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Laukka M, Kauhanen S, Hockerstedt A, Peuhu E, Hartiala P. Tissue-Level Effects of Autologous Fat Grafting in Hypertrophic Scars-A Case Series Study. J Surg Res 2025; 305:246-257. [PMID: 39937557 DOI: 10.1016/j.jss.2024.11.039] [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: 03/01/2024] [Revised: 11/09/2024] [Accepted: 11/28/2024] [Indexed: 02/13/2025]
Abstract
INTRODUCTION Fat grafting has antifibrotic effects and it improves scar quality. However, the biological mechanisms of fat grafts on scar healing are poorly understood. METHODS This was a prospective study to identify differences in the epidermal and dermal structure, macrophage infiltration, or inflammatory and fibrotic markers in hypertrophic scars before and after fat grafting surgery compared to normal skin. Seven patients with hypertrophic scar completed the study. Biopsies from hypertrophic scars and normal skin were taken at the time of fat grafting surgery and follow-up biopsies 6 mo postoperatively. A clinical Patient and Observer Scar Assessment Scale was used to monitor the clinical aspects of the scars. Immunohistochemical stainings were performed to analyze the changes occurring in the hypertrophic scar tissue after fat grafting. RESULTS Hypertrophic scars demonstrated decreased presence of rete ridges and increased levels of the profibrotic transforming growth factor beta-1 (TGF-β1) (P < 0.05) compared to normal skin. Fat grafting significantly increased the presence of rete ridges to the level of normal skin and reduced TGF-β1 expression (hypertrophic scars + fat) (P < 0.05). Fat grafting also increased the total macrophage count (CD68 pan-macrophage marker) (P < 0.05) and M1 macrophage count (inducible nitric oxide synthase M1 macrophage marker) (P < 0.05). The clinical evaluation of the scars (Patient and Observer Scar Assessment Scale) by the observer and patients improved after fat grafting (P < 0.05). CONCLUSIONS Our findings indicate that fat grafting promotes normalization of skin by improving epidermal structure and reducing TGF-β1 levels and favors less fibrotic healing by regulating macrophages levels.
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Affiliation(s)
- Mervi Laukka
- Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland; Institute of Biomedicine, University of Turku, Turku Finland; Medicity Research Laboratories, InFLAMES Research Flagship, University of Turku, Turku, Finland
| | - Susanna Kauhanen
- Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland
| | - Anna Hockerstedt
- Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland
| | - Emilia Peuhu
- Institute of Biomedicine, University of Turku, Turku Finland; FICAN West Cancer Laboratory, Turku University Hospital and University of Turku, Turku, Finland; Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland
| | - Pauliina Hartiala
- Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland; Medicity Research Laboratories, InFLAMES Research Flagship, University of Turku, Turku, Finland.
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Kim HJ, Kim YH. Comprehensive Insights into Keloid Pathogenesis and Advanced Therapeutic Strategies. Int J Mol Sci 2024; 25:8776. [PMID: 39201463 PMCID: PMC11354446 DOI: 10.3390/ijms25168776] [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: 06/26/2024] [Revised: 08/07/2024] [Accepted: 08/10/2024] [Indexed: 09/02/2024] Open
Abstract
Keloid scars, characterized by abnormal fibroproliferation and excessive extracellular matrix (ECM) production that extends beyond the original wound, often cause pruritus, pain, and hyperpigmentation, significantly impacting the quality of life. Keloid pathogenesis is multifactorial, involving genetic predisposition, immune response dysregulation, and aberrant wound-healing processes. Central molecular pathways such as TGF-β/Smad and JAK/STAT are important in keloid formation by sustaining fibroblast activation and ECM deposition. Conventional treatments, including surgical excision, radiation, laser therapies, and intralesional injections, yield variable success but are limited by high recurrence rates and potential adverse effects. Emerging therapies targeting specific immune pathways, small molecule inhibitors, RNA interference, and mesenchymal stem cells show promise in disrupting the underlying mechanisms of keloid pathogenesis, potentially offering more effective and lasting treatment outcomes. Despite advancements, further research is essential to fully elucidate the precise mechanisms of keloid formation and to develop targeted therapies. Ongoing clinical trials and research efforts are vital for translating these scientific insights into practical treatments that can markedly enhance the quality of life for individuals affected by keloid scars.
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Affiliation(s)
- Hyun Jee Kim
- Department of Dermatology, International St. Mary’s Hospital, College of Medicine, Catholic Kwandong University, Incheon 22711, Republic of Korea;
| | - Yeong Ho Kim
- Department of Dermatology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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Liu M, Lu F, Feng J. Aging and homeostasis of the hypodermis in the age-related deterioration of skin function. Cell Death Dis 2024; 15:443. [PMID: 38914551 PMCID: PMC11196735 DOI: 10.1038/s41419-024-06818-z] [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: 02/22/2023] [Revised: 02/01/2024] [Accepted: 06/10/2024] [Indexed: 06/26/2024]
Abstract
Adipose tissues in the hypodermis, the crucial stem cell reservoir in the skin and the endocrine organ for the maintenance of skin homeostasis undergo significant changes during skin aging. Dermal white adipose tissue (dWAT) has recently been recognized as an important organ for both non-metabolic and metabolic health in skin regeneration and rejuvenation. Defective differentiation, adipogenesis, improper adipocytokine production, and immunological dissonance dysfunction in dWAT lead to age-associated clinical changes. Here, we review age-related alterations in dWAT across levels, emphasizing the mechanisms underlying the regulation of aging. We also discuss the pathogenic changes involved in age-related fat dysfunction and the unfavorable consequences of accelerated skin aging, such as chronic inflammaging, immunosenescence, delayed wound healing, and fibrosis. Research has shown that adipose aging is an early initiation event and a potential target for extending longevity. We believe that adipose tissues play an essential role in aging and form a potential therapeutic target for the treatment of age-related skin diseases. Further research is needed to improve our understanding of this phenomenon.
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Affiliation(s)
- Meiqi Liu
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong, 510515, People's Republic of China
| | - Feng Lu
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong, 510515, People's Republic of China
| | - Jingwei Feng
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong, 510515, People's Republic of China.
