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1
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Dervenis V. The Role of HPV in the Development of Cutaneous Squamous Cell Carcinoma-Friend or Foe? Cancers (Basel) 2025; 17:1195. [PMID: 40227794 PMCID: PMC11988061 DOI: 10.3390/cancers17071195] [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: 01/30/2025] [Revised: 03/19/2025] [Accepted: 03/30/2025] [Indexed: 04/15/2025] Open
Abstract
The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing, with UV radiation being the main cause. Other risk factors are age, sex, skin type and immunosuppression. Human papillomaviruses (HPVs) are associated with benign and malignant skin tumours. In contrast to anogenital and oropharyngeal carcinomas, which are caused by alpha papillomaviruses, the HPV types associated with cSCC belong to the beta-HPV genus. These viruses infect the skin epithelium and are widespread in skin samples from healthy people. It is assumed that HPV amplifies the DNA damage caused by UV radiation and disrupts the repair mechanisms of the cells, without remaining permanently detectable in the tumour tissue, the so-called hit-and-run theory. The HPV status of tumours appears to have a positive influence on prognosis and response to therapy due to increased immune infiltration, in particular by tissue-resident memory T cells and activation of immune effector cells. This favours responses to immunotherapies such as PD-1/PD-L1 inhibitors, whereas immunosuppression may promote a pro-carcinogenic effect. In conclusion, the role of beta HPV in the development of cSCC appears to be closely associated with the immune status of the host. Depending on the immune status, beta HPV can play either a protective or a tumour-promoting role, and in view of the increasing incidence of skin cancer worldwide, enhancing the immune response against virus-infected keratinocytes, e.g., through HPV vaccination, could represent a promising approach for the prevention and therapy of squamous cell carcinomas.
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Affiliation(s)
- Vasileios Dervenis
- Department of Dermatology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany
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2
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Jiang TX, Wu P, Li A, Widelitz RB, Chuong CM. Wound-Induced Regeneration in Feather Follicles: A Stepwise Strategy to Regenerate Stem Cells. J Dev Biol 2025; 13:10. [PMID: 40265368 PMCID: PMC12015844 DOI: 10.3390/jdb13020010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/12/2025] [Accepted: 03/25/2025] [Indexed: 04/24/2025] Open
Abstract
How to elicit and harness regeneration is a major issue in wound healing. Skin injury in most amniotes leads to repair rather than regeneration, except in hair and feathers. Feather follicles are unique organs that undergo physiological cyclic renewal, supported by a dynamic stem cell niche. During normal feather cycling, growth-phase proximal follicle collar bulge stem cells adopt a ring configuration. At the resting and initiation phases, these stem cells descend to the dermal papilla to form papillary ectoderm and ascend to the proximal follicle in a new growth phase. Plucking resting-phase feathers accelerates papillary ectoderm cell activation. Plucking growth-phase feathers depletes collar bulge stem cells; however, a blastema reforms the collar bulge stem cells, expressing KRT15, LGR6, Sox9, integrin-α6, and tenascin C. Removing the follicle base and dermal papilla prevents feather regeneration. Yet, transplanting an exogenous dermal papilla to the follicle base can induce re-epithelialization from the lower follicle sheath, followed by feather regeneration. Thus, there is a stepwise regenerative strategy using stem cells located in the collar bulge, papillary ectoderm, and de-differentiated lower follicle sheath to generate new feathers after different levels of injuries. This adaptable regenerative mechanism is based on the hierarchy of stem cell regenerative capacity and underscores the remarkable resilience of feather follicle regenerative abilities.
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Affiliation(s)
- Ting-Xin Jiang
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (T.-X.J.); (P.W.); (A.L.); (R.B.W.)
| | - Ping Wu
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (T.-X.J.); (P.W.); (A.L.); (R.B.W.)
| | - Ang Li
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (T.-X.J.); (P.W.); (A.L.); (R.B.W.)
- Department of Kinesiology, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76019, USA
| | - Randall B. Widelitz
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (T.-X.J.); (P.W.); (A.L.); (R.B.W.)
| | - Cheng-Ming Chuong
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (T.-X.J.); (P.W.); (A.L.); (R.B.W.)
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3
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Bao A, Bordone LA, Aguh C. A Review of Metabolic Dysregulation in Lymphocytic Cicatricial Alopecia: Exploring the Connections and Therapeutic Implications. J Invest Dermatol 2025:S0022-202X(25)00293-3. [PMID: 40100177 DOI: 10.1016/j.jid.2025.01.036] [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: 10/20/2024] [Revised: 01/22/2025] [Accepted: 01/27/2025] [Indexed: 03/20/2025]
Abstract
Lymphocytic primary cicatricial alopecia (LPCA) is an inflammatory disorder characterized by permanent hair follicle destruction and fibrosis. Recent evidence suggests a significant link between LPCA and metabolic dysregulation, particularly diabetes and dyslipidemia. This review examines the emerging role of metabolism in LPCA pathogenesis and its implications for novel therapeutic approaches. Epidemiologic studies demonstrate increased prevalence of metabolic disorders among patients with LPCA, whereas molecular investigations reveal altered metabolic pathways in affected hair follicles, including disruptions in peroxisome proliferator-activated receptor γ signaling and adenosine monophosphate-activated protein kinase activation, mechanisms that parallel those observed in other fibrotic diseases. These pathways appear to precede inflammatory changes, suggesting metabolic dysfunction as a primary trigger rather than a secondary effect. Preliminary treatments targeting these pathways, such as pioglitazone and metformin, have shown promising results in normalizing lipid metabolism and reducing inflammation, although their clinical efficacy across LPCA subtypes requires further investigation. The review also explores emerging therapeutic possibilities, including glucagon-like peptide-1 agonists. Understanding the interplay between metabolic disturbances, fibrosis, and inflammation in the pathogenesis of LPCA offers new avenues for both research and treatment. This paradigm shift suggests the need for metabolic screening in patients with LPCA and highlights the potential for developing more comprehensive, metabolism-targeted therapies to improve outcomes in these challenging hair disorders.
