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Zhao H, Zhou L, Siegfried L, Supp D, Boyce S, Andl T, Zhang Y. CD133-positive dermal papilla cells are a major driver in promoting hair follicle formation. RESEARCH SQUARE 2025:rs.3.rs-5054470. [PMID: 40313747 PMCID: PMC12045375 DOI: 10.21203/rs.3.rs-5054470/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
A major contributing factor to the failure of cell-based human hair follicle (HF) engineering is our inability to cultivate highly specialized, inductive mesenchymal fibroblasts, which reside in a unique niche at the HF base, called the dermal papilla (DP). We and other groups have discovered a unique DP fibroblast subpopulation that can be identified by the cell surface marker CD133. However, the biological difference between CD133-positive (CD133+) and CD133-negative (CD133-) DP cells remains unknown. Using a newly developed double fluorescent transgenic mouse strain, we isolated CD133 + and CD133- DP cells from mouse anagen HFs. In monolayer culture, both DP populations gradually lost expression of the anagen DP signature gene, versican. When maintained in three-dimensional spheroid culture, versican expression was restored in both CD133 + and CD133- DP cells. Importantly, CD133 + DP spheroids appeared more compact, showed stronger alkaline phosphatase staining (AP), and expressed higher levels of DP signature genes. In in vivo skin reconstitution assays, mice grafted with CD133 + DP spheroids grew more hairs in healed wounds than those grafted with CD133- DP spheroids. The data underscore the importance of CD133 + DP cells as a driver of HF formation, which may present a unique opportunity to improve the use of human DP cells in tissue-engineered skin substitutes (TESS).
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Affiliation(s)
| | - Linli Zhou
- University of Cincinnati College of Pharmacy
| | | | | | | | - Thomas Andl
- University of Central Florida Burnett School of Biological Sciences
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Hamida OB, Kim MK, Sung YK, Kim MK, Kwack MH. Hair Regeneration Methods Using Cells Derived from Human Hair Follicles and Challenges to Overcome. Cells 2024; 14:7. [PMID: 39791708 PMCID: PMC11720663 DOI: 10.3390/cells14010007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/12/2024] [Accepted: 12/23/2024] [Indexed: 01/12/2025] Open
Abstract
The hair follicle is a complex of mesenchymal and epithelial cells acquiring different properties and characteristics responsible for fulfilling its inductive and regenerative role. The epidermal and dermal crosstalk induces morphogenesis and maintains hair follicle cycling properties. The hair follicle is enriched with pluripotent stem cells, where dermal papilla (DP) cells and dermal sheath (DS) cells constitute the dermal compartment and the epithelial stem cells existing in the bulge region exert their regenerative role by mediating the epithelial-mesenchymal interaction (EMI). Many studies have developed and focused on various methods to optimize the EMI through in vivo and in vitro approaches for hair regeneration. The culturing of human hair mesenchymal cells resulted in the loss of trichogenicity and inductive properties of DP cells, limiting their potential application in de novo hair follicle generation in vivo. Epithelial stem cells derived from human hair follicles are challenging to isolate and culture, making it difficult to obtain enough cells for hair regeneration purposes. Mesenchymal stem cells and epithelial stem cells derived from human hair follicles lose their ability to form hair follicles during culture, limiting the study of hair follicle formation in vivo. Therefore, many attempts and methods have been developed to overcome these limitations. Here, we review the possible and necessary cell methods and techniques used for human hair follicle regeneration and the restoration of hair follicle cell inductivity in culture.
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Affiliation(s)
- Ons Ben Hamida
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (O.B.H.); (M.K.K.); (Y.K.S.); (M.K.K.)
| | - Moon Kyu Kim
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (O.B.H.); (M.K.K.); (Y.K.S.); (M.K.K.)
- Hair Transplantation Center, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Young Kwan Sung
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (O.B.H.); (M.K.K.); (Y.K.S.); (M.K.K.)
| | - Min Kyu Kim
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (O.B.H.); (M.K.K.); (Y.K.S.); (M.K.K.)
| | - Mi Hee Kwack
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (O.B.H.); (M.K.K.); (Y.K.S.); (M.K.K.)
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Wei Q, An Y, Zhao X, Li M, Zhang J. Three-dimensional bioprinting of tissue-engineered skin: Biomaterials, fabrication techniques, challenging difficulties, and future directions: A review. Int J Biol Macromol 2024; 266:131281. [PMID: 38641503 DOI: 10.1016/j.ijbiomac.2024.131281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/17/2024] [Accepted: 03/29/2024] [Indexed: 04/21/2024]
Abstract
As an emerging new manufacturing technology, Three-dimensional (3D) bioprinting provides the potential for the biomimetic construction of multifaceted and intricate architectures of functional integument, particularly functional biomimetic dermal structures inclusive of cutaneous appendages. Although the tissue-engineered skin with complete biological activity and physiological functions is still cannot be manufactured, it is believed that with the advances in matrix materials, molding process, and biotechnology, a new generation of physiologically active skin will be born in the future. In pursuit of furnishing readers and researchers involved in relevant research to have a systematic and comprehensive understanding of 3D printed tissue-engineered skin, this paper furnishes an exegesis on the prevailing research landscape, formidable obstacles, and forthcoming trajectories within the sphere of tissue-engineered skin, including: (1) the prevalent biomaterials (collagen, chitosan, agarose, alginate, etc.) routinely employed in tissue-engineered skin, and a discerning analysis and comparison of their respective merits, demerits, and inherent characteristics; (2) the underlying principles and distinguishing attributes of various current printing methodologies utilized in tissue-engineered skin fabrication; (3) the present research status and progression in the realm of tissue-engineered biomimetic skin; (4) meticulous scrutiny and summation of the extant research underpinning tissue-engineered skin inform the identification of prevailing challenges and issues.
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Affiliation(s)
- Qinghua Wei
- School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an 710072, China; Innovation Center NPU Chongqing, Northwestern Polytechnical University, Chongqing 400000, China.
| | - Yalong An
- School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an 710072, China
| | - Xudong Zhao
- School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an 710072, China
| | - Mingyang Li
- School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an 710072, China
| | - Juan Zhang
- School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an 710072, China
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4
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Lv X, Li Y, Chen W, Wang S, Cao X, Yuan Z, Getachew T, Mwacharo J, Haile A, Li Y, Sun W. Association between DNA Methylation in the Core Promoter Region of the CUT-like Homeobox 1 ( CUX1) Gene and Lambskin Pattern in Hu Sheep. Genes (Basel) 2023; 14:1873. [PMID: 37895221 PMCID: PMC10606103 DOI: 10.3390/genes14101873] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/29/2023] Open
Abstract
CUT-like homeobox 1 (CUX1) has been proven to be a key regulator in sheep hair follicle development. In our previous study, CUX1 was identified as a differential expressed gene between Hu sheep lambskin with small wave patterns (SM) and straight wool patterns (ST); however, the exact molecular mechanism of CUX1 expression has been obscure. As DNA methylation can regulate the gene expression, the potential association between CUX1 core promotor region methylation and lambskin pattern in Hu sheep was explored in the present study. The results show that the core promoter region of CUX1 was present at (-1601-(-1) bp) upstream of the transcription start site. A repressive region (-1151-(-751) bp) was also detected, which had a strong inhibitory effect on CUX1 promoter activity. Bisulfite amplicon sequencing revealed that no significant difference was detected between the methylation levels of CUX1 core promoter region in SM tissues and ST tissues. Although the data demonstrated the differential expression of CUX1 between SM and ST probably has no association with DNA methylation, the identification of the core region and a potential repressive region of CUX1 promoter can enrich the role of CUX1 in Hu sheep hair follicle development.