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Tamarat R, Satyamitra MM, Benderitter M, DiCarlo AL. Radiation-induced gastrointestinal and cutaneous injuries: understanding models, pathologies, assessments, and clinically accepted practices. Int J Radiat Biol 2024; 100:969-981. [PMID: 38787685 PMCID: PMC11494497 DOI: 10.1080/09553002.2024.2356544] [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: 01/30/2024] [Revised: 04/02/2024] [Accepted: 04/29/2024] [Indexed: 05/26/2024]
Abstract
PURPOSE A U. S. and European joint effort fostering the development of medical countermeasures (MCMs) operable in case of radiological or nuclear emergencies. METHODS Based on the joint engagement between the U.S. National Institute of Allergy and Infectious Diseases (NIAID) and the French Institut de Radioprotection et de Sûreté Nucléaire (IRSN), a Statement of Intent to Collaborate was signed in 2014 and a series of working group meeting were established. In December 2022, the NIAID and IRSN hosted a five-day, U.S./European meeting titled 'Radiation-Induced Cutaneous and Gastrointestinal Injuries: Advances in Understanding Pathologies, Assessment, and Clinically Accepted Practices' in Paris, France. The goals of the meeting were to bring together U.S. and European investigators to explore new research avenues for the medical management of skin and gastrointestinal injuries, including specific diagnostics for each organ system, animal models, and promising medical countermeasures (MCMs) to mitigate radiation damage. There was also an emphasis on exploring additional areas of medicine and response to understand best practices from other emergency scenarios, which could be leveraged to improve radiation preparedness, and the importance of accurate dosimetry in preclinical work. RESULTS Subsequent to the workshop, seven collaborative projects, funded by both organizations, were established on topics ranging from MCMs and predictive biomarkers, and using physical methods to assess cutaneous radiation injuries, to mechanistic studies to understand radiation-induced damage in multiple organ systems. The importance of accurate dosimetry in preclinical works was highlighted and two recently published U.S./European commentaries that focus on the need for dosimetry standardization in the reported literature had their origins in this meeting. This commentary summarizes the workshop and open discussions among academic investigators, industry researchers, and U.S. and IRSN program representatives. CONCLUSIONS Given the substantive progress made due to these interactions, both groups plan to expand out these meetings by incorporating high-level investigators from across the globe, while endeavoring to maintain the informal setting that was conducive to in-depth scientific discussion and enhanced the state of the science in radiation research.
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Affiliation(s)
- Radia Tamarat
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Merriline M. Satyamitra
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology, and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Marc Benderitter
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Andrea L. DiCarlo
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology, and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
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Wang M, Zhao J, Li J, Meng M, Zhu M. Insights into the role of adipose-derived stem cells and secretome: potential biology and clinical applications in hypertrophic scarring. Stem Cell Res Ther 2024; 15:137. [PMID: 38735979 PMCID: PMC11089711 DOI: 10.1186/s13287-024-03749-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 05/01/2024] [Indexed: 05/14/2024] Open
Abstract
Scar tissue is the inevitable result of repairing human skin after it has been subjected to external destructive stimuli. It leads to localized damage to the appearance of the skin, accompanied by symptoms such as itching and pain, which reduces the quality of life of the patient and causes serious medical burdens. With the continuous development of economy and society, there is an increasing demand for beauty. People are looking forward to a safer and more effective method to eliminate pathological scarring. In recent years, adipose-derived stem cells (ADSCs) have received increasing attention from researchers. It can effectively improve pathological scarring by mediating inflammation, regulating fibroblast proliferation and activation, and vascular reconstruction. This review focuses on the pathophysiological mechanisms of hypertrophic scarring, summarizing the therapeutic effects of in vitro, in vivo, and clinical studies on the therapeutic effects of ADSCs in the field of hypertrophic scarring prevention and treatment, the latest application techniques, such as cell-free therapies utilizing ADSCs, and discussing the advantages and limitations of ADSCs. Through this review, we hope to further understand the characterization of ADSC and clarify the effectiveness of its application in hypertrophic scarring treatment, so as to provide clinical guidance.
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Affiliation(s)
- Menglin Wang
- Department of Plastic Surgery, The First Affiliated Hospital, Dalian Medical University, No. 222, Zhongshan Road, Xigang District, Dalian, 116011, China
| | - Jianyu Zhao
- Department of Orthopaedics, The First Affiliated Hospital, Dalian Medical University, No. 222, Zhongshan Road, Xigang District, Dalian, 116011, China
| | - Jiacheng Li
- Department of Plastic Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Meng Meng
- Department of Orthopaedics, The First Affiliated Hospital, Dalian Medical University, No. 222, Zhongshan Road, Xigang District, Dalian, 116011, China.
| | - Mengru Zhu
- Department of Plastic Surgery, The First Affiliated Hospital, Dalian Medical University, No. 222, Zhongshan Road, Xigang District, Dalian, 116011, China.
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Fani N, Moradi M, Zavari R, Parvizpour F, Soltani A, Arabpour Z, Jafarian A. Current Advances in Wound Healing and Regenerative Medicine. Curr Stem Cell Res Ther 2024; 19:277-291. [PMID: 36856176 DOI: 10.2174/1574888x18666230301140659] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 03/02/2023]
Abstract
Treating chronic wounds is a common and costly challenge worldwide. More advanced treatments are needed to improve wound healing and prevent severe complications such as infection and amputation. Like other medical fields, there have been advances in new technologies promoting wound healing potential. Regenerative medicine as a new method has aroused hope in treating chronic wounds. The technology improving wound healing includes using customizable matrices based on synthetic and natural polymers, different types of autologous and allogeneic cells at different differentiation phases, small molecules, peptides, and proteins as a growth factor, RNA interference, and gene therapy. In the last decade, various types of wound dressings have been designed. Emerging dressings include a variety of interactive/ bioactive dressings and tissue-engineering skin options. However, there is still no suitable and effective dressing to treat all chronic wounds. This article reviews different wounds and common treatments, advanced technologies and wound dressings, the advanced wound care market, and some interactive/bioactive wound dressings in the market.