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Affiliation(s)
- Aaron Bao
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lindsey A Bordone
- Columbia University Irving Medical Center of Medicine, New York, New York, USA
| | - Crystal Aguh
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
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4
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Messenger AG, Asfour L, Harries M. Frontal Fibrosing Alopecia: An Update. Am J Clin Dermatol 2025; 26:155-174. [PMID: 39699852 DOI: 10.1007/s40257-024-00912-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2024] [Indexed: 12/20/2024]
Abstract
In this review, we discuss recent developments in our understanding of frontal fibrosing alopecia, a disease that has become increasingly common and widespread since its first description in 1994. An inherited predisposition to frontal fibrosing alopecia, previously suspected from the occurrence of familial cases, has been confirmed through genetic studies. Nevertheless, the epidemiology continues to implicate environmental factors in the aetiology. The search has focussed mainly on personal skin care products such as facial moisturisers and UV filters, and there is also some evidence implicating exogenous oestrogens, but confirmation of direct causal links has so far proved elusive. The pathologic mechanisms underlying follicular deletion are being clarified, including the nature of the inflammatory component, the loss of follicular immune privilege in the bulge region and the role of epithelial-mesenchymal transition in the scarring process. Lichen planus pigmentosus, a common accompaniment to frontal fibrosing alopecia in those with darker skin, is probably a feature of the same pathology affecting interfollicular epidermis, rather than a co-morbidity, and may offer new clues to the aetiology. Treatment is still based largely on retrospective case series and variable endpoints. However, methods for assessing frontal fibrosing alopecia and monitoring treatment responses have been strengthened and randomised controlled trials with novel agents (e.g. Janus kinase inhibitors) are in progress. As the main aim of effective treatment is to prevent disease progression, early diagnosis will remain an important target, as will prevention in the longer term.
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Affiliation(s)
| | - Leila Asfour
- Chelsea and Westminster NHS Foundation Trust, London, SW10 9NH, UK
| | - Matthew Harries
- Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M6 8HD, UK
- Faculty of Biology, Medicine and Health, Centre for Dermatology Research, University of Manchester and NIHR Biomedical Research Centre, Manchester, UK
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5
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Li J, Zhao B, Yu Y, Bao Z, Zheng F, Cai J, Chen Y, Wu X. Decorin-mediated dermal papilla cell-derived exosomes regulate hair follicle growth and development through miR-129-2-3p/SMAD3/TGF-β axis. Int J Biol Macromol 2025; 295:139292. [PMID: 39755296 DOI: 10.1016/j.ijbiomac.2024.139292] [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: 10/04/2024] [Revised: 12/13/2024] [Accepted: 12/27/2024] [Indexed: 01/06/2025]
Abstract
Decorin (DCN) is a member of the small leucine-rich proteoglycan family within the extracellular matrix, playing a role in the growth and development of hair follicle (HF). Exosomes serve as significant mediators of intercellular communication and are involved in the cyclic regeneration of HF. Exosomes derived from dermal papilla cells (DPC-Exos) are essential for the cycling and regrowth of HF. The present study demonstrated that DCN treatment significantly enhances the proliferation of DPCs, thereby promoting hair follicle growth. miRNA sequencing revealed 442 differentially expressed exosomal miRNAs. The regulatory mechanism of exosomal miR-129-2-3p, an up-regulated differential miRNA, was further investigated. The study identified its role in transporting DPCs to HFSCs through DPC-Exos. miR-129-2-3p has been shown to suppress the expression of genes associated with HF growth and development, lower the expression of genes and proteins downstream of the TGF-β signaling pathway, promote HFSC proliferation, and decrease HFSC apoptosis. Furthermore, miR-129-2-3p displayed an antagonistic effect on activating the TGF-β/SMAD3 signaling pathway induced by SRI-011381. The findings indicate that DCN-mediated DPC-Exos influence HF growth and development through the miR-129-2-3p/SMAD3/TGF-β regulatory axis. These results may facilitate novel strategies for the diagnosis and treatment of human hair disorders, in addition to enhancing industrial wool production.
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Affiliation(s)
- Jiali Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China; Department of Chemical Engineering, Faculty of Engineering, Kyushu University, Fukuoka 819-0395, Japan
| | - Bohao Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Yongqi Yu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Zhiyuan Bao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Feiyang Zheng
- Department of Chemical Engineering, Faculty of Engineering, Kyushu University, Fukuoka 819-0395, Japan
| | - Jiawei Cai
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Yang Chen
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
| | - Xinsheng Wu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China; Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou, Jiangsu 225009, China.