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Affiliation(s)
- Xiaoyang Lv
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
| | - Yue Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Animal Husbandry and Veterinary Station, Zhuba Street, Hongze District, Huai’an 223100, China
| | - Weihao Chen
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Shanhe Wang
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xiukai Cao
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
| | - Zehu Yuan
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
| | - Tesfaye Getachew
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
- International Centre for Agricultural Research in the Dry Areas, Addis Ababa 999047, Ethiopia
| | - Joram Mwacharo
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
- International Centre for Agricultural Research in the Dry Areas, Addis Ababa 999047, Ethiopia
| | - Aynalem Haile
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
- International Centre for Agricultural Research in the Dry Areas, Addis Ababa 999047, Ethiopia
| | - Yutao Li
- CSIRO Agriculture and Food, 306 Carmody Rd., Saint Lucia, QLD 4067, Australia;
| | - Wei Sun
- Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou University, Yangzhou 225009, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- “Innovative China” “Belt and Road” International Agricultural Technology Innovation Institute for Evaluation, Protection, and Improvement on Sheep Genetic Resource, Yangzhou 225009, China
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Abstract
Pathological hair loss (also known as alopecia) and shortage of hair follicle (HF) donors have posed an urgent requirement for HF regeneration. With the revelation of mechanisms in tissue engineering, the proliferation of HFs in vitro has achieved more promising trust for the treatments of alopecia and other skin impairments. Theoretically, HF organoids have great potential to develop into native HFs and attachments such as sweat glands after transplantation. However, since the rich extracellular matrix (ECM) deficiency, the induction characteristics of skin-derived cells gradually fade away along with their trichogenic capacity after continuous cell passaging in vitro. Therefore, ECM-mimicking support is an essential prelude before HF transplantation is implemented. This review summarizes the status of providing various epidermal and dermal cells with a three-dimensional (3D) scaffold to support the cell homeostasis and better mimic in vivo environments for the sake of HF regeneration. HF-relevant cells including dermal papilla cells (DPCs), hair follicle stem cells (HFSCs), and mesenchymal stem cells (MSCs) are able to be induced to form HF organoids in the vitro culture system. The niche microenvironment simulated by different forms of biomaterial scaffold can offer the cells a network of ordered growth environment to alleviate inductivity loss and promote the expression of functional proteins. The scaffolds often play the role of ECM substrates and bring about epithelial-mesenchymal interaction (EMI) through coculture to ensure the functional preservation of HF cells during in vitro passage. Functional HF organoids can be formed either before or after transplantation into the dermis layer. Here, we review and emphasize the importance of 3D culture in HF regeneration in vitro. Finally, the latest progress in treatment trials and critical analysis of the properties and benefits of different emerging biomaterials for HF regeneration along with the main challenges and prospects of HF regenerative approaches are discussed.
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Affiliation(s)
- Wei Zheng
- College of Food Science & Technology, Shanghai Ocean University, Shanghai 201306, P.R. China
| | - Chang-Hua Xu
- College of Food Science & Technology, Shanghai Ocean University, Shanghai 201306, P.R. China
- Shanghai Engineering Research Center of Aquatic-Product Processing & Preservation, Shanghai 201306, China
- Laboratory of Quality and Safety Risk Assessment for Aquatic Products on Storage and Preservation (Shanghai), Ministry of Agriculture, Shanghai 201306, China
- National R&D Branch Center for Freshwater Aquatic Products Processing Technology (Shanghai), Shanghai 201306, China
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Weng T, Zhang W, Xia Y, Wu P, Yang M, Jin R, Xia S, Wang J, You C, Han C, Wang X. 3D bioprinting for skin tissue engineering: Current status and perspectives. J Tissue Eng 2021; 12:20417314211028574. [PMID: 34345398 PMCID: PMC8283073 DOI: 10.1177/20417314211028574] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/10/2021] [Indexed: 12/25/2022] Open
Abstract
Skin and skin appendages are vulnerable to injury, requiring rapidly reliable regeneration methods. In recent years, 3D bioprinting has shown potential for wound repair and regeneration. 3D bioprinting can be customized for skin shape with cells and other materials distributed precisely, achieving rapid and reliable production of bionic skin substitutes, therefore, meeting clinical and industrial requirements. Additionally, it has excellent performance with high resolution, flexibility, reproducibility, and high throughput, showing great potential for the fabrication of tissue-engineered skin. This review introduces the common techniques of 3D bioprinting and their application in skin tissue engineering, focusing on the latest research progress in skin appendages (hair follicles and sweat glands) and vascularization, and summarizes current challenges and future development of 3D skin printing.
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Affiliation(s)
- Tingting Weng
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- The Key Laboratory of Trauma and Burns of Zhejiang University, Hangzhou, Zhejiang, China
| | - Wei Zhang
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- The Key Laboratory of Trauma and Burns of Zhejiang University, Hangzhou, Zhejiang, China
| | - Yilan Xia
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Pan Wu
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- The Key Laboratory of Trauma and Burns of Zhejiang University, Hangzhou, Zhejiang, China
| | - Min Yang
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- The Key Laboratory of Trauma and Burns of Zhejiang University, Hangzhou, Zhejiang, China
| | - Ronghua Jin
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- The Key Laboratory of Trauma and Burns of Zhejiang University, Hangzhou, Zhejiang, China
| | - Sizhan Xia
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- The Key Laboratory of Trauma and Burns of Zhejiang University, Hangzhou, Zhejiang, China
| | - Jialiang Wang
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- The Key Laboratory of Trauma and Burns of Zhejiang University, Hangzhou, Zhejiang, China
| | - Chuangang You
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- The Key Laboratory of Trauma and Burns of Zhejiang University, Hangzhou, Zhejiang, China
| | - Chunmao Han
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- The Key Laboratory of Trauma and Burns of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xingang Wang
- Department of Burns & Wound Care Centre, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- The Key Laboratory of Trauma and Burns of Zhejiang University, Hangzhou, Zhejiang, China
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7
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Advanced Medical Therapies in the Management of Non-Scarring Alopecia: Areata and Androgenic Alopecia. Int J Mol Sci 2020; 21:ijms21218390. [PMID: 33182308 PMCID: PMC7664905 DOI: 10.3390/ijms21218390] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 11/02/2020] [Accepted: 11/06/2020] [Indexed: 12/28/2022] Open
Abstract
Alopecia is a challenging condition for both physicians and patients. Several topical, intralesional, oral, and surgical treatments have been developed in recent decades, but some of those therapies only provide partial improvement. Advanced medical therapies are medical products based on genes, cells, and/or tissue engineering products that have properties in regenerating, repairing, or replacing human tissue. In recent years, numerous applications have been described for advanced medical therapies. With this background, those therapies may have a role in the treatment of various types of alopecia such as alopecia areata and androgenic alopecia. The aim of this review is to provide dermatologists an overview of the different advanced medical therapies that have been applied in the treatment of alopecia, by reviewing clinical and basic research studies as well as ongoing clinical trials.
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Przekora A. A Concise Review on Tissue Engineered Artificial Skin Grafts for Chronic Wound Treatment: Can We Reconstruct Functional Skin Tissue In Vitro? Cells 2020; 9:cells9071622. [PMID: 32640572 PMCID: PMC7407512 DOI: 10.3390/cells9071622] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/17/2020] [Accepted: 06/21/2020] [Indexed: 12/12/2022] Open
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.
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Affiliation(s)
- Agata Przekora
- Department of Biochemistry and Biotechnology, Medical University of Lublin, Chodzki 1 Street, 20-093 Lublin, Poland
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9
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Kalabusheva EP, Vorotelyak EA. Generation of Hair Follicle Germs In Vitro Using Human Postnatal Skin Cells. Methods Mol Biol 2020; 2154:153-163. [PMID: 32314215 DOI: 10.1007/978-1-0716-0648-3_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
Modeling organoids with hair follicle germ-like properties provides an opportunity for developing strategies for alopecia drug discovery and replacement therapy, as well as investigating the molecular mechanisms underlying human hair follicle regeneration in vitro. Hair follicle germ reconstruction in vitro is based on dermal papilla hair-inducing abilities and the plasticity of skin epidermal keratinocytes. The current protocol describes a highly efficient approach suitable for adult human skin cell applications. This method allows to obtain hair follicle germs using tissues from one donor. Isolated and cultured for 2 weeks, adult hair follicle dermal papilla cells and skin epidermal keratinocytes self-organize in hanging drop cultures generating organoids that exhibit the features of folliculogenesis onset.