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Affiliation(s)
- Nesa Fani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Maryam Moradi
- MD-MPH Iran University of Medical Sciences, Tehran, Iran
| | - Roxana Zavari
- Iranian Tissue Bank & Research Center, Gene, Cell & Tissue Institute; Tehran University of Medical Sciences, Tehran, Iran
| | - Farzad Parvizpour
- Iranian Tissue Bank & Research Center, Gene, Cell & Tissue Institute; Tehran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Adele Soltani
- CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran
- CinnaGen Research and Production Co., Alborz, Iran
| | - Zohreh Arabpour
- Iranian Tissue Bank & Research Center, Gene, Cell & Tissue Institute; Tehran University of Medical Sciences, Tehran, Iran
| | - Arefeh Jafarian
- Iranian Tissue Bank & Research Center, Gene, Cell & Tissue Institute; Tehran University of Medical Sciences, Tehran, Iran
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Ziegler ME, Staben A, Lem M, Pham J, Alaniz L, Halaseh FF, Obagi S, Leis A, Widgerow AD. Targeting Myofibroblasts as a Treatment Modality for Dupuytren Disease. J Hand Surg Am 2023; 48:914-922. [PMID: 37480917 DOI: 10.1016/j.jhsa.2023.06.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 04/13/2023] [Accepted: 04/13/2023] [Indexed: 07/24/2023]
Abstract
PURPOSE Currently, no treatment corrects the contractile nature of Dupuytren myofibroblasts (DMFs) or prevents recurrence following surgery. Antifibrotic and proadipogenic growth factors are released when adipose-derived stem cells (ASCs) are cultured with platelet-rich plasma (PRP), a platelet concentration from whole blood. Reprograming myofibroblasts into adipocytes via growth factors is proposed as a powerful potential tool to target fibrosis. We aimed to assess whether the combination of ASCs and PRP reprograms DMFs into adipocytes in vitro and alters their contractile nature in vivo. METHODS Normal human dermal fibroblasts (NHDFs) and DMFs from Dupuytren patients were isolated and cocultured with ASCs and PRP either alone or together. Adipocytes were detected by Oil Red O and perilipin staining. DMFs and NHDFs were transplanted into the forepaws of rats (Rowett Nude [rnu/rnu]) and treated with saline, PRP+ASCs, or collagenase Clostridium histolyticum (clinical comparison) 2 months later. After 2 weeks, the tissue was harvested and subjected to Masson trichrome staining, and collagen I and III and alpha-smooth muscle actin detection by immunohistochemistry. RESULTS Myofibroblasts transform into adipocytes upon coculture with PRP+ASCs. DMFs show increased alpha-smooth muscle actin expression in vivo compared with NHDFs, which is significantly decreased after PRP+ASCs and collagenase Clostridium histolyticum treatments. DMFs induce collagen I and III expressions in rat paws compared with NHDFs, with a type III to I ratio increase. Treatment with PRP+ASC reduced the ratio, but collagenase Clostridium histolyticum did not. CONCLUSIONS Treating DMFs with PRP+ASCs provides factors that induce myofibroblast to adipocyte transformation. This treatment reduces the contractile phenotype and fibrosis markers in vivo. Future studies should detail the mechanism of this conversion. CLINICAL RELEVANCE The combination of PRP and ASCs to induce the differentiation of DMFs into adipocytes may serve to limit surgery to a percutaneous contracture release and biological injection, rather than a moderate or radical fasciectomy, and reduce the recurrence of Dupuytren contracture.
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Affiliation(s)
- Mary E Ziegler
- Center for Tissue Engineering, Department of Plastic Surgery, University of California, Orange, CA
| | - Andres Staben
- Center for Tissue Engineering, Department of Plastic Surgery, University of California, Orange, CA
| | - Melinda Lem
- Center for Tissue Engineering, Department of Plastic Surgery, University of California, Orange, CA
| | - Jason Pham
- Center for Tissue Engineering, Department of Plastic Surgery, University of California, Orange, CA
| | - Leonardo Alaniz
- Center for Tissue Engineering, Department of Plastic Surgery, University of California, Orange, CA
| | - Faris F Halaseh
- Center for Tissue Engineering, Department of Plastic Surgery, University of California, Orange, CA
| | - Sabine Obagi
- Center for Tissue Engineering, Department of Plastic Surgery, University of California, Orange, CA
| | - Amber Leis
- Center for Tissue Engineering, Department of Plastic Surgery, University of California, Orange, CA
| | - Alan D Widgerow
- Center for Tissue Engineering, Department of Plastic Surgery, University of California, Orange, CA.
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Li J, Yin Y, Zou J, Zhang E, Li Q, Chen L, Li J. The adipose-derived stem cell peptide ADSCP2 alleviates hypertrophic scar fibrosis via binding with pyruvate carboxylase and remodeling the metabolic landscape. Acta Physiol (Oxf) 2023; 238:e14010. [PMID: 37366253 DOI: 10.1111/apha.14010] [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: 03/28/2023] [Revised: 05/29/2023] [Accepted: 06/04/2023] [Indexed: 06/28/2023]
Abstract
AIM The purpose of this study was to investigate the function and mechanism of a novel peptide derived from adipose-derived stem cell-conditioned medium (ADSC-CM). METHODS Mass spectrometry was applied to identify expressed peptides in ADSC-CM obtained at different time points. The cell counting kit-8 assay and quantitative reverse transcription polymerase chain reactions were performed to screen the functional peptides contained within ADSC-CM. RNA-seq, western blot, a back skin excisional model of BALB/c mice, the peptide pull-down assay, rescue experiments, untargeted metabolomics, and mixOmics analysis were performed to thoroughly understand the functional mechanism of selected peptide. RESULTS A total of 93, 827, 1108, and 631 peptides were identified in ADSC-CM at 0, 24, 48, and 72 h of conditioning, respectively. A peptide named ADSCP2 (DENREKVNDQAKL) derived from ADSC-CM inhibited collagen and ACTA2 mRNAs in hypertrophic scar fibroblasts. Moreover, ADSCP2 facilitated wound healing and attenuated collagen deposition in a mouse model. ADSCP2 bound with the pyruvate carboxylase (PC) protein and inhibited PC protein expression. Overexpressing PC rescued the reduction in collagen and ACTA2 mRNAs caused by ADSCP2. Untargeted metabolomics identified 258 and 447 differential metabolites in the negative and positive mode, respectively, in the ADSCP2-treated group. The mixOmics analysis, which integrated RNA-seq and untargeted metabolomics data, provided a more holistic view of the functions of ADSCP2. CONCLUSION Overall, a novel peptide derived from ADSC-CM, named ADSCP2, attenuated hypertrophic scar fibrosis in vitro and in vivo, and the novel peptide ADSCP2 might be a promising drug candidate for clinical scar therapy.