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6
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Cattier B, Guignard R, Martel I, Martel C, Simard-Bisson C, Larouche D, Guiraud B, Bessou-Touya S, Germain L. Bulge-Derived Epithelial Cells Isolated from Human Hair Follicles Using Enzymatic Digestion or Explants Result in Comparable Tissue-Engineered Skin. Int J Mol Sci 2025; 26:1852. [PMID: 40076477 PMCID: PMC11899990 DOI: 10.3390/ijms26051852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 03/14/2025] Open
Abstract
Hair follicle stem cells, located in the bulge region of the outer root sheath, are multipotent epithelial stem cells capable of differentiating into epidermal, sebaceous gland, and hair shaft cells. Efficient culturing of these cells is crucial for advancements in dermatology, regenerative medicine, and skin model development. This investigation aimed to develop a protocol for isolating enriched bulge-derived epithelial cells from scalp specimens to produce tissue-engineered substitutes. The epithelium, including hair follicles, was separated from the dermis using thermolysin, followed by microdissection of the bulge region. Epithelial stem cells were isolated using enzymatic dissociation to create a single-cell suspension and compared with the direct explant culture and a benchmark method which isolates cells from the epidermis and pilosebaceous units. After 8 days of culture, the enzymatic digestion of microdissected bulges yielded 5.3 times more epithelial cells compared to explant cultures and proliferated faster than the benchmark method. Cells cultured from all methods exhibited comparable morphology and growth rates. The fully stratified epidermis of tissue-engineered skin was similar, indicating comparable differentiation potential. This enzymatic digestion method improved early-stage cell recovery and expansion while maintaining keratinocyte functionality, offering an efficient hair bulge cell-extraction technique for tissue engineering and regenerative medicine applications.
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Affiliation(s)
- Bettina Cattier
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada; (B.C.); (R.G.); (I.M.); (C.M.); (C.S.-B.); (D.L.)
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada
- CHU de Québec-Université Laval Research Centre, Quebec City, QC G1J 5B3, Canada
| | - Rina Guignard
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada; (B.C.); (R.G.); (I.M.); (C.M.); (C.S.-B.); (D.L.)
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada
- CHU de Québec-Université Laval Research Centre, Quebec City, QC G1J 5B3, Canada
| | - Israël Martel
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada; (B.C.); (R.G.); (I.M.); (C.M.); (C.S.-B.); (D.L.)
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada
- CHU de Québec-Université Laval Research Centre, Quebec City, QC G1J 5B3, Canada
| | - Christian Martel
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada; (B.C.); (R.G.); (I.M.); (C.M.); (C.S.-B.); (D.L.)
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada
- CHU de Québec-Université Laval Research Centre, Quebec City, QC G1J 5B3, Canada
| | - Carolyne Simard-Bisson
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada; (B.C.); (R.G.); (I.M.); (C.M.); (C.S.-B.); (D.L.)
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada
- CHU de Québec-Université Laval Research Centre, Quebec City, QC G1J 5B3, Canada
| | - Danielle Larouche
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada; (B.C.); (R.G.); (I.M.); (C.M.); (C.S.-B.); (D.L.)
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada
- CHU de Québec-Université Laval Research Centre, Quebec City, QC G1J 5B3, Canada
| | - Béatrice Guiraud
- R&D Center, Pierre Fabre Dermo-Cosmétique, 31100 Toulouse, France; (B.G.); (S.B.-T.)
| | - Sandrine Bessou-Touya
- R&D Center, Pierre Fabre Dermo-Cosmétique, 31100 Toulouse, France; (B.G.); (S.B.-T.)
| | - Lucie Germain
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Quebec City, QC G1J 5B3, Canada; (B.C.); (R.G.); (I.M.); (C.M.); (C.S.-B.); (D.L.)
- Department of Surgery, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada
- CHU de Québec-Université Laval Research Centre, Quebec City, QC G1J 5B3, Canada
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7
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Derman ID, Rivera T, Garriga Cerda L, Singh YP, Saini S, Abaci HE, Ozbolat IT. Advancements in 3D skin bioprinting: processes, bioinks, applications and sensor integration. INTERNATIONAL JOURNAL OF EXTREME MANUFACTURING 2025; 7:012009. [PMID: 39569402 PMCID: PMC11574952 DOI: 10.1088/2631-7990/ad878c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/23/2024] [Accepted: 10/16/2024] [Indexed: 11/22/2024]
Abstract
This comprehensive review explores the multifaceted landscape of skin bioprinting, revolutionizing dermatological research. The applications of skin bioprinting utilizing techniques like extrusion-, droplet-, laser- and light-based methods, with specialized bioinks for skin biofabrication have been critically reviewed along with the intricate aspects of bioprinting hair follicles, sweat glands, and achieving skin pigmentation. Challenges remain with the need for vascularization, safety concerns, and the integration of automated processes for effective clinical translation. The review further investigates the incorporation of biosensor technologies, emphasizing their role in monitoring and enhancing the wound healing process. While highlighting the remarkable progress in the field, critical limitations and concerns are critically examined to provide a balanced perspective. This synthesis aims to guide scientists, engineers, and healthcare providers, fostering a deeper understanding of the current state, challenges, and future directions in skin bioprinting for transformative applications in tissue engineering and regenerative medicine.