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Affiliation(s)
- Ekaterina P Kalabusheva
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow, Russia.
- Pirogov Russian National Research Medical University, Moscow, Russia.
| | - Ekaterina A Vorotelyak
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow, Russia
- Pirogov Russian National Research Medical University, Moscow, Russia
- Lomonosov Moscow State University, Moscow, Russia
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10
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Weng T, Wu P, Zhang W, Zheng Y, Li Q, Jin R, Chen H, You C, Guo S, Han C, Wang X. Regeneration of skin appendages and nerves: current status and further challenges. J Transl Med 2020; 18:53. [PMID: 32014004 PMCID: PMC6996190 DOI: 10.1186/s12967-020-02248-5] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 01/28/2020] [Indexed: 12/14/2022] Open
Abstract
Tissue-engineered skin (TES), as an analogue of native skin, is promising for wound repair and regeneration. However, a major drawback of TES products is a lack of skin appendages and nerves to enhance skin healing, structural integrity and skin vitality. Skin appendages and nerves are important constituents for fully functional skin. To date, many studies have yielded remarkable results in the field of skin appendages reconstruction and nerve regeneration. However, patients often complain about a loss of skin sensation and even cutaneous chronic pain. Restoration of pain, temperature, and touch perceptions should now be a major challenge to solve in order to improve patients’ quality of life. Current strategies to create skin appendages and sensory nerve regeneration are mainly based on different types of seeding cells, scaffold materials, bioactive factors and involved signaling pathways. This article provides a comprehensive overview of different strategies for, and advances in, skin appendages and sensory nerve regeneration, which is an important issue in the field of tissue engineering and regenerative medicine.
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Affiliation(s)
- Tingting Weng
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Pan Wu
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Wei Zhang
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Yurong Zheng
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China
| | - Qiong Li
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Ronghua Jin
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Haojiao Chen
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Chuangang You
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Songxue Guo
- Department of Plastic Surgery, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310009, China
| | - Chunmao Han
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Xingang Wang
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China.
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11
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Zhang L, Wang WH, Jin JY, Degan S, Zhang GQ, Erdmann D, Hall RP, Zhang JY. Induction of hair follicle neogenesis with cultured mouse dermal papilla cells in de novo regenerated skin tissues. J Tissue Eng Regen Med 2019; 13:1641-1650. [PMID: 31216101 DOI: 10.1002/term.2918] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 04/30/2019] [Accepted: 05/24/2019] [Indexed: 12/19/2022]
Abstract
De novo skin regeneration with human keratinocytes amplified in culture is a life-saving procedure for patients with extensive skin loss and chronic wounds. It also provides a valuable platform for gene function and therapeutic assessments. Nevertheless, tissues generated in this manner lack hair follicles that are important for skin homeostasis, barrier function, and repair. In this study, we generated skin tissues with human keratinocytes combined with dermal papilla (DP) cells isolated from mouse whisker hair. For this, cultured keratinocytes and mouse DP (mDP) cells were mixed at 10:1 ratio and seeded onto devitalized human dermal matrix derived from surgically discarded human abdominoplasty skin. After 1 week in submerged culture, the cell/matrix composites were grafted onto the skin wound beds of immunocompromised NSG.SCID mice. Histological analysis of 6-week-old skin grafts showed that tissues generated with the addition of mDP cells contained Sox2-positive dermal condensates and well-differentiated folliculoid structures that express human keratinocyte markers. These results indicate that cultured mDP cells can induce hair follicle neogenesis in the de novo regenerated skin tissues. Our method offers a new experimental system for mechanistic studies of hair follicle morphogenesis and tissue regeneration and provides insights to solving an important clinical challenge in generation of fully functional skin with a limited source of donor cells.
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Affiliation(s)
- Long Zhang
- Department of Interventional Radiology and Vascular Surgery, Peking University Third Hospital, Beijing, China.,Department of Dermatology, Duke University Medical Center, Durham, NC
| | - Wen-Hui Wang
- Department of Dermatology, Duke University Medical Center, Durham, NC.,Department of Dermatology, Peking University Third Hospital, Beijing, China
| | - Jane Y Jin
- Department of Dermatology, Duke University Medical Center, Durham, NC
| | - Simone Degan
- Department of Dermatology, Duke University Medical Center, Durham, NC
| | - Guo-Qiang Zhang
- Department of Dermatology, Duke University Medical Center, Durham, NC.,Department of Dermatology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Detlev Erdmann
- Department of Surgery, Division of Plastic, Maxillofacial and Oral Surgery, Duke University Medical Center, Durham, NC
| | - Russell P Hall
- Department of Dermatology, Duke University Medical Center, Durham, NC
| | - Jennifer Y Zhang
- Department of Dermatology, Duke University Medical Center, Durham, NC
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12
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Abstract
Fabrication of engineered skin substitutes provides an alternative approach for the treatment of full-thickness burns and other skin injuries. Improving the functionality of current skin substitute models requires incorporation of skin appendages, including hair follicles, sebaceous glands, and sweat glands. In this chapter, methods for generating skin substitutes incorporating chimeric hair follicles are described. Isolation of human keratinocytes, human fibroblasts, and murine dermal papilla cells is first outlined. These cell types are then combined with collagen-glycosaminoglycan (GAG) scaffolds to generate human-murine chimeric grafts which are then grafted to full-thickness surgical wounds in immunodeficient mice. The methods described allow for the generation of a human-mouse follicular structure.
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Affiliation(s)
- Andrea L Lalley
- Research Department, Shriners Hospitals for Children, Cincinnati, OH, USA
| | - Steven T Boyce
- Research Department, Shriners Hospitals for Children, Cincinnati, OH, USA.
- Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.
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13
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Randomized, Paired-Site Comparison of Autologous Engineered Skin Substitutes and Split-Thickness Skin Graft for Closure of Extensive, Full-Thickness Burns. J Burn Care Res 2018; 38:61-70. [PMID: 27404165 DOI: 10.1097/bcr.0000000000000401] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Stable closure of full-thickness burn wounds remains a limitation to recovery from burns of greater than 50% of the total body surface area (TBSA). Hypothetically, engineered skin substitutes (ESS) consisting of autologous keratinocytes and fibroblasts attached to collagen-based scaffolds may reduce requirements for donor skin, and decrease mortality. ESS were prepared from split-thickness skin biopsies collected after enrollment of 16 pediatric burn patients into an approved study protocol. ESS and split-thickness autograft (AG) were applied to 15 subjects with full-thickness burns involving a mean of 76.9% TBSA. Data consisted of photographs, tracings of donor skin and healed wounds, comparison of mortality with the National Burn Repository, correlation of TBSA closed wounds with TBSA full-thickness burn, frequencies of regrafting, and immunoreactivity to the biopolymer scaffold. One subject expired before ESS application, and 15 subjects received 2056 ESS grafts. The ratio of closed wound to donor areas was 108.7 ± 9.7 for ESS compared with a maximum of 4.0 ± 0.0 for AG. Mortality for enrolled subjects was 6.25%, and 30.3% for a comparable population from the National Burn Repository (P < .05). Engraftment was 83.5 ± 2.0% for ESS and 96.5 ± 0.9% for AG. Percentage TBSA closed was 29.9 ± 3.3% for ESS, and 47.0 ± 2.0% for AG. These values were significantly different between the graft types. Correlation of % TBSA closed with ESS with % TBSA full-thickness burn generated an R value of 0.65 (P < .001). These results indicate that autologous ESS reduce mortality and requirements for donor skin harvesting, for grafting of full-thickness burns of greater than 50% TBSA.