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Affiliation(s)
- Jingyun Li
- Nanjing Maternal and Child Health Medical Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Yiliang Yin
- Department of Plastic & Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Jijun Zou
- Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Enyuan Zhang
- Department of Plastic & Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Qian Li
- Department of Plastic & Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Ling Chen
- Department of Plastic & Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Jun Li
- Department of Plastic & Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
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Liu YX, Sun JM, Ho CK, Gao Y, Wen DS, Liu YD, Huang L, Zhang YF. Advancements in adipose-derived stem cell therapy for skin fibrosis. World J Stem Cells 2023; 15:342-353. [PMID: 37342214 PMCID: PMC10277960 DOI: 10.4252/wjsc.v15.i5.342] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/30/2023] [Accepted: 04/13/2023] [Indexed: 05/26/2023] Open
Abstract
Pathological scarring and scleroderma, which are the most common conditions of skin fibrosis, pathologically manifest as fibroblast proliferation and extracellular matrix (ECM) hyperplasia. Fibroblast proliferation and ECM hyperplasia lead to fibrotic tissue remodeling, causing an exaggerated and prolonged wound-healing response. The pathogenesis of these diseases has not been fully clarified and is unfortunately accompanied by exceptionally high medical needs and poor treatment effects. Currently, a promising and relatively low-cost treatment has emerged-adipose-derived stem cell (ASC) therapy as a branch of stem cell therapy, including ASCs and their derivatives-purified ASC, stromal vascular fraction, ASC-conditioned medium, ASC exosomes, etc., which are rich in sources and easy to obtain. ASCs have been widely used in therapeutic settings for patients, primarily for the defection of soft tissues, such as breast enhancement and facial contouring. In the field of skin regeneration, ASC therapy has become a hot research topic because it is beneficial for reversing skin fibrosis. The ability of ASCs to control profibrotic factors as well as anti-inflammatory and immunomodulatory actions will be discussed in this review, as well as their new applications in the treatment of skin fibrosis. Although the long-term effect of ASC therapy is still unclear, ASCs have emerged as one of the most promising systemic antifibrotic therapies under development.
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Affiliation(s)
- Yu-Xin Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Jia-Ming Sun
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Chia-Kang Ho
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Ya Gao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Dong-Sheng Wen
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Yang-Dan Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Lu Huang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Yi-Fan Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
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Ajit A, Kumar TRS, Harikrishnan VS, Anil A, Sabareeswaran A, Krishnan LK. Enriched adipose stem cell secretome as an effective therapeutic strategy for in vivo wound repair and angiogenesis. 3 Biotech 2023; 13:83. [PMID: 36798854 PMCID: PMC9925643 DOI: 10.1007/s13205-023-03496-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 01/24/2023] [Indexed: 02/16/2023] Open
Abstract
The therapeutic potential of adipose tissue-derived mesenchymal stem cells (ADMSCs) is well studied for use in non-healing wounds. However, concerns on the transplantable cell number requirement, cell expansion, cell viability, retained cell multipotency and the limited cell implantation time for efficient impact hinders cell therapy. Recent literature is much inclined to the superiority of the ADMSCs' secretome, pre-dominating its paracrine-mediated therapeutic impact. In this context, the possibility of attaining accelerated wound angiogenesis through non-viral mediated enrichment of the ADMSCs secretome with pro-angiogenic growth factors (AGF) seems promising. Accordingly, this study aimed to explore the effect of AGF-enriched ADMSCs secretome for accelerating wound angiogenesis and repair in acute large area full thickness excision rabbit wound model, as adopted from Salgado et al. (Chir Buchar Rom 108:706-710, 1990). Using sub-dermal single-dose injections along the margin of the dorsal wound, native ADMSCs secretome, AGF-enriched ADMSC secretome, allogenic rabbit ADMSCs and a combination of AGF-enriched ADMSC secretome with allogenic rabbit ADMSCs were transplanted independently. Twenty-eight days (28 days) post-transplantation, histopathological analysis was performed to assess the effect. Hematoxylin and eosin (H&E) staining showed enhanced epithelization, notable granulation tissue and collagen fiber deposition in AGF-enriched secretome transplanted groups. This was confirmed by elevated CD31 detection, faster wound closure time and collagen organization. The use of single-dose AGF-enriched ADMSCs' secretome for therapeutic angiogenesis and wound repair seems to be a promising cell-free therapeutic option. Further investigations using multiple doses on larger animal groups remains to be explored in order to ascertain the comparative potential of AGF-enriched ADMSCs' secretome.
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Affiliation(s)
- Amita Ajit
- Division of Thrombosis Research, Department of Applied Biology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Poojappura, Thiruvananthapuram, Kerala 695012 India
| | - T. Retnabai Santhosh Kumar
- Integrated Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala 695014 India
| | - V. S. Harikrishnan
- Division of Laboratory Animal Science, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala 695012 India
| | - Arya Anil
- Division of Laboratory Animal Science, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala 695012 India
| | - A. Sabareeswaran
- Histopathology Laboratory, Department of Applied Biology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala 695012 India
| | - Lissy Kalliyana Krishnan
- Division of Thrombosis Research, Department of Applied Biology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Poojappura, Thiruvananthapuram, Kerala 695012 India
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Zivec K, Veber M, Pizem J, Jez M, Bozikov K, Svajger U. Intraoperative Intradermal Application of Stromal Vascular Fraction into the Abdominal Suture Line: Histological Analysis of Abdominal Scar Tissue. Aesthetic Plast Surg 2022; 46:2853-2862. [PMID: 35353217 DOI: 10.1007/s00266-022-02860-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/26/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND Stem cell therapy is a promising new approach to wound healing. Stromal vascular fraction is a heterogeneous collection of cells, including adipose-derived stem cells, which are traditionally isolated using a manual collagenase-based technique. To our knowledge, this is the first human study that histologically assesses the potential of intraoperative intradermal injection of stromal vascular fraction on skin regeneration. METHODS In this controlled study, 20 patients undergoing deep inferior epigastric perforator flap breast reconstruction and bilateral flank liposuction were included. Stromal vascular fraction was injected intradermally into one side of the abdominal suture line, while the other side served as a control. Outcome measures included analysis of stromal vascular fraction by flow cytometry, histological analysis of scar tissue, and scar photography. RESULTS Cell yield for application and cell viability were 55.9 ± 28.5 × 106 and 75.1% ± 14.5%, respectively. Age and body mass index were positively correlated with the number of cells for application and adipose-derived stem cells. Mean vascular density, elastic fiber content, collagen maturity (scar index), epidermal thickness, and number of rete ridges all showed higher values on the treated side. Furthermore, the injected number of adipose-derived stem cells and pericytes positively correlated with vascular density. CONCLUSIONS It is safe to speculate that intradermal stromal vascular fraction injection at the beginning of the healing process increases vascular density, collagen maturity and organization, elastic fiber content, epidermal thickness, epidermal-dermal anchoring of the scarring skin and is therefore responsible for improved skin regeneration. It is a viable and safe method that can be used as an adjunctive treatment in plastic surgery procedures where suboptimal wound healing is anticipated. LEVEL OF EVIDENCE IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Affiliation(s)
- Katarina Zivec
- Department of Plastic Surgery, University Medical Center Ljubljana, Zaloska 7, 1000, Ljubljana, Slovenia. .,Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000, Ljubljana, Slovenia.