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Affiliation(s)
- I Deniz Derman
- Engineering Science and Mechanics Department, Penn State University, University Park, PA, United States of America
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA, United States of America
| | - Taino Rivera
- Biomedical Engineering Department, Penn State University, University Park, PA, United States of America
| | - Laura Garriga Cerda
- Department of Dermatology, Columbia University Irving Medical Center, New York, NY, United States of America
| | - Yogendra Pratap Singh
- Engineering Science and Mechanics Department, Penn State University, University Park, PA, United States of America
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA, United States of America
| | - Shweta Saini
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA, United States of America
| | - Hasan Erbil Abaci
- Department of Dermatology, Columbia University Irving Medical Center, New York, NY, United States of America
- Department of Biomedical Engineering, Columbia University, New York, NY, United States of America
| | - Ibrahim T Ozbolat
- Engineering Science and Mechanics Department, Penn State University, University Park, PA, United States of America
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA, United States of America
- Biomedical Engineering Department, Penn State University, University Park, PA, United States of America
- Materials Research Institute, Penn State University, University Park, PA, United States of America
- Cancer Institute, Penn State University, University Park, PA, United States of America
- Neurosurgery Department, Penn State University, University Park, PA, United States of America
- Department of Medical Oncology, Cukurova University, Adana, Turkey
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8
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Derman ID, Moses JC, Rivera T, Ozbolat IT. Understanding the cellular dynamics, engineering perspectives and translation prospects in bioprinting epithelial tissues. Bioact Mater 2025; 43:195-224. [PMID: 39386221 PMCID: PMC11462153 DOI: 10.1016/j.bioactmat.2024.09.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/04/2024] [Accepted: 09/18/2024] [Indexed: 10/12/2024] Open
Abstract
The epithelium is one of the important tissues in the body as it plays a crucial barrier role serving as a gateway into and out of the body. Most organs in the body contain an epithelial tissue component, where the tightly connected, organ-specific epithelial cells organize into cysts, invaginations, or tubules, thereby performing distinct to endocrine or exocrine secretory functions. Despite the significance of epithelium, engineering functional epithelium in vitro has remained a challenge due to it is special architecture, heterotypic composition of epithelial tissues, and most importantly, difficulty in attaining the apico-basal and planar polarity of epithelial cells. Bioprinting has brought a paradigm shift in fabricating such apico-basal polarized tissues. In this review, we provide an overview of epithelial tissues and provide insights on recapitulating their cellular arrangement and polarization to achieve epithelial function. We describe the different bioprinting techniques that have been successful in engineering polarized epithelium, which can serve as in vitro models for understanding homeostasis and studying diseased conditions. We also discuss the different attempts that have been investigated to study these 3D bioprinted engineered epithelium for preclinical use. Finally, we highlight the challenges and the opportunities that need to be addressed for translation of 3D bioprinted epithelial tissues towards paving way for personalized healthcare in the future.
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Affiliation(s)
- Irem Deniz Derman
- Engineering Science and Mechanics Department, Penn State University, University Park, PA, 16802, USA
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA, 16802, USA
| | - Joseph Christakiran Moses
- Engineering Science and Mechanics Department, Penn State University, University Park, PA, 16802, USA
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA, 16802, USA
| | - Taino Rivera
- Biomedical Engineering Department, Penn State University, University Park, PA, 16802, USA
| | - Ibrahim T. Ozbolat
- Engineering Science and Mechanics Department, Penn State University, University Park, PA, 16802, USA
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA, 16802, USA
- Biomedical Engineering Department, Penn State University, University Park, PA, 16802, USA
- Materials Research Institute, Penn State University, University Park, PA, 16802, USA
- Cancer Institute, Penn State University, University Park, PA, 16802, USA
- Neurosurgery Department, Penn State University, University Park, PA, 16802, USA
- Department of Medical Oncology, Cukurova University, Adana, 01330, Turkey
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9
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Lyu Y, Kim SJ, Humphrey ES, Nayak R, Guan Y, Liang Q, Kim KH, Tan Y, Dou J, Sun H, Song X, Nagarajan P, Gerner-Mauro KN, Jin K, Liu V, Hassan RH, Johnson ML, Deliu LP, You Y, Sharma A, Pasolli HA, Lu Y, Zhang J, Mohanty V, Chen K, Yang YJ, Chen T, Ge Y. Stem cell activity-coupled suppression of endogenous retrovirus governs adult tissue regeneration. Cell 2024; 187:7414-7432.e26. [PMID: 39476839 DOI: 10.1016/j.cell.2024.10.007] [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: 02/05/2024] [Revised: 06/14/2024] [Accepted: 10/04/2024] [Indexed: 12/29/2024]
Abstract
Mammalian retrotransposons constitute 40% of the genome. During tissue regeneration, adult stem cells coordinately repress retrotransposons and activate lineage genes, but how this coordination is controlled is poorly understood. Here, we observed that dynamic expression of histone methyltransferase SETDB1 (a retrotransposon repressor) closely mirrors stem cell activities in murine skin. SETDB1 ablation leads to the reactivation of endogenous retroviruses (ERVs, a type of retrotransposon) and the assembly of viral-like particles, resulting in hair loss and stem cell exhaustion that is reversible by antiviral drugs. Mechanistically, at least two molecularly and spatially distinct pathways are responsible: antiviral defense mediated by hair follicle stem cells and progenitors and antiviral-independent response due to replication stress in transient amplifying cells. ERV reactivation is promoted by DNA demethylase ten-eleven translocation (TET)-mediated hydroxymethylation and recapitulated by ablating cell fate transcription factors. Together, we demonstrated ERV silencing is coupled with stem cell activity and essential for adult hair regeneration.
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Affiliation(s)
- Ying Lyu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Soo Jin Kim
- Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Ericka S Humphrey
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Richa Nayak
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Yinglu Guan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qingnan Liang
- Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Kun Hee Kim
- Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA; Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Yukun Tan
- Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Jinzhuang Dou
- Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Huandong Sun
- Department of Genome Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Xingzhi Song
- Department of Genome Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
| | | | - Kamryn N Gerner-Mauro
- Department of Pulmonary Medicine, UT MD Anderson Cancer Center, Houston, TX, USA; Development, Disease Models, and Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, USA
| | - Kevin Jin
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Wiess School of Natural Sciences, Rice University, Houston, TX, USA
| | - Virginia Liu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Wiess School of Natural Sciences, Rice University, Houston, TX, USA
| | - Rehman H Hassan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Miranda L Johnson
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lisa P Deliu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun You
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anurag Sharma
- Electron Microscopy Resource Center, The Rockefeller University, New York, NY, USA
| | - H Amalia Pasolli
- Electron Microscopy Resource Center, The Rockefeller University, New York, NY, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Jianhua Zhang
- Department of Genome Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Vakul Mohanty
- Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Ken Chen
- Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA; Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Youn Joo Yang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Taiping Chen
- Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA; Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA
| | - Yejing Ge
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA.