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14
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Goodarzi P, Falahzadeh K, Nematizadeh M, Farazandeh P, Payab M, Larijani B, Tayanloo Beik A, Arjmand B. Tissue Engineered Skin Substitutes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1107:143-188. [PMID: 29855826 DOI: 10.1007/5584_2018_226] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The fundamental skin role is to supply a supportive barrier to protect body against harmful agents and injuries. Three layers of skin including epidermis, dermis and hypodermis form a sophisticated tissue composed of extracellular matrix (ECM) mainly made of collagens and glycosaminoglycans (GAGs) as a scaffold, different cell types such as keratinocytes, fibroblasts and functional cells embedded in the ECM. When the skin is injured, depends on its severity, the majority of mentioned components are recruited to wound regeneration. Additionally, different growth factors like fibroblast growth factor (FGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) are needed to orchestrated wound healing process. In case of large surface area wounds, natural wound repair seems inefficient. Inspired by nature, scientists in tissue engineering field attempt to engineered constructs mimicking natural healing process to promote skin restoration in untreatable injuries. There are three main types of commercially available engineered skin substitutes including epidermal, dermal, and dermoepidermal. Each of them could be composed of scaffold, desired cell types or growth factors. These substitutes could have autologous, allogeneic, or xenogeneic origin. Moreover, they may be cellular or acellular. They are used to accelerate wound healing and recover normal skin functions with pain relief. Although there are a wide variety of commercially available skin substitutes, almost none of them considered as an ideal equivalents required for proper wound healing.
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Affiliation(s)
- Parisa Goodarzi
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Khadijeh Falahzadeh
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehran Nematizadeh
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Parham Farazandeh
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moloud Payab
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Tayanloo Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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15
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Higgins CA, Roger MF, Hill RP, Ali-Khan AS, Garlick JA, Christiano AM, Jahoda CAB. Multifaceted role of hair follicle dermal cells in bioengineered skins. Br J Dermatol 2017; 176:1259-1269. [PMID: 27679975 DOI: 10.1111/bjd.15087] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2016] [Indexed: 01/16/2023]
Abstract
BACKGROUND The method of generating bioengineered skin constructs was pioneered several decades ago; nowadays these constructs are used regularly for the treatment of severe burns and nonhealing wounds. Commonly, these constructs are comprised of skin fibroblasts within a collagen scaffold, forming the skin dermis, and stratified keratinocytes overlying this, forming the skin epidermis. In the past decade there has been a surge of interest in bioengineered skins, with researchers seeking alternative cell sources, or scaffolds, from which constructs can be established, and for more biomimetic equivalents with skin appendages. OBJECTIVES To evaluate whether human hair follicle dermal cells can act as an alternative cell source for engineering the dermal component of engineered skin constructs. METHODS We established in vitro skin constructs by incorporating into the collagenous dermal compartment: (i) primary interfollicular dermal fibroblasts, (ii) hair follicle dermal papilla cells or (iii) hair follicle dermal sheath cells. In vivo skins were established by mixing dermal cells and keratinocytes in chambers on top of immunologically compromised mice. RESULTS All fibroblast subtypes were capable of supporting growth of overlying epithelial cells, both in vitro and in vivo. However, we found hair follicle dermal sheath cells to be superior to fibroblasts in their capacity to influence the establishment of a basal lamina. CONCLUSIONS Human hair follicle dermal cells can be readily interchanged with interfollicular fibroblasts and used as an alternative cell source for establishing the dermal component of engineered skin both in vitro and in vivo.
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Affiliation(s)
- C A Higgins
- Department of Dermatology, Columbia University, New York, NY, U.S.A.,Department of Bioengineering, Imperial College London, London, U.K
| | - M F Roger
- School of Biological and Biomedical Sciences, Durham University, Durham, U.K
| | - R P Hill
- School of Biological and Biomedical Sciences, Durham University, Durham, U.K
| | - A S Ali-Khan
- Department of Plastic Surgery, University Hospital of Durham, Durham, U.K
| | - J A Garlick
- Sackler Graduate School of Biomedical Sciences, Tufts University, Boston, MA, U.S.A
| | - A M Christiano
- Department of Dermatology, Columbia University, New York, NY, U.S.A.,Department of Genetics and Development, Columbia University, New York, NY, U.S.A
| | - C A B Jahoda
- School of Biological and Biomedical Sciences, Durham University, Durham, U.K
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16
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Mohammadi P, Youssef KK, Abbasalizadeh S, Baharvand H, Aghdami N. Human Hair Reconstruction: Close, But Yet So Far. Stem Cells Dev 2016; 25:1767-1779. [PMID: 27649771 DOI: 10.1089/scd.2016.0137] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Billions of dollars are annually invested in pharmaceutical industry and cosmetic sector with intent to develop new drugs and treatment strategies for alopecia. Because the hair looks an important characteristic of humans-an effective appendage in perception, expression of beauty, and preservation of self-esteem-the global market for hair loss treatment products is exponentially increasing. However, current methods to treat hair loss endure yet multiple challenges, such as unfavorable outcomes, nonpermanent and patient-dependent results, as well as unpredictable impacts, which limit their application. Over recent years, remarkable advances in the fields of regenerative medicine and hair tissue engineering have raised new hopes for introducing novel cell-based approaches to treat hair loss. Through cell-based approaches, it is possible to produce hair-like structures in the laboratory setting or manipulate cells in their native niche (in vivo lineage reprogramming) to reconstruct the hair follicle. However, challenging issues still exist with the functionality of cultured human hair cells, the proper selection of nonhair cell sources in cases of shortage of donor hair, and the development of defined culture conditions. Moreover, in the case of in vivo lineage reprogramming, selecting appropriate induction factors and their efficient delivery to guide resident cells into a hair fate-with the aim of reconstructing functional hair-still needs further explorations. In this study, we highlight recent advances and current challenges in hair loss treatment using cell-based approaches and provide novel insights for crucial steps, which must be taken into account to develop reproducible, safe, and efficient cell-based treatment.
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Affiliation(s)
- Parvaneh Mohammadi
- 1 Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology , ACECR, Tehran, Iran .,2 Department of Developmental Biology, University of Science and Culture , Tehran, Iran
| | - Khalil Kass Youssef
- 3 Department of Developmental Neurobiology, Instituto de Neurociencias CSIC-UMH , San Juan de Alicante, Spain
| | - Saeed Abbasalizadeh
- 1 Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology , ACECR, Tehran, Iran
| | - Hossein Baharvand
- 1 Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology , ACECR, Tehran, Iran .,2 Department of Developmental Biology, University of Science and Culture , Tehran, Iran
| | - Nasser Aghdami
- 1 Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology , ACECR, Tehran, Iran
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17
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Nicholas MN, Jeschke MG, Amini-Nik S. Methodologies in creating skin substitutes. Cell Mol Life Sci 2016; 73:3453-72. [PMID: 27154041 PMCID: PMC4982839 DOI: 10.1007/s00018-016-2252-8] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Revised: 04/21/2016] [Accepted: 04/22/2016] [Indexed: 12/14/2022]
Abstract
The creation of skin substitutes has significantly decreased morbidity and mortality of skin wounds. Although there are still a number of disadvantages of currently available skin substitutes, there has been a significant decline in research advances over the past several years in improving these skin substitutes. Clinically most skin substitutes used are acellular and do not use growth factors to assist wound healing, key areas of potential in this field of research. This article discusses the five necessary attributes of an ideal skin substitute. It comprehensively discusses the three major basic components of currently available skin substitutes: scaffold materials, growth factors, and cells, comparing and contrasting what has been used so far. It then examines a variety of techniques in how to incorporate these basic components together to act as a guide for further research in the field to create cellular skin substitutes with better clinical results.