| | | | - Joze Pizem
- Faculty of Medicine, Institute of Pathology, Korytkova 2, 1000, Ljubljana, Slovenia
| | - Mojca Jez
- Blood Transfusion Center of Slovenia, 1000, Ljubljana, Slovenia
| | | | - Urban Svajger
- Blood Transfusion Center of Slovenia, 1000, Ljubljana, Slovenia.,Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000, Ljubljana, Slovenia
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12
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Mistry R, Veres M, Issa F. A Systematic Review Comparing Animal and Human Scarring Models. Front Surg 2022; 9:711094. [PMID: 35529910 PMCID: PMC9073696 DOI: 10.3389/fsurg.2022.711094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 04/05/2022] [Indexed: 11/29/2022] Open
Abstract
Introduction A reproducible, standardised model for cutaneous scar tissue to assess therapeutics is crucial to the progress of the field. A systematic review was performed to critically evaluate scarring models in both animal and human research. Method All studies in which cutaneous scars are modelling in animals or humans were included. Models that were focused on the wound healing process or those in humans with scars from an existing injury were excluded. Ovid Medline® was searched on 25 February 2019 to perform two near identical searches; one aimed at animals and the other aimed at humans. Two reviewers independently screened the titles and abstracts for study selection. Full texts of potentially suitable studies were then obtained for analysis. Results The animal kingdom search yielded 818 results, of which 71 were included in the review. Animals utilised included rabbits, mice, pigs, dogs and primates. Methods used for creating scar tissue included sharp excision, dermatome injury, thermal injury and injection of fibrotic substances. The search for scar assessment in humans yielded 287 results, of which 9 met the inclusion criteria. In all human studies, sharp incision was used to create scar tissue. Some studies focused on patients before or after elective surgery, including bilateral breast reduction, knee replacement or midline sternotomy. Discussion The rabbit ear scar model was the most popular tool for scar research, although pigs produce scar tissue which most closely resembles that of humans. Immunodeficient mouse models allow for in vivo engraftment and study of human scar tissue, however, there are limitations relating to the systemic response to these xenografts. Factors that determine the use of animals include cost of housing requirements, genetic traceability, and ethical concerns. In humans, surgical patients are often studied for scarring responses and outcomes, but reproducibility and patient factors that impact healing can limit interpretation. Human tissue use in vitro may serve as a good basis to rapidly screen and assess treatments prior to clinical use, with the advantage of reduced cost and setup requirements.
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Affiliation(s)
- Riyam Mistry
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
- Correspondence: Riyam Mistry
| | - Mark Veres
- John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
| | - Fadi Issa
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
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13
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Li ZJ, Wang LQ, Li YZ, Wang CY, Huang JZ, Yu NZ, Long X. Application of adipose-derived stem cells in treating fibrosis. World J Stem Cells 2021; 13:1747-1761. [PMID: 34909121 PMCID: PMC8641015 DOI: 10.4252/wjsc.v13.i11.1747] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/18/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is the hyperactivation of fibroblasts that results in excessive accumulation of extracellular matrix, which is involved in numerous pathological changes and diseases. Adipose-derived stem cells (ASCs) are promising seed cells for regenerative medicine due to their bountiful source, low immunogenicity and lack of ethical issues. Their anti-fibrosis, immunomodulation, angiogenesis and other therapeutic effects have made them suitable for treating fibrosis-related diseases. Here, we review the literature on ASCs treating fibrosis, elaborate and discuss their mechanisms of action, changes in disease environment, ways to enhance therapeutic effects, as well as current preclinical and clinical studies, in order to provide a general picture of ASCs treating fibrotic diseases.
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Affiliation(s)
- Zhu-Jun Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Li-Quan Wang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yun-Zhu Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Chen-Yu Wang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jiu-Zuo Huang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Nan-Ze Yu
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xiao Long
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
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14
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Otsuka T, Kan HM, Laurencin CT. Regenerative Engineering Approaches to Scar-Free Skin Regeneration. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2021. [DOI: 10.1007/s40883-021-00229-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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15
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Zhang D, Li B, Zhao M. Therapeutic Strategies by Regulating Interleukin Family to Suppress Inflammation in Hypertrophic Scar and Keloid. Front Pharmacol 2021; 12:667763. [PMID: 33959031 PMCID: PMC8093926 DOI: 10.3389/fphar.2021.667763] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 03/05/2021] [Indexed: 12/28/2022] Open
Abstract
Hypertrophic scar (HS) and keloid are fibroproliferative disorders (FPDs) of the skin due to aberrant wound healing, which cause disfigured appearance, discomfort, dysfunction, psychological stress, and patient frustration. The unclear pathogenesis behind HS and keloid is partially responsible for the clinical treatment stagnancy. However, there are now increasing evidences suggesting that inflammation is the initiator of HS and keloid formation. Interleukins are known to participate in inflammatory and immune responses, and play a critical role in wound healing and scar formation. In this review, we summarize the function of related interleukins, and focus on their potentials as the therapeutic target for the treatment of HS and keloid.
