cells 2020, 9(4), 914; https://doi.org/10.3390/cells9040914 - 08 Apr 2020

Cited by 9 | Viewed by 2988

Abstract

Human skin-derived precursors (SKP) represent a group of somatic stem/precursor cells that reside in dermal skin throughout life that harbor clinical potential. SKP have a high self-renewal capacity, the ability to differentiate into multiple cell types and low immunogenicity, rendering them key candidates for allogeneic cell-based, off-the-shelf therapy. However, potential clinical application of allogeneic SKP requires that these cells retain their therapeutic properties under all circumstances and, in particular, in the presence of an inflammation state. Therefore, in this study, we investigated the impact of pro-inflammatory stimulation on the secretome and immunosuppressive properties of SKP. We demonstrated that pro-inflammatory stimulation of SKP significantly changes their expression and the secretion profile of chemo/cytokines and growth factors. Most importantly, we observed that pro-inflammatory stimulated SKP were still able to suppress the graft-versus-host response when cotransplanted with human PBMC in severe-combined immune deficient (SCID) mice, albeit to a much lesser extent than unstimulated SKP. Altogether, this study demonstrates that an inflammatory microenvironment has a significant impact on the immunological properties of SKP. These alterations need to be taken into account when developing allogeneic SKP-based therapies. Full article

(This article belongs to the Special Issue Stem Cell Therapy: Wound Healing and Skin Regeneration)

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Review

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21 pages, 600 KiB

Open AccessReview

Systematic Review of Stem-Cell-Based Therapy of Burn Wounds: Lessons Learned from Animal and Clinical Studies

by Josefine Lin Henriksen, Nana Brandborg Sørensen, Trine Fink, Vladimir Zachar and Simone Riis Porsborg

Cells 2020, 9(12), 2545; https://doi.org/10.3390/cells9122545 - 26 Nov 2020

Cited by 14 | Viewed by 3024

Abstract

Treatment of severe burn wounds presents a daunting medical challenge, and novel approaches promoting healing and reducing scarring are highly desirable. The application of mesenchymal stem/stromal cells (MSCs) has been suggested as a novel treatment. In this paper, we present systematic reviews of pre-clinical and clinical studies of MSC therapy for second- or third-degree thermal burn wounds. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, the PubMed and Embase databases were searched, and interventional studies of MSC therapy using rodent models (21 studies) or human burn patients (three studies) were included in the pre-clinical and clinical reviews, respectively, where both overall outcome and wound-healing-phase-specific methodologies and effects were assessed. The pre-clinical studies demonstrated a promising effect of the application of MSCs on several wound healing phases. The clinical studies also suggested that the MSC treatment was beneficial, particularly in the remodeling phase. However, the limited number of studies, their lack of homogeneity in study design, relatively high risk of bias, lack of reporting on mode of action (MOA), and discontinuity of evidence restrict the strength of these findings. This comprehensive review presents an overview of available methodologies to assess the MOA of MSC treatment for distinct wound healing phases. Furthermore, it includes a set of recommendations for the design of high-quality clinical studies that can determine the efficacy of MSCs as a therapy for burn wounds. Full article

(This article belongs to the Special Issue Stem Cell Therapy: Wound Healing and Skin Regeneration)

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Graphical abstract

29 pages, 3816 KiB

Open AccessReview

A Concise Review on Tissue Engineered Artificial Skin Grafts for Chronic Wound Treatment: Can We Reconstruct Functional Skin Tissue In Vitro?

by Agata Przekora

Cells 2020, 9(7), 1622; https://doi.org/10.3390/cells9071622 - 06 Jul 2020

Cited by 96 | Viewed by 16883

Abstract

Chronic wounds occur as a consequence of a prolonged inflammatory phase during the healing process, which precludes skin regeneration. Typical treatment for chronic wounds includes application of autografts, allografts collected from cadaver, and topical delivery of antioxidant, anti-inflammatory, and antibacterial agents. Nevertheless, the mentioned therapies are not sufficient for extensive or deep wounds. Moreover, application of allogeneic skin grafts carries high risk of rejection and treatment failure. Advanced therapies for chronic wounds involve application of bioengineered artificial skin substitutes to overcome graft rejection as well as topical delivery of mesenchymal stem cells to reduce inflammation and accelerate the healing process. This review focuses on the concept of skin tissue engineering, which is a modern approach to chronic wound treatment. The aim of the article is to summarize common therapies for chronic wounds and recent achievements in the development of bioengineered artificial skin constructs, including analysis of biomaterials and cells widely used for skin graft production. This review also presents attempts to reconstruct nerves, pigmentation, and skin appendages (hair follicles, sweat glands) using artificial skin grafts as well as recent trends in the engineering of biomaterials, aiming to produce nanocomposite skin substitutes (nanofilled polymer composites) with controlled antibacterial activity. Finally, the article describes the composition, advantages, and limitations of both newly developed and commercially available bioengineered skin substitutes. Full article

(This article belongs to the Special Issue Stem Cell Therapy: Wound Healing and Skin Regeneration)

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