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Affiliation(s)
- Mathew N Nicholas
- Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Ross Tilley Burn Centre, Sunnybrook Research Institute, Room: M7-140, 2075 Bayview Ave., Toronto, ON, M4N 3M5, Canada
| | - Marc G Jeschke
- Department of Surgery, University of Toronto, Toronto, ON, Canada
- Ross Tilley Burn Centre, Sunnybrook Research Institute, Room: M7-140, 2075 Bayview Ave., Toronto, ON, M4N 3M5, Canada
| | - Saeid Amini-Nik
- Department of Surgery, University of Toronto, Toronto, ON, Canada.
- Ross Tilley Burn Centre, Sunnybrook Research Institute, Room: M7-140, 2075 Bayview Ave., Toronto, ON, M4N 3M5, Canada.
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18
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Nicholas MN, Yeung J. Current Status and Future of Skin Substitutes for Chronic Wound Healing. J Cutan Med Surg 2016; 21:23-30. [PMID: 27530398 DOI: 10.1177/1203475416664037] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Chronic wounds, including diabetic ulcers, pressure ulcers, venous ulcers, and arterial insufficiency ulcers, are both difficult and expensive to treat. Conventional wound care may sometimes lead to suboptimal wound healing and significant morbidity and mortality for patients. The use of skin substitutes provides an alternative therapy showing superior efficacy and, in some cases, similar cost-effectiveness compared to traditional treatments. This review discusses the different types of currently available commercial skin substitutes for use in chronic wounds as well as the paucity of strong evidence supporting their use. It then delves into the limitations of these skin substitutes and examines the most recent research targeting these limitations.
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Affiliation(s)
| | - Jensen Yeung
- 2 Department of Dermatology, Women's College Hospital and Sunnybrook Health Sciences Centre, Toronto, ON, Canada.,3 Division of Dermatology, University of Toronto, Toronto, ON, Canada
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19
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Budnick I, Hamburg-Shields E, Chen D, Torre E, Jarrell A, Akhtar-Zaidi B, Cordovan O, Spitale RC, Scacheri P, Atit RP. Defining the identity of mouse embryonic dermal fibroblasts. Genesis 2016; 54:415-30. [PMID: 27265328 DOI: 10.1002/dvg.22952] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 06/01/2016] [Accepted: 06/01/2016] [Indexed: 01/14/2023]
Abstract
Embryonic dermal fibroblasts in the skin have the exceptional ability to initiate hair follicle morphogenesis and contribute to scarless wound healing. Activation of the Wnt signaling pathway is critical for dermal fibroblast fate selection and hair follicle induction. In humans, mutations in Wnt pathway components and target genes lead to congenital focal dermal hypoplasias with diminished hair. The gene expression signature of embryonic dermal fibroblasts during differentiation and its dependence on Wnt signaling is unknown. Here we applied Shannon entropy analysis to identify the gene expression signature of mouse embryonic dermal fibroblasts. We used available human DNase-seq and histone modification ChiP-seq data on various cell-types to demonstrate that genes in the fibroblast cell identity signature can be epigenetically repressed in other cell-types. We found a subset of the signature genes whose expression is dependent on Wnt/β-catenin activity in vivo. With our approach, we have defined and validated a statistically derived gene expression signature that may mediate dermal fibroblast identity and function in development and disease. genesis 54:415-430, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Isadore Budnick
- Department of Biology, Case Western Reserve University, Cleveland, Ohio
| | | | - Demeng Chen
- Department of Biology, Case Western Reserve University, Cleveland, Ohio
| | - Eduardo Torre
- Epithelial Biology Program, Department of Dermatology, Stanford University, California
| | - Andrew Jarrell
- Department of Biology, Case Western Reserve University, Cleveland, Ohio
| | - Batool Akhtar-Zaidi
- Department of Pharmaceutical Sciences, University of California, Irvine, California
| | - Olivia Cordovan
- Department of Pharmaceutical Sciences, University of California, Irvine, California
| | - Rob C Spitale
- Epithelial Biology Program, Department of Dermatology, Stanford University, California.,Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio
| | - Peter Scacheri
- Department of Pharmaceutical Sciences, University of California, Irvine, California
| | - Radhika P Atit
- Department of Biology, Case Western Reserve University, Cleveland, Ohio.,Department of Pharmaceutical Sciences, University of California, Irvine, California.,Department of Dermatology, Case Western Reserve University, Cleveland, Ohio
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20
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Pereira RF, Bártolo PJ. Traditional Therapies for Skin Wound Healing. Adv Wound Care (New Rochelle) 2016; 5:208-229. [PMID: 27134765 DOI: 10.1089/wound.2013.0506] [Citation(s) in RCA: 251] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Significance: The regeneration of healthy and functional skin remains a huge challenge due to its multilayer structure and the presence of different cell types within the extracellular matrix in an organized way. Despite recent advances in wound care products, traditional therapies based on natural origin compounds, such as plant extracts, honey, and larvae, are interesting alternatives. These therapies offer new possibilities for the treatment of skin diseases, enhancing the access to the healthcare, and allowing overcoming some limitations associated to the modern products and therapies, such as the high costs, the long manufacturing times, and the increase in the bacterial resistance. This article gives a general overview about the recent advances in traditional therapies for skin wound healing, focusing on the therapeutic activity, action mechanisms, and clinical trials of the most commonly used natural compounds. New insights in the combination of traditional products with modern treatments and future challenges in the field are also highlighted. Recent Advances: Natural compounds have been used in skin wound care for many years due to their therapeutic activities, including anti-inflammatory, antimicrobial, and cell-stimulating properties. The clinical efficacy of these compounds has been investigated through in vitro and in vivo trials using both animal models and humans. Besides the important progress regarding the development of novel extraction methods, purification procedures, quality control assessment, and treatment protocols, the exact mechanisms of action, side effects, and safety of these compounds need further research. Critical Issues: The repair of skin lesions is one of the most complex biological processes in humans, occurring throughout an orchestrated cascade of overlapping biochemical and cellular events. To stimulate the regeneration process and prevent the wound to fail the healing, traditional therapies and natural products have been used with promising results. Although these products are in general less expensive than the modern treatments, they can be sensitive to the geographic location and season, and exhibit batch-to-batch variation, which can lead to unexpected allergic reactions, side effects, and contradictory clinical results. Future Directions: The scientific evidence for the use of traditional therapies in wound healing indicates beneficial effects in the treatment of different lesions. However, specific challenges remain unsolved. To extend the efficacy and the usage of natural substances in wound care, multidisciplinary efforts are necessary to prove the safety of these products, investigate their side effects, and develop standard controlled trials. The development of good manufacturing practices and regulatory legislation also assume a pivotal role in order to improve the use of traditional therapies by the clinicians and to promote their integration into the national health system. Current trends move to the development of innovative wound care treatments, combining the use of traditional healing agents and modern products/practices, such as nanofibers containing silver nanoparticles, Aloe vera loaded into alginate hydrogels, propolis into dressing films, and hydrogel sheets containing honey.