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Affiliation(s)
- Dan Zhang
- Department of Plastic and Cosmetic Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Bo Li
- Department of Plastic and Cosmetic Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Muxin Zhao
- Department of Plastic and Cosmetic Surgery, The Second Hospital of Dalian Medical University, Dalian, China
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16
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Bojanic C, To K, Hatoum A, Shea J, Seah KTM, Khan W, Malata CM. Mesenchymal stem cell therapy in hypertrophic and keloid scars. Cell Tissue Res 2021; 383:915-930. [PMID: 33386995 PMCID: PMC7960584 DOI: 10.1007/s00441-020-03361-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 11/19/2020] [Indexed: 12/20/2022]
Abstract
Scars are the normal outcome of wound repair and involve a co-ordinated inflammatory and fibrotic process. When a scar does not resolve, uncontrolled chronic inflammation can persist and elicits excessive scarring that leads to a range of abnormal phenotypes such as hypertrophic and keloid scars. These pathologies result in significant impairment of quality of life over a long period of time. Existing treatment options are generally unsatisfactory, and there is mounting interest in innovative cell-based therapies. Despite the interest in mesenchymal stem cells (MSCs), there is yet to be a human clinical trial that investigates the potential of MSCs in treating abnormal scarring. A synthesis of existing evidence of animal studies may therefore provide insight into the barriers to human application. The aim of this PRISMA systematic review was to evaluate the effectiveness of MSC transplantation in the treatment of hypertrophic and keloid scars in in vivo models. A total of 11 case-control studies were identified that treated a total of 156 subjects with MSCs or MSC-conditioned media. Ten studies assessed hypertrophic scars, and one looked at keloid scars. All studies evaluated scars in terms of macroscopic and histological appearances and most incorporated immunohistochemistry. The included studies all found improvements in the above outcomes with MSC or MSC-conditioned media without complications. The studies reviewed support a role for MSC therapy in treating scars that needs further exploration. The transferability of these findings to humans is limited by factors such as the reliability and validity of the disease model, the need to identify the optimal MSC cell source, and the outcome measures employed.
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Affiliation(s)
- Christine Bojanic
- Plastic & Reconstructive Surgery Department, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Kendrick To
- Division of Trauma and Orthopaedics, Department of Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Adam Hatoum
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Jessie Shea
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - K T Matthew Seah
- Division of Trauma and Orthopaedics, Department of Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Wasim Khan
- Division of Trauma and Orthopaedics, Department of Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
| | - Charles M Malata
- Plastic & Reconstructive Surgery Department, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- School of Medicine, Anglia Ruskin University, Cambridge & Chelmsford, UK
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17
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Zhang C, Wang T, Zhang L, Chen P, Tang S, Chen A, Li M, Peng G, Gao H, Weng H, Zhang H, Li S, Chen J, Chen L, Chen X. Combination of lyophilized adipose-derived stem cell concentrated conditioned medium and polysaccharide hydrogel in the inhibition of hypertrophic scarring. Stem Cell Res Ther 2021; 12:23. [PMID: 33413617 PMCID: PMC7792059 DOI: 10.1186/s13287-020-02061-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 11/27/2020] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Mesenchymal stem cell-based acellular therapies have been widely exploited in managing hypertrophic scars. However, low maintenance dose and transitory therapeutic effects during topical medication remain a thorny issue. Herein, this study aimed to optimize the curative effect of adipose-derived stem cell conditioned medium (ADSC-CM) in the prevention of hypertrophic scarring. METHODS In the present study, ADSC-CM was concentrated via the freeze-drying procedure. The efficacy of different dose groups (CM, CM5, CM10) was conducted on the proliferation, apoptosis, and α-smooth muscle actin (α-SMA) expression of human keloid fibroblasts (HKFs) in vitro. Incorporation of adipose-derived stem cell concentrated conditioned medium (ADSCC-CM) into polysaccharide hydrogel was investigated in rabbit ear, in vivo. Haematoxylin-eosin (H&E) and Masson's trichrome staining were performed for the evaluation of scar hyperplasia. RESULTS We noted that ADSCC-CM could downregulate the α-SMA expression of HKFs in a dose-dependent manner. In the rabbit ear model, the scar hyperplasia in the medium-dose group (CM5) and high-dose group (CM10) was inhibited with reduced scar elevation index (SEI) under 4 months of observation. It is noteworthy that the union of CM5 and polysaccharide hydrogel (CM5+H) yielded the best preventive effect on scar hyperplasia. Briefly, melanin, height, vascularity, and pliability in the CM5+H group were better than those of the control group. Collagen was evenly distributed, and skin appendages could be regenerated. CONCLUSIONS Altogether, ADSCC-CM can downregulate the expression of α-SMA due to its anti-fibrosis effect and promote the rearrangement of collagen fibres, which is integral to scar precaution. The in situ cross bonding of ADSCC-CM and polysaccharide hydrogel could remarkably enhance the therapeutic outcomes in inhibiting scar proliferation. Hence, the alliance of ADSCC-CM and hydrogel may become a potential alternative in hypertrophic scar prophylaxis.
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Affiliation(s)
- Chaoyu Zhang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, China
| | - Ting Wang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
| | - Li Zhang
- Department of Central Sterile Supply, Fujian Medical University Union Hospital, Fuzhou, China
| | - Penghong Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, China
| | - Shijie Tang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, China
| | - Aizhen Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, China
| | - Ming Li
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
| | - Guohao Peng
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.,Department of Stem Cell Research Institute, Fujian Medical University, Fuzhou, China
| | - Hangqi Gao
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
| | - Haiyan Weng
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
| | - Haoruo Zhang
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China
| | - Shirong Li
- Department of Plastic and Reconstructive Surgery, Southwestern Hospital, Army Military Medical University, Chongqing, China
| | - Jinghua Chen
- Department of Pharmaceutical Analysis, The School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Liangwan Chen
- Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
| | - Xiaosong Chen
- Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, China. .,Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, China.