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10
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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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11
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Niu Y, Li Y, Gao C, Li W, Li L, Wang H, Shen W, Ge W. Melatonin promotes hair regeneration by modulating the Wnt/β-catenin signalling pathway. Cell Prolif 2024; 57:e13656. [PMID: 38773710 PMCID: PMC11503254 DOI: 10.1111/cpr.13656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 04/23/2024] [Accepted: 05/03/2024] [Indexed: 05/24/2024] Open
Abstract
Melatonin (MLT) is a circadian hormone that reportedly influences the development and cyclic growth of secondary hair follicles; however, the mechanism of regulation remains unknown. Here, we systematically investigated the role of MLT in hair regeneration using a hair depilation mouse model. We found that MLT supplementation significantly promoted hair regeneration in the hair depilation mouse model, whereas supplementation of MLT receptor antagonist luzindole significantly suppressed hair regeneration. By analysing gene expression dynamics between the MLT group and luzindole-treated groups, we revealed that MLT supplementation significantly up-regulated Wnt/β-catenin signalling pathway-related genes. In-depth analysis of the expression of key molecules in the Wnt/β-catenin signalling pathway revealed that MLT up-regulated the Wnt/β-catenin signalling pathway in dermal papillae (DP), whereas these effects were facilitated through mediating Wnt ligand expression levels in the hair follicle stem cells (HFSCs). Using a DP-HFSCs co-culture system, we verified that MLT activated Wnt/β-catenin signalling in DPs when co-cultured with HFSCs, whereas supplementation of DP cells with MLT alone failed to activate Wnt/β-catenin signalling. In summary, our work identified a critical role for MLT in promoting hair regeneration and will have potential implications for future hair loss treatment in humans.
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Affiliation(s)
- Yi‐Lin Niu
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of ShandongQingdao Agricultural UniversityQingdaoChina
| | - Yu‐Kang Li
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of ShandongQingdao Agricultural UniversityQingdaoChina
| | - Chen‐Xi Gao
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of ShandongQingdao Agricultural UniversityQingdaoChina
| | - Wen‐Wen Li
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of ShandongQingdao Agricultural UniversityQingdaoChina
| | - Li Li
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of ShandongQingdao Agricultural UniversityQingdaoChina
| | - Han Wang
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of ShandongQingdao Agricultural UniversityQingdaoChina
| | - Wei Shen
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of ShandongQingdao Agricultural UniversityQingdaoChina
| | - Wei Ge
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of ShandongQingdao Agricultural UniversityQingdaoChina
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12
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White A, Reilly DA. Management of the Sequelae of Skin Grafting: Pruritis, Folliculitis, Pigmentation Changes, and More. Clin Plast Surg 2024; 51:409-418. [PMID: 38789150 DOI: 10.1016/j.cps.2023.12.004] [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: 05/26/2024]
Abstract
Scars commonly give rise to unpredictable, potentially irritating, cutaneous complications including pruritis, folliculitis, and pigment changes. These problems can be self-limiting and are prevalent in many burn cases, although their expression varies among individuals. A better understanding of the presentation, risk factors, and pathophysiology of these long-term sequelae allows for more comprehensive care of burn survivors.
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Affiliation(s)
- Anna White
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-3280, USA
| | - Debra Ann Reilly
- Department of Surgery (Plastic), University of Nebraska Medical Center, 1430 South 85th Avenue, Omaha, NE 68124, USA.
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13
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Xiao X, Gao Y, Yan L, Deng C, Wu W, Lu X, Lu Q, Zhong W, Xu Y, Zhang C, Chen W, Huang B. M1 polarization of macrophages promotes stress-induced hair loss via interleukin-18 and interleukin-1β. J Cell Physiol 2024; 239:e31181. [PMID: 38219076 DOI: 10.1002/jcp.31181] [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: 10/04/2023] [Revised: 11/23/2023] [Accepted: 12/12/2023] [Indexed: 01/15/2024]
Abstract
Stress-induced hair loss is a prevalent health concern, with mechanisms that remain unclear, and effective treatment options are not yet available. In this study, we investigated whether stress-induced hair loss was related to an imbalanced immune microenvironment. Screening the skin-infiltrated immune cells in a stressed mouse model, we discovered a significant increase in macrophages upon stress induction. Clearance of macrophages rescues mice from stress-induced hair shedding and depletion of hair follicle stem cells (HFSCs) in the skin, demonstrating the role of macrophages in triggering hair loss in response to stress. Further flow cytometry analysis revealed a significant increase in M1 phenotype macrophages in mice under stressed conditions. In searching for humoral factors mediating stress-induced macrophage polarization, we found that the hormone Norepinephrine (NE) was elevated in the blood of stressed mice. In addition, in-vivo and in-vitro studies confirm that NE can induce macrophage polarization toward M1 through the β-adrenergic receptor, Adrb2. Transcriptome, enzyme-linked immunosorbent assay (ELISA), and western blot analyses reveal that the NLRP3/caspase-1 inflammasome signaling and its downstream effector interleukin 18 (IL-18) and interleukin 1 beta (IL-1β) were significantly upregulated in the NE-treated macrophages. However, inhibition of the NE receptor Adrb2 with ICI118551 reversed the upregulation of NLRP3/caspase-1, IL-18, and IL-1β. Indeed, IL-18 and IL-1β treatments lead to apoptosis of HFSCs. More importantly, blocking IL-18 and IL-1β signals reversed HFSCs depletion in skin organoid models and attenuated stress-induced hair shedding in mice. Taken together, this study demonstrates the role of the neural (stress)-endocrine (NE)-immune (M1 macrophages) axis in stress-induced hair shedding and suggestes that IL-18 or IL-1β may be promising therapeutic targets.