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Affiliation(s)
- Rúben F. Pereira
- Centre for Rapid and Sustainable Product Development (CDRsp), Polytechnic Institute of Leiria, Marinha Grande, Portugal
- INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Paulo J. Bártolo
- Centre for Rapid and Sustainable Product Development (CDRsp), Polytechnic Institute of Leiria, Marinha Grande, Portugal
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21
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Yannas IV, Tzeranis D, So PT. Surface biology of collagen scaffold explains blocking of wound contraction and regeneration of skin and peripheral nerves. Biomed Mater 2015; 11:014106. [PMID: 26694657 PMCID: PMC5775477 DOI: 10.1088/1748-6041/11/1/014106] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
We review the details of preparation and of the recently elucidated mechanism of biological (regenerative) activity of a collagen scaffold (dermis regeneration template, DRT) that has induced regeneration of skin and peripheral nerves (PN) in a variety of animal models and in the clinic. DRT is a 3D protein network with optimized pore size in the range 20-125 µm, degradation half-life 14 ± 7 d and ligand densities that exceed 200 µM α1β1 or α2β1 ligands. The pore has been optimized to allow migration of contractile cells (myofibroblasts, MFB) into the scaffold and to provide sufficient specific surface for cell-scaffold interaction; the degradation half-life provides the required time window for satisfactory binding interaction of MFB with the scaffold surface; and the ligand density supplies the appropriate ligands for specific binding of MFB on the scaffold surface. A dramatic change in MFB phenotype takes place following MFB-scaffold binding which has been shown to result in blocking of wound contraction. In both skin wounds and PN wounds the evidence has shown clearly that contraction blocking by DRT is followed by induction of regeneration of nearly perfect organs. The biologically active structure of DRT is required for contraction blocking; well-matched collagen scaffold controls of DRT, with structures that varied from that of DRT, have failed to induce regeneration. Careful processing of collagen scaffolds is required for adequate biological activity of the scaffold surface. The newly understood mechanism provides a relatively complete paradigm of regenerative medicine that can be used to prepare scaffolds that may induce regeneration of other organs in future studies.
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Affiliation(s)
- I V Yannas
- Departments of Mechanical and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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22
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Wu X, Scott L, Washenik K, Stenn K. Full-thickness skin with mature hair follicles generated from tissue culture expanded human cells. Tissue Eng Part A 2015; 20:3314-21. [PMID: 25074625 DOI: 10.1089/ten.tea.2013.0759] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The goal of regenerative medicine is to reconstruct fully functional organs from tissue culture expanded human cells. In this study, we report a method for human reconstructed skin (hRSK) when starting with human cells. We implanted tissue culture expanded human epidermal and dermal cells into an excision wound on the back of immunodeficient mice. Pigmented skin covered the wound 4 weeks after implantation. Hair shafts were visible at 12 weeks and prominent at 14 weeks. Histologically, the hRSK comprises an intact epidermis and dermis with mature hair follicles, sebaceous glands and most notably, and unique to this system, subcutis. Morphogenesis, differentiation, and maturation of the hRSK mirror the human fetal process. Human antigen markers demonstrate that the constituent cells are of human origin for at least 6 months. The degree of new skin formation is most complete when using tissue culture expanded cells from fetal skin, but it also occurs with expanded newborn and adult cells; however, no appendages formed when we grafted both adult dermal and epidermal cells. The hRSK system promises to be valuable as a laboratory model for studying biological, pathological, and pharmaceutical problems of human skin.
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Affiliation(s)
- Xunwei Wu
- Aderans Research Institute, Inc. , Marietta, Georgia
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23
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Balañá ME, Charreau HE, Leirós GJ. Epidermal stem cells and skin tissue engineering in hair follicle regeneration. World J Stem Cells 2015; 7:711-27. [PMID: 26029343 PMCID: PMC4444612 DOI: 10.4252/wjsc.v7.i4.711] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 10/02/2014] [Accepted: 02/04/2015] [Indexed: 02/06/2023] Open
Abstract
The reconstitution of a fully organized and functional hair follicle from dissociated cells propagated under defined tissue culture conditions is a challenge still pending in tissue engineering. The loss of hair follicles caused by injuries or pathologies such as alopecia not only affects the patients' psychological well-being, but also endangers certain inherent functions of the skin. It is then of great interest to find different strategies aiming to regenerate or neogenerate the hair follicle under conditions proper of an adult individual. Based upon current knowledge on the epithelial and dermal cells and their interactions during the embryonic hair generation and adult hair cycling, many researchers have tried to obtain mature hair follicles using different strategies and approaches depending on the causes of hair loss. This review summarizes current advances in the different experimental strategies to regenerate or neogenerate hair follicles, with emphasis on those involving neogenesis of hair follicles in adult individuals using isolated cells and tissue engineering. Most of these experiments were performed using rodent cells, particularly from embryonic or newborn origin. However, no successful strategy to generate human hair follicles from adult cells has yet been reported. This review identifies several issues that should be considered to achieve this objective. Perhaps the most important challenge is to provide three-dimensional culture conditions mimicking the structure of living tissue. Improving culture conditions that allow the expansion of specific cells while protecting their inductive properties, as well as methods for selecting populations of epithelial stem cells, should give us the necessary tools to overcome the difficulties that constrain human hair follicle neogenesis. An analysis of patent trends shows that the number of patent applications aimed at hair follicle regeneration and neogenesis has been increasing during the last decade. This field is attractive not only to academic researchers but also to the companies that own almost half of the patents in this field.
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Affiliation(s)
- María Eugenia Balañá
- María Eugenia Balañá, Gustavo José Leirós, Fundación Pablo Cassará -Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Saladillo 2468 C1440FFX, Ciudad de Buenos Aires, Argentina
| | - Hernán Eduardo Charreau
- María Eugenia Balañá, Gustavo José Leirós, Fundación Pablo Cassará -Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Saladillo 2468 C1440FFX, Ciudad de Buenos Aires, Argentina
| | - Gustavo José Leirós
- María Eugenia Balañá, Gustavo José Leirós, Fundación Pablo Cassará -Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Saladillo 2468 C1440FFX, Ciudad de Buenos Aires, Argentina
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24
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Thangapazham RL, Klover P, Li S, Wang JA, Sperling L, Darling TN. A model system to analyse the ability of human keratinocytes to form hair follicles. Exp Dermatol 2015; 23:443-6. [PMID: 24758480 DOI: 10.1111/exd.12424] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2014] [Indexed: 01/21/2023]
Abstract
Earlier studies showed that dermal cells lose trichogenic capacity with passage, but studies on the effect of keratinocyte passage on human hair follicle neogenesis and graft quality have been hampered by the lack of a suitable model system. We recently documented human hair follicle neogenesis in grafted dermal-epidermal composites, and in the present study, we determined the effects of keratinocyte passage on hair follicle neogenesis. Dermal equivalents were made with cultured human dermal papilla cells and were overlaid with either primary or passaged human keratinocytes to form dermal-epidermal composites; these were then grafted onto immunodeficient mice. Superior hair follicle neogenesis was observed using early keratinocyte cultures. Characteristics such as formation of hair shafts and sebaceous glands, presence of hair follicles with features of anagen or telogen follicles, and reproducible hair and skin function parameters make this model a tool to study human hair follicle neogenesis and development.
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Affiliation(s)
- Rajesh L Thangapazham
- Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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25
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Lei M, Guo H, Qiu W, Lai X, Yang T, Widelitz RB, Chuong CM, Lian X, Yang L. Modulating hair follicle size with Wnt10b/DKK1 during hair regeneration. Exp Dermatol 2015; 23:407-13. [PMID: 24750467 DOI: 10.1111/exd.12416] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2014] [Indexed: 12/11/2022]
Abstract
Hair follicles have characteristic sizes corresponding to their cycle-specific stage. However, how the anagen hair follicle specifies its size remains elusive. Here, we showed that in response to prolonged ectopic Wnt10b-mediated β-catenin activation, regenerating anagen hair follicles grew larger in size. In particular, the hair bulb, dermal papilla and hair shaft became enlarged, while the formation of different hair types (Guard, Awl, Auchene and Zigzag) was unaffected. Interestingly, we found that the effect of exogenous WNT10b was mainly on Zigzag and less on the other kinds of hairs. We observed dramatically enhanced proliferation within the matrix, DP and hair shaft of the enlarged AdWnt10b-treated hair follicles compared with those of normal hair follicles at P98. Furthermore, expression of CD34, a specific hair stem cell marker, was increased in its number to the bulge region after AdWnt10b treatment. Ectopic expression of CD34 throughout the ORS region was also observed. Many CD34-positive hair stem cells were actively proliferating in AdWnt10b-induced hair follicles. Importantly, subsequent co-treatment with the Wnt inhibitor, DKK1, reduced hair follicle enlargement and decreased proliferation and ectopic localization of hair stem cells. Moreover, injection of DKK1 during early anagen significantly reduced the width of prospective hairs. Together, these findings strongly suggest that Wnt10b/DKK1 can modulate hair follicle size during hair regeneration.