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18
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Chyle Fat-Derived Stem Cells Conditioned Medium Inhibits Hypertrophic Scar Fibroblast Activity. Ann Plast Surg 2020; 83:271-277. [PMID: 31149905 DOI: 10.1097/sap.0000000000001932] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Hypertrophic scars (HSs) generally form after injury to the deep layers of the dermis and are characterized by excessive collagen deposition. An increasing amount of evidence has determined that human adipose tissue-derived mesenchymal stem cells attenuate fibrosis in various conditions. We explored the effect and possible mechanism of chyle fat-derived stem cells (CFSCs) on HS formation. METHODS Hypertrophic scar-derived fibroblasts (HSFs) and CFSCs were isolated from individual patients. Third-passage CFSCs were isolated and cultured using a mechanical emulsification method, and their surface CD markers were analyzed by flow cytometry. The adipogenic and osteogenic differentiation capacity of the CFSCs was determined using oil red O staining and alizarin red S staining, respectively. Then, the effects of CFSCs on HSFs were assessed in vitro. Hypertrophic scar-derived fibroblasts were treated with starvation-induced conditioned medium from the CFSCs (CFSC-CM). The change in HSF cellular behaviors, such as cell proliferation, migration, and protein expression of scar-related molecules, was evaluated by cell counting assay, scratch wound assay, enzyme-linked immunosorbent assay, and western blotting. All data were analyzed using SPSS 17.0. RESULTS The CFSCs expressed CD90, CD105, and CD73 but did not express CD34, CD45, or CD31. The CFSCs differentiated into adipocytes and osteoblasts under the appropriate induction conditions. Chyle fat-derived stem cells conditioned medium inhibited HSF proliferation and migration. The in vitro and ex vivo studies revealed that CFSC-CM decreased type I collagen, type III collagen, and α smooth muscle actin expression. CONCLUSIONS Our results suggest that CFSCs are associated with the inhibition of fibrosis in HSFs by a paracrine effect. The use of CFSC-CM may be a novel therapeutic strategy for HSs.
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19
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Piccolo NS, Piccolo MS, de Paula Piccolo N, de Paula Piccolo P, de Paula Piccolo N, Daher RP, Lobo RP, Daher SP, Sarto Piccolo MT. Fat Grafting for Treatment of Facial Burns and Burn Scars. Clin Plast Surg 2019; 47:119-130. [PMID: 31739888 DOI: 10.1016/j.cps.2019.08.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
This article presents the authors' experience with the use of fat grafting via the Coleman technique, for the adjuvant treatment of facial burn wounds and their sequelae. It demonstrates the regenerative effects of fat injected under the wound and/or the scar as well as of fat delivered to the debrided surface of the wound and to the surface of the scar after laser treatment or microneedling.
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Affiliation(s)
- Nelson Sarto Piccolo
- Division of Plastic Surgery, Pronto Socorro para Queimaduras, Rua 5, n. 439, Setor Oeste, Goiânia, Goiás 74115 060, Brazil.
| | - Mônica Sarto Piccolo
- Division of Plastic Surgery, Pronto Socorro para Queimaduras, Rua 5, n. 439, Setor Oeste, Goiânia, Goiás 74115 060, Brazil
| | - Nelson de Paula Piccolo
- Division of Plastic Surgery, Pronto Socorro para Queimaduras, Rua 5, n. 439, Setor Oeste, Goiânia, Goiás 74115 060, Brazil
| | - Paulo de Paula Piccolo
- Division of Plastic Surgery, Pronto Socorro para Queimaduras, Rua 5, n. 439, Setor Oeste, Goiânia, Goiás 74115 060, Brazil
| | - Natalia de Paula Piccolo
- Division of Anesthesiology, Pronto Socorro para Queimaduras, Rua 5, n. 439, Setor Oeste, Goiânia, Goiás 74115 060, Brazil
| | - Ricardo Piccolo Daher
- Division of Outpatient Care, Pronto Socorro para Queimaduras, Rua 5, n. 439, Setor Oeste, Goiânia, Goiás 74115 060, Brazil
| | - Roberta Piccolo Lobo
- Division of Plastic Surgery, Pronto Socorro para Queimaduras, Rua 5, n. 439, Setor Oeste, Goiânia, Goiás 74115 060, Brazil
| | - Silvia Piccolo Daher
- Division of Anesthesiology, Pronto Socorro para Queimaduras, Rua 5, n. 439, Setor Oeste, Goiânia, Goiás 74115 060, Brazil
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20
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Li J, Wang J, Wang Z, Xia Y, Zhou M, Zhong A, Sun J. Experimental models for cutaneous hypertrophic scar research. Wound Repair Regen 2019; 28:126-144. [PMID: 31509318 DOI: 10.1111/wrr.12760] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 08/29/2019] [Accepted: 09/06/2019] [Indexed: 01/07/2023]
Abstract
Human skin wound repair may result in various outcomes with most of them leading to scar formation. Commonly seen in many cutaneous wound healing cases, hypertrophic scars are considered as phenotypes of abnormal wound repair. To prevent the formation of hypertrophic scars, efforts have been made to understand the mechanism of scarring following wound closure. Numerous in vivo and in vitro models have been created to facilitate investigations into cutaneous scarring and the development of antiscarring treatments. To select the best model for a specific study, background knowledge of the current models of hypertrophic scars is necessary. In this review, we describe in vivo and in vitro models for studying hypertrophic scars, as well as the distinct characteristics of these models. The choice of models for a specific study should be based on the characteristics of the model and the goal of the study. In general, in vivo animal models are often used in phenotypical scar formation analysis, development of antiscarring treatment, and functional analyses of individual genes. In contrast, in vitro models are chosen to pathway identification during scar formation as well as in high-throughput analysis in drug development. Besides helping investigators choose the best scarring model for their research, the goal of this review is to provide knowledge for improving the existing models and development of new models. These will contribute to the progress of scarring studies.