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Affiliation(s)
- Xing Xiao
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Digestive Disease Center, The Seventh Affiliated Hospital of Sun Yat‑Sen University, Shenzhen, China
| | - Ying Gao
- School of Pharmaceutical Sciences Shenzhen, Sun Yat-sen University, Shenzhen, China
| | - Lingchen Yan
- School of Pharmaceutical Sciences Shenzhen, Sun Yat-sen University, Shenzhen, China
| | - Cuncan Deng
- Digestive Disease Center, The Seventh Affiliated Hospital of Sun Yat‑Sen University, Shenzhen, China
| | - Wang Wu
- Digestive Disease Center, The Seventh Affiliated Hospital of Sun Yat‑Sen University, Shenzhen, China
| | - Xiaofang Lu
- Department of Pathology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Qiumei Lu
- School of Pharmaceutical Sciences Shenzhen, Sun Yat-sen University, Shenzhen, China
| | - Wenwei Zhong
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yunsheng Xu
- Department of Dermatology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Changhua Zhang
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Digestive Disease Center, The Seventh Affiliated Hospital of Sun Yat‑Sen University, Shenzhen, China
| | - Wei Chen
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Digestive Disease Center, The Seventh Affiliated Hospital of Sun Yat‑Sen University, Shenzhen, China
| | - Bihui Huang
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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14
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Quílez C, Valencia L, González‐Rico J, Suárez‐Cabrera L, Amigo‐Morán L, Jorcano JL, Velasco D. In vitro induction of hair follicle signatures using human dermal papilla cells encapsulated in fibrin microgels. Cell Prolif 2024; 57:e13528. [PMID: 37539497 PMCID: PMC10771113 DOI: 10.1111/cpr.13528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 06/13/2023] [Accepted: 06/27/2023] [Indexed: 08/05/2023] Open
Abstract
Cellular spheroids have been described as an appropriate culture system to restore human follicle dermal papilla cells (hFDPc) intrinsic properties; however, they show a low and variable efficiency to promote complete hair follicle formation in in vivo experiments. In this work, a conscientious analysis revealed a 25% cell viability in the surface of the dermal papilla spheroid (DPS) for all culture conditions, questioning whether it is an appropriate culture system for hFDPc. To overcome this problem, we propose the use of human blood plasma for the generation of fibrin microgels (FM) with encapsulated hFDPc to restore its inductive signature, either in the presence or in the absence of blood platelets. FM showed a morphology and extracellular matrix composition similar to the native dermal papilla, including Versican and Collagen IV and increasing cell viability up to 85%. While both systems induce epidermal invaginations expressing hair-specific keratins K14, K15, K71, and K75 in in vitro skin cultures, the number of generated structures increases from 17% to 49% when DPS and FM were used, respectively. These data show the potential of our experimental setting for in vitro hair follicle neogenesis with wild adult hFDPc using FM, being a crucial step in the pursuit of human hair follicle regeneration therapies.
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Affiliation(s)
- Cristina Quílez
- Department of BioengineeringUniversidad Carlos III de MadridLeganésSpain
- Fundación Instituto de Investigación Sanitaria de la Fundación Jiménez DíazMadridSpain
| | - Leticia Valencia
- Department of BioengineeringUniversidad Carlos III de MadridLeganésSpain
| | - Jorge González‐Rico
- Department of Continuum Mechanics and Structural AnalysisUniversidad Carlos III de MadridLeganésSpain
| | | | - Lidia Amigo‐Morán
- Department of BioengineeringUniversidad Carlos III de MadridLeganésSpain
| | - José Luis Jorcano
- Department of BioengineeringUniversidad Carlos III de MadridLeganésSpain
- Instituto De Investigacion Sanitaria Gregorio MarañonMadridSpain
| | - Diego Velasco
- Department of BioengineeringUniversidad Carlos III de MadridLeganésSpain
- Fundación Instituto de Investigación Sanitaria de la Fundación Jiménez DíazMadridSpain
- Instituto De Investigacion Sanitaria Gregorio MarañonMadridSpain
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15
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Wang W, Wang H, Long Y, Li Z, Li J. Controlling Hair Loss by Regulating Apoptosis in Hair Follicles: A Comprehensive Overview. Biomolecules 2023; 14:20. [PMID: 38254620 PMCID: PMC10813359 DOI: 10.3390/biom14010020] [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: 11/12/2023] [Revised: 12/16/2023] [Accepted: 12/18/2023] [Indexed: 01/24/2024] Open
Abstract
Apoptosis is a physiological process that occurs in all cell types of the human body, and it profoundly changes the fate of hair by affecting hair follicle cells. This review outlines the cellular changes, intrinsic biochemical characteristics, and mechanisms underlying apoptosis and summarizes the hair follicle life cycle, including development, cycle stages, and corresponding cellular changes. Finally, the relationship between apoptosis and the hair cycle is discussed and the significance of apoptosis in hair loss conditions and drug treatments is highlighted. Apoptosis induces cellular changes and exhibits distinctive properties through intricate signaling pathways. Hair follicles undergo cyclic periods of growth, regression, and dormancy. Apoptosis is closely correlated with the regression phase by triggering hair follicle cell death and shedding. Regulation of apoptosis in hair follicles plays an essential role in hair loss due to maladies and drug treatments. Mitigating apoptosis can enhance hair growth and minimize hair loss. A comprehensive understanding of the correlation between apoptosis and the hair cycle can facilitate the development of novel treatments to prevent hair loss and stimulate hair regeneration.