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Affiliation(s)
- Mingxing Lei
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China; '111' Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing, China
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Su YS, Miao Y, Jiang JD, Liu H, Hu J, Hu ZQ. A simple and rapid model for hair-follicle regeneration in the nude mouse. Clin Exp Dermatol 2015; 40:653-8. [PMID: 25623661 DOI: 10.1111/ced.12563] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2014] [Indexed: 01/10/2023]
Abstract
BACKGROUND Methods for hair-follicle regeneration are important tools for investigating signalling and cytokines during hair-follicle morphogenesis and cycling. Several animal models for hair reconstitution have been established; however, these models have several shortcomings. AIM To develop a simple and rapid model for hair induction in nude mouse. METHODS We designed an improved flap model (IFM) for hair regeneration based on the existing flap assay. Histological sections and scanning electron microscopy were used to evaluate the regenerated hair. The fates of grafted cells were traced by fluorescence. The time required for hair induction was analysed and compared. RESULTS IFM produced a large number of normal hairs, and the time required for hair induction using IFM was 20.67 ± 0.67 days, compared with 29.33 ± 0.67 days for the traditional flap assay. CONCLUSIONS The time required for hair regeneration is considerably shortened with IFM. We speculate that this is due to increased blood supply at the transplantation sites.
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Affiliation(s)
- Y-S Su
- Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Y Miao
- Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - J-D Jiang
- Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - H Liu
- Department of Burn and Plastic Surgery, The Shenzhen Baoan Hospital Affiliated to Southern Medical University, Shenzhen, China
| | - J Hu
- Department of Burn and Plastic Surgery, The Shenzhen Baoan Hospital Affiliated to Southern Medical University, Shenzhen, China
| | - Z-Q Hu
- Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Leirós GJ, Kusinsky AG, Drago H, Bossi S, Sturla F, Castellanos ML, Stella IY, Balañá ME. Dermal papilla cells improve the wound healing process and generate hair bud-like structures in grafted skin substitutes using hair follicle stem cells. Stem Cells Transl Med 2014; 3:1209-19. [PMID: 25161315 DOI: 10.5966/sctm.2013-0217] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Tissue-engineered skin represents a useful strategy for the treatment of deep skin injuries and might contribute to the understanding of skin regeneration. The use of dermal papilla cells (DPCs) as a dermal component in a permanent composite skin with human hair follicle stem cells (HFSCs) was evaluated by studying the tissue-engineered skin architecture, stem cell persistence, hair regeneration, and graft-take in nude mice. A porcine acellular dermal matrix was seeded with HFSCs alone and with HFSCs plus human DPCs or dermal fibroblasts (DFs). In vitro, the presence of DPCs induced a more regular and multilayered stratified epidermis with more basal p63-positive cells and invaginations. The DPC-containing constructs more accurately mimicked the skin architecture by properly stratifying the differentiating HFSCs and developing a well-ordered epithelia that contributed to more closely recapitulate an artificial human skin. This acellular dermal matrix previously repopulated in vitro with HFSCs and DFs or DPCs as the dermal component was grafted in nude mice. The presence of DPCs in the composite substitute not only favored early neovascularization, good assimilation and remodeling after grafting but also contributed to the neovascular network maturation, which might reduce the inflammation process, resulting in a better healing process, with less scarring and wound contraction. Interestingly, only DPC-containing constructs showed embryonic hair bud-like structures with cells of human origin, presence of precursor epithelial cells, and expression of a hair differentiation marker. Although preliminary, these findings have demonstrated the importance of the presence of DPCs for proper skin repair.
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Affiliation(s)
- Gustavo José Leirós
- Fundación Pablo Cassará, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Argentina; Banco de Tejidos, Hospital de Quemados de la Ciudad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Centro de Estudios Biomédicos, Ambientales y Diagnóstico, Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina
| | - Ana Gabriela Kusinsky
- Fundación Pablo Cassará, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Argentina; Banco de Tejidos, Hospital de Quemados de la Ciudad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Centro de Estudios Biomédicos, Ambientales y Diagnóstico, Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina
| | - Hugo Drago
- Fundación Pablo Cassará, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Argentina; Banco de Tejidos, Hospital de Quemados de la Ciudad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Centro de Estudios Biomédicos, Ambientales y Diagnóstico, Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina
| | - Silvia Bossi
- Fundación Pablo Cassará, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Argentina; Banco de Tejidos, Hospital de Quemados de la Ciudad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Centro de Estudios Biomédicos, Ambientales y Diagnóstico, Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina
| | - Flavio Sturla
- Fundación Pablo Cassará, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Argentina; Banco de Tejidos, Hospital de Quemados de la Ciudad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Centro de Estudios Biomédicos, Ambientales y Diagnóstico, Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina
| | - María Lía Castellanos
- Fundación Pablo Cassará, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Argentina; Banco de Tejidos, Hospital de Quemados de la Ciudad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Centro de Estudios Biomédicos, Ambientales y Diagnóstico, Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina
| | - Inés Yolanda Stella
- Fundación Pablo Cassará, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Argentina; Banco de Tejidos, Hospital de Quemados de la Ciudad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Centro de Estudios Biomédicos, Ambientales y Diagnóstico, Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina
| | - María Eugenia Balañá
- Fundación Pablo Cassará, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Argentina; Banco de Tejidos, Hospital de Quemados de la Ciudad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Centro de Estudios Biomédicos, Ambientales y Diagnóstico, Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina
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28
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Eungdamrong NJ, Higgins C, Guo Z, Lee WH, Gillette B, Sia S, Christiano AM. Challenges and promises in modeling dermatologic disorders with bioengineered skin. Exp Biol Med (Maywood) 2014; 239:1215-24. [PMID: 24951469 DOI: 10.1177/1535370214538747] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The tremendous cost of drug development is often attributed to the long time interval between identifying lead compounds in preclinical studies to assessing clinical efficacy in randomized clinical trials. Many candidate molecules show promise in cell culture or animal models, only to fail in late stage in human investigations. There is a need for novel technologies that allow investigators to quickly and reliably predict drug safety and efficacy. The advent of microtechnology has made it possible to integrate multiple microphysiologic organ systems into a single microfabricated chip. This review focuses on three-dimensional engineered skin, which has enjoyed a long history of uses both in clinical treatments of refractory ulcers and as a laboratory model. We discuss current biological and engineering challenges in construction of a robust bioengineered skin and provide a blueprint for its potential utility to model dermatologic disorders such as psoriasis or cutaneous drug reactions.
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Affiliation(s)
- Narat J Eungdamrong
- The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA Departments of Dermatology, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
| | - Claire Higgins
- Departments of Dermatology, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
| | - Zongyou Guo
- Departments of Dermatology, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
| | - Wen-Han Lee
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Brian Gillette
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Samuel Sia
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Angela M Christiano
- Departments of Dermatology, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA Department of Genetics & Development, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
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29
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Blackstone BN, Drexler JW, Powell HM. Tunable engineered skin mechanics via coaxial electrospun fiber core diameter. Tissue Eng Part A 2014; 20:2746-55. [PMID: 24712409 DOI: 10.1089/ten.tea.2013.0687] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Autologous engineered skin (ES) offers promise as a treatment for massive full thickness burns. Unfortunately, ES is orders of magnitude weaker than normal human skin causing it to be difficult to apply surgically and subject to damage by mechanical shear in the early phases of engraftment. In addition, no manufacturing strategy has been developed to tune ES biomechanics to approximate the native biomechanics at different anatomic locations. To enhance and tune ES biomechanics, a coaxial (CoA) electrospun scaffold platform was developed from polycaprolactone (PCL, core) and gelatin (shell). The ability of the coaxial fiber core diameter to control both scaffold and tissue mechanics was investigated along with the ability of the gelatin shell to facilitate cell adhesion and skin development compared to pure gelatin, pure PCL, and a gelatin-PCL blended fiber scaffold. CoA ES exhibited increased cellular adhesion and metabolism versus PCL alone or gelatin-PCL blend and promoted the development of well stratified skin with a dense dermal layer and a differentiated epidermal layer. Biomechanics of the scaffold and ES scaled linearly with core diameter suggesting that this scaffold platform could be utilized to tailor ES mechanics for their intended grafting site and reduce graft damage in vitro and in vivo.