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Affiliation(s)
- Jialun Li
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Jiecong Wang
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Zhenxing Wang
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yun Xia
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Muran Zhou
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Aimei Zhong
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Jiaming Sun
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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21
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Lee S, Moon S, Oh JY, Seo EH, Kim YH, Jun E, Shim IK, Kim SC. Enhanced insulin production and reprogramming efficiency of mesenchymal stem cells derived from porcine pancreas using suitable induction medium. Xenotransplantation 2019; 26:e12451. [PMID: 30252163 DOI: 10.1111/xen.12451] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 05/23/2018] [Accepted: 06/26/2018] [Indexed: 01/21/2023]
Abstract
BACKGROUND Genetic reprogramming is a powerful method for altering cell properties and inducing differentiation. However, even if the same gene is reprogrammed, the results vary among cells. Therefore, a better possible strategy involves treating cells with factors that further stimulate differentiation while using stem cells with the same tissue origin. This study aimed to increase induction efficiency and insulin production in reprogrammed cells using a combination of factors that promote cell differentiation. METHODS Porcine pancreatic cells were cultured to obtain mesenchymal stem cells expressing pancreatic cell-specific markers through sequential passages. The characteristics of these cells were identified, and the M3 gene (Pdx1, Ngn3, MafA) was reprogrammed to induce differentiation into insulin-producing cells. Additionally, the differentiation efficiency of insulin-producing cells was compared by treating reprogrammed cells with a differentiation-promoting factor. RESULTS Mesenchymal stem cells isolated from porcine pancreatic tissues expressed exocrine cell markers, including amylase and cytokeratin 18, and most cells continuously expressed the beta cell transcription factors Ngn3 and NeuroD. Reprogramming of the M3 gene resulted in differentiation into insulin-producing cells. Moreover, significantly increased insulin and glucagon expressions were observed in the suitable induction medium, and the characteristic beta cell transcription factors Pdx1, Ngn3, and MafA were expressed at levels as high as those in pancreatic islet cells. CONCLUSIONS Differentiation into insulin-producing cells represents an alternative therapy for insufficient pancreatic islet cells when treating diabetes. Therefore, cells with the characteristics of the target cell should be used to improve differentiation efficiency by creating an environment that promotes reprogramming and differentiation.
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Affiliation(s)
- Song Lee
- Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soobin Moon
- Department of Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ju Yun Oh
- Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun Ha Seo
- Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yang Hee Kim
- Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eunsung Jun
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In Kyoung Shim
- Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Song Cheol Kim
- Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Foubert P, Liu M, Anderson S, Rajoria R, Gutierrez D, Zafra D, Tenenhaus M, Fraser JK. Preclinical assessment of safety and efficacy of intravenous delivery of autologous adipose-derived regenerative cells (ADRCs) in the treatment of severe thermal burns using a porcine model. Burns 2018; 44:1531-1542. [PMID: 29958745 DOI: 10.1016/j.burns.2018.05.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 04/10/2018] [Accepted: 05/16/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVE A number of studies have reported that application of autologous adipose-derived cell populations leads to improved outcome in different preclinical models of thermal burn injury. However, these studies were limited to assessment of relatively small injuries amounting to only ∼2% of total body surface area (TBSA) in which the complications associated with large burns (e.g.: systemic inflammation and the need for fluid resuscitation) are absent. In anticipation of translating this approach to a clinical trial in which these complications would be present we applied a preclinical model that more closely resembles a patient with large thermal burn injury requiring skin grafting. Thus, the present study used a porcine model to investigate safety and efficacy of intravenous delivery of ADRCs in the treatment of a complex burn injury comprising ∼20% TBSA and including both moderately deep (44%) partial and full thickness burns, and the injury associated with skin graft harvest. METHODS Two pairs of full thickness and partial thickness burns involving in total ∼20% TBSA were created on the back of Yorkshire pigs (n=15). Three days post-burn, full thickness wounds were excised and grafted with a 3:1 meshed autologous split thickness skin graft (STSG). Partial thickness wounds were not treated other than with dressings. Animals were then randomized to receive intravenous delivery of ADRCs (n=8) or vehicle control (n=7). Safety was assessed by monitoring systemic parameters (blood gases, hematology, and clinical chemistry) throughout the course of the study. Wound healing for both types of burn wound and for the skin graft donor sites was followed for 18days using wound imaging, histology, and trans-epidermal water loss (TEWL; skin barrier function assessment). RESULTS No serious adverse events related to ADRC infusion were noted in any of the animals. Delivery of ADRCs appeared to be safe with none of the systemic safety parameters worsened compared to the control group. TEWL and histological analyses revealed that ADRC treatment was associated with significantly accelerated healing of skin graft (27.1% vs. 1.1% on Day 5 post-grafting), donor site (52.8% vs. 33.1% on Day 5 post-excision) and partial thickness burn (81.8% vs. 59.8% on Day 18 post-treatment). Data also suggested that ADRC treatment improved parameters associated with skin graft elasticity. CONCLUSIONS This study demonstrated that intravenous delivery of autologous ADRCs appears to be a safe and feasible approach to the treatment of large burns and supports the use of ADRCs as an adjunct therapy to skin grafting in patients with severe burns.
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Affiliation(s)
| | - Mike Liu
- Cytori Therapeutics Inc, San Diego, CA, USA
| | | | | | | | | | - Mayer Tenenhaus
- UCSD Medical Center, University of California, San Diego, CA, USA
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Li Z, Maitz P. Cell therapy for severe burn wound healing. BURNS & TRAUMA 2018; 6:13. [PMID: 29854856 PMCID: PMC5971426 DOI: 10.1186/s41038-018-0117-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 04/26/2018] [Indexed: 12/14/2022]
Abstract
Cell therapy has emerged as an important component of life-saving procedures in treating burns. Over past decades, advances in stem cells and regenerative medicine have offered exciting opportunities of developing cell-based alternatives and demonstrated the potential and feasibility of various stem cells for burn wound healing. However, there are still scientific and technical issues that should be resolved to facilitate the full potential of the cellular devices. More evidence from large, randomly controlled trials is also needed to understand the clinical impact of cell therapy in burns. This article aims to provide an up-to-date review of the research development and clinical applications of cell therapies in burn wound healing and skin regeneration.
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Affiliation(s)
- Zhe Li
- Burns Unit, Concord Hospital, Concord, New South Wales 2139 Australia
- Skin Laboratory, NSW Statewide Burns Service, Concord, New South Wales Australia
- Discipline of Surgery, University of Sydney Medical School, Camperdown, New South Wales Australia
| | - Peter Maitz
- Burns Unit, Concord Hospital, Concord, New South Wales 2139 Australia
- Skin Laboratory, NSW Statewide Burns Service, Concord, New South Wales Australia
- Discipline of Surgery, University of Sydney Medical School, Camperdown, New South Wales Australia
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