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Affiliation(s)
- Wuji Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, China; (W.W.); (H.W.); (Y.L.); (Z.L.)
- Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi 563006, China
- Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi 563006, China
| | - Honglan Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, China; (W.W.); (H.W.); (Y.L.); (Z.L.)
- Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi 563006, China
- Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi 563006, China
| | - Yunluan Long
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, China; (W.W.); (H.W.); (Y.L.); (Z.L.)
- Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi 563006, China
- Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi 563006, China
| | - Zheng Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, China; (W.W.); (H.W.); (Y.L.); (Z.L.)
- Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi 563006, China
- Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi 563006, China
| | - Jingjie Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, China; (W.W.); (H.W.); (Y.L.); (Z.L.)
- Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical University, Zunyi 563006, China
- Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi 563006, China
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16
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Abstract
Diseases affecting the hair follicle are common in domestic animals, but despite the importance of an intact skin barrier and a fully functional hair coat, knowledge about the detailed morphological features and the diversity of these complex mini-organs are often limited, although mandatory to evaluate skin biopsies with a history of alopecia. The factors that regulate the innate hair follicle formation and the postnatal hair cycle are still not completely understood in rodents, only rudimentarily known in humans, and are poorly understood in our companion animals. This review aims to summarize the current knowledge about hair follicle and hair shaft anatomy, the arrangement of hair follicles, hair follicle morphogenesis in the embryo, and the lifelong regeneration during the postnatal hair cycle in domestic animals. The role of follicular stem cells and the need for a multitude of interacting signaling events during hair follicle morphogenesis and regeneration is unquestioned. Because of the lack of state of the art methods that can be applied in rodents but are not feasible in companion animals, most of the information in this review is based on rodent studies. However, the few data from domestic animals that are available will be discussed, and it can be assumed that at least the principal molecular mechanisms are similar in rodents and other species.
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17
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Lim C, Lim J, Choi S. Wound-Induced Hair Follicle Neogenesis as a Promising Approach for Hair Regeneration. Mol Cells 2023; 46:573-578. [PMID: 37650216 PMCID: PMC10590709 DOI: 10.14348/molcells.2023.0071] [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: 04/29/2023] [Revised: 07/21/2023] [Accepted: 08/16/2023] [Indexed: 09/01/2023] Open
Abstract
The mammalian skin contains hair follicles, which are epidermal appendages that undergo periodic cycles and exhibit mini-organ features, such as discrete stem cell compartments and different cellular components. Wound-induced hair follicle neogenesis (WIHN) is the remarkable ability to regenerate hair follicles after large-scale wounding and occurs in several adult mammals. WIHN is comparable to embryonic hair follicle development in its processes. Researchers are beginning to identify the stem cells that, in response to wounding, develop into neogenic hair follicles, as well as to understand the functions of immune cells, mesenchymal cells, and several signaling pathways that are essential for this process. WIHN represents a promising therapeutic approach to the reprogramming of cellular states for promoting hair follicle regeneration and preventing scar formation. In the scope of this review, we investigate the contribution of several cell types and molecular mechanisms to WIHN.
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Affiliation(s)
- Chaeryeong Lim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
| | - Jooyoung Lim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
| | - Sekyu Choi
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- School of Medical Science and Engineering, POSTECH, Pohang 37673, Korea
- School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang 37673, Korea
- Institute for Convergence Research and Education in Advanced Technology (I_CREATE), Yonsei University, Incheon 21983, Korea
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18
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Lorenzo-Martín LF, Bustelo XR. The Rho GTPase exchange factor Vav2 promotes extensive age-dependent rewiring of the hair follicle stem cell transcriptome. Front Cell Dev Biol 2023; 11:1252834. [PMID: 37822868 PMCID: PMC10562702 DOI: 10.3389/fcell.2023.1252834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/11/2023] [Indexed: 10/13/2023] Open
Abstract
Both the number and regenerative activity of hair follicle stem cells (HFSCs) are regulated by Vav2, a GDP/GTP exchange factor involved in the catalytic stimulation of the GTPases Rac1 and RhoA. However, whether Vav2 signaling changes in HFSCs over the mouse lifespan is not yet known. Using a mouse knock-in mouse model, we now show that the expression of a catalytically active version of Vav2 (Vav2Onc) promotes an extensive rewiring of the overall transcriptome of HFSCs, the generation of new transcription factor hubs, and the synchronization of many transcriptional programs associated with specific HFSC states and well-defined signaling pathways. Interestingly, this transcriptome rewiring is not fixed in time, as it involves the induction of 15 gene expression waves with diverse distribution patterns during the life of the animals. These expression waves are consistent with the promotion by Vav2Onc of several functional HFSC states that differ from those normally observed in wild-type HFSCs. These results further underscore the role of Vav2 in the regulation of the functional state of HFSCs. They also indicate that, unlike other Vav2-dependent biological processes, the signaling output of this exchange factor is highly contingent on age-dependent intrinsic and/or extrinsic HFSC factors that shape the final biological readouts triggered in this cell type.