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30
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Plikus MV. At the dawn of hair research - testing the limits of hair follicle regeneration. Exp Dermatol 2014; 23:314-5. [DOI: 10.1111/exd.12334] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2014] [Indexed: 12/17/2022]
Affiliation(s)
- Maksim V. Plikus
- Department of Developmental and Cell Biology; Sue and Bill Gross Stem Cell Research Center; University of California; Irvine CA 92697 USA
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31
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Abstract
Outcomes of patients with burns have improved substantially over the past two decades. Findings from a 2012 study in The Lancet showed that a burn size of more than 60% total body surface area burned (an increase from 40% a decade ago) is associated with risks and mortality. Similar data have been obtained in adults and elderly people who have been severely burned. We discuss recent and future developments in burn care to improve outcomes of children.
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Affiliation(s)
- Marc G Jeschke
- Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Surgery, Division of Plastic Surgery, Department of Immunology, University of Toronto, Toronto, Canada; Sunnybrook Research Institute, Toronto, Canada.
| | - David N Herndon
- Shriners Hospitals for Children and Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
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32
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Nissimov JN, Das Chaudhuri AB. Hair curvature: a natural dialectic and review. Biol Rev Camb Philos Soc 2014; 89:723-66. [PMID: 24617997 DOI: 10.1111/brv.12081] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 12/18/2013] [Accepted: 01/01/2014] [Indexed: 12/19/2022]
Abstract
Although hair forms (straight, curly, wavy, etc.) are present in apparently infinite variations, each fibre can be reduced to a finite sequence of tandem segments of just three types: straight, bent/curly, or twisted. Hair forms can thus be regarded as resulting from genetic pathways that induce, reverse or modulate these basic curvature modes. However, physical interconversions between twists and curls demonstrate that strict one-to-one correspondences between them and their genetic causes do not exist. Current hair-curvature theories do not distinguish between bending and twisting mechanisms. We here introduce a multiple papillary centres (MPC) model which is particularly suitable to explain twisting. The model combines previously known features of hair cross-sectional morphology with partially/completely separated dermal papillae within single follicles, and requires such papillae to induce differential growth rates of hair cortical material in their immediate neighbourhoods. The MPC model can further help to explain other, poorly understood, aspects of hair growth and morphology. Separate bending and twisting mechanisms would be preferentially affected at the major or minor ellipsoidal sides of fibres, respectively, and together they exhaust the possibilities for influencing hair-form phenotypes. As such they suggest dialectic for hair-curvature development. We define a natural-dialectic (ND) which could take advantage of speculative aspects of dialectic, but would verify its input data and results by experimental methods. We use this as a top-down approach to first define routes by which hair bending or twisting may be brought about and then review evidence in support of such routes. In particular we consider the wingless (Wnt) and mammalian target of rapamycin (mTOR) pathways as paradigm pathways for molecular hair bending and twisting mechanisms, respectively. In addition to the Wnt canonical pathway, the Wnt/Ca(2+) and planar cell polarity (PCP) pathways, and others, can explain many alternatives and specific variations of hair bending phenotypes. Mechanisms for hair papilla budding or its division by bisection or fission can explain MPC formation. Epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions, acting in collaboration with epithelial-mesenchymal communications are also considered as mechanisms affecting hair growth and its bending and twisting. These may be treated as sub-mechanisms of an overall development from neural-crest stem cell (NCSC) lineages to differentiated hair follicle (HF) cell types, thus providing a unified framework for hair growth and development.
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33
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Takemoto R, Jinnin M, Wang Z, Kudo H, Inoue K, Nakayama W, Ichihara A, Igata T, Kajihara I, Fukushima S, Ihn H. Hair miR-29a levels are decreased in patients with scleroderma. Exp Dermatol 2013; 22:832-3. [DOI: 10.1111/exd.12245] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2013] [Indexed: 12/28/2022]
Affiliation(s)
- Risa Takemoto
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
| | - Masatoshi Jinnin
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
| | - Zhongzhi Wang
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
| | - Hideo Kudo
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
| | - Kuniko Inoue
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
| | - Wakana Nakayama
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
| | - Asako Ichihara
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
| | - Toshikatsu Igata
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
| | - Ikko Kajihara
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
| | - Satoshi Fukushima
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
| | - Hironobu Ihn
- Department of Dermatology and Plastic Surgery; Faculty of Life Sciences; Kumamoto University; Kumamoto Japan
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Kwack MH, Kim MK, Kim JC, Sung YK. Wnt5a attenuates Wnt/β-catenin signalling in human dermal papilla cells. Exp Dermatol 2013; 22:229-31. [PMID: 23489428 DOI: 10.1111/exd.12101] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2013] [Indexed: 12/16/2022]
Abstract
Findings of recent studies have demonstrated modulation of Wnt/β-catenin signalling by Wnt5a, which is highly expressed in hair follicular dermal papilla (DP) in vivo. Here, we investigated the question of whether Wnt5a can affect canonical Wnt/β-catenin signalling in DP cells. Treatment with Wnt5a resulted in attenuation of Wnt3a-mediated elevation of β-catenin signalling, which was increased by Wnt5a siRNA transfection in cultured DP cells, as examined by reporter assay. In addition, treatment with Wnt5a resulted in repressed Wnt3a-mediated expression of Axin2, EP2 and LEF1 in cultured DP cells, whereas Wnt5a siRNA transfection resulted in increased Wnt3a-mediated expression of the genes in isolated DPs of cultured hair follicles. Moreover, treatment with Wnt5a resulted in attenuation of Wnt3a-mediated accumulation of β-catenin in the nucleus in DP cells. Our data strongly suggest that Wnt5a acts as an autocrine factor and attenuates canonical Wnt signalling pathway in human DP cells.
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35
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Pereira RF, Barrias CC, Granja PL, Bartolo PJ. Advanced biofabrication strategies for skin regeneration and repair. Nanomedicine (Lond) 2013; 8:603-21. [DOI: 10.2217/nnm.13.50] [Citation(s) in RCA: 207] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Skin is the largest organ of human body, acting as a barrier with protective, immunologic and sensorial functions. Its permanent exposure to the external environment can result in different kinds of damage with loss of variable volumes of extracellular matrix. For the treatment of skin lesions, several strategies are currently available, such as the application of autografts, allografts, wound dressings and tissue-engineered substitutes. Although proven clinically effective, these strategies are still characterized by key limitations such as patient morbidity, inadequate vascularization, low adherence to the wound bed, the inability to reproduce skin appendages and high manufacturing costs. Advanced strategies based on both bottom-up and top-down approaches offer an effective, permanent and viable alternative to solve the abovementioned drawbacks by combining biomaterials, cells, growth factors and advanced biomanufacturing techniques. This review details recent advances in skin regeneration and repair strategies, and describes their major advantages and limitations. Future prospects for skin regeneration are also outlined.
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Affiliation(s)
- Rúben F Pereira
- Centre for Rapid & Sustainable Product Development, Polytechnic Institute of Leiria, Portugal
- Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Cristina C Barrias
- Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Pedro L Granja
- Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- Faculdade de Engenharia da Universidade do Porto, Departamento de Engenharia Metalúrgica & Materiais, Porto, Portugal
| | - Paulo J Bartolo
- Centre for Rapid & Sustainable Product Development, Polytechnic Institute of Leiria, Portugal.
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