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Affiliation(s)
- L. Francisco Lorenzo-Martín
- Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Salamanca, Spain
- Instituto de Biología Molecular y Celular del Cáncer, CSIC and University of Salamanca, Salamanca, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Salamanca, Spain
| | - Xosé R. Bustelo
- Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Salamanca, Spain
- Instituto de Biología Molecular y Celular del Cáncer, CSIC and University of Salamanca, Salamanca, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Salamanca, Spain
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19
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Liu TY, Hughes MW, Wang HV, Yang WC, Chuong CM, Wu P. Molecular and Cellular Characterization of Avian Reticulate Scales Implies the Evo-Devo Novelty of Skin Appendages in Foot Sole. J Dev Biol 2023; 11:30. [PMID: 37489331 PMCID: PMC10366821 DOI: 10.3390/jdb11030030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/25/2023] [Accepted: 06/27/2023] [Indexed: 07/26/2023] Open
Abstract
Among amniotic skin appendages, avian feathers and mammalian hairs protect their stem cells in specialized niches, located in the collar bulge and hair bulge, respectively. In chickens and alligators, label retaining cells (LRCs), which are putative stem cells, are distributed in the hinge regions of both avian scutate scales and reptilian overlapping scales. These LRCs take part in scale regeneration. However, it is unknown whether other types of scales, for example, symmetrically shaped reticulate scales, have a similar way of preserving their stem cells. In particular, the foot sole represents a special interface between animal feet and external environments, with heavy mechanical loading. This is different from scutate-scale-covered metatarsal feet that function as protection. Avian reticulate scales on foot soles display specialized characteristics in development. They do not have a placode stage and lack β-keratin expression. Here, we explore the molecular and cellular characteristics of avian reticulate scales. RNAscope analysis reveals different molecular profiles during surface and hinge determination compared with scutate scales. Furthermore, reticulate scales express Keratin 15 (K15) sporadically in both surface- and hinge-region basal layer cells, and LRCs are not localized. Upon wounding, the reticulate scale region undergoes repair but does not regenerate. Our results suggest that successful skin appendage regeneration requires localized stem cell niches to guide regeneration.
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Affiliation(s)
- Tzu-Yu Liu
- Department of Life Sciences, National Cheng Kung University, Tainan 701, Taiwan
- Marine Biology and Cetacean Research Center, National Cheng Kung University, Tainan 701, Taiwan
| | - Michael W Hughes
- Institute of Clinical Medicine and Department of Life Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Hao-Ven Wang
- Department of Life Sciences, National Cheng Kung University, Tainan 701, Taiwan
- Marine Biology and Cetacean Research Center, National Cheng Kung University, Tainan 701, Taiwan
| | - Wei-Cheng Yang
- School of Veterinary Medicine, National Taiwan University, Taipei 106216, Taiwan
| | - Cheng-Ming Chuong
- Department of Pathology, Keck School of Medicine, University Southern California, Los Angeles, CA 90033, USA
| | - Ping Wu
- Department of Pathology, Keck School of Medicine, University Southern California, Los Angeles, CA 90033, USA
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20
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El-Husseiny HM, Mady EA, El-Dakroury WA, Doghish AS, Tanaka R. Stimuli-responsive hydrogels: smart state of-the-art platforms for cardiac tissue engineering. Front Bioeng Biotechnol 2023; 11:1174075. [PMID: 37449088 PMCID: PMC10337592 DOI: 10.3389/fbioe.2023.1174075] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 06/15/2023] [Indexed: 07/18/2023] Open
Abstract
Biomedicine and tissue regeneration have made significant advancements recently, positively affecting the whole healthcare spectrum. This opened the way for them to develop their applications for revitalizing damaged tissues. Thus, their functionality will be restored. Cardiac tissue engineering (CTE) using curative procedures that combine biomolecules, biomimetic scaffolds, and cells plays a critical part in this path. Stimuli-responsive hydrogels (SRHs) are excellent three-dimensional (3D) biomaterials for tissue engineering (TE) and various biomedical applications. They can mimic the intrinsic tissues' physicochemical, mechanical, and biological characteristics in a variety of ways. They also provide for 3D setup, adequate aqueous conditions, and the mechanical consistency required for cell development. Furthermore, they function as competent delivery platforms for various biomolecules. Many natural and synthetic polymers were used to fabricate these intelligent platforms with innovative enhanced features and specialized capabilities that are appropriate for CTE applications. In the present review, different strategies employed for CTE were outlined. The light was shed on the limitations of the use of conventional hydrogels in CTE. Moreover, diverse types of SRHs, their characteristics, assembly and exploitation for CTE were discussed. To summarize, recent development in the construction of SRHs increases their potential to operate as intelligent, sophisticated systems in the reconstruction of degenerated cardiac tissues.
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Affiliation(s)
- Hussein M. El-Husseiny
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, Benha, Egypt
| | - Eman A. Mady
- Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
- Department of Animal Hygiene, Behavior and Management, Faculty of Veterinary Medicine, Benha University, Benha, Egypt
| | - Walaa A. El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Egypt
| | - Ahmed S. Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Ryou Tanaka
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
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21
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Vatanashevanopakorn C, Sartyoungkul T. iPSC-based approach for human hair follicle regeneration. Front Cell Dev Biol 2023; 11:1149050. [PMID: 37325563 PMCID: PMC10266356 DOI: 10.3389/fcell.2023.1149050] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/15/2023] [Indexed: 06/17/2023] Open
Abstract
Hair follicles (HFs) are a multifunctional structure involved in physical protection, thermoregulation, sensational detection, and wound healing. Formation and cycling of HFs require dynamic interaction between different cell types of the follicles. Although the processes have been well studied, the generation of human functional HFs with a normal cycling pattern for clinical utilization has yet to be achieved. Recently, human pluripotent stem cells (hPSCs) serve as an unlimited cell source for generating various types of cells including cells of the HFs. In this review, HF morphogenesis and cycling, different cell sources used for HF regeneration, and potential strategies for HF bioengineering using induced pluripotent stem cells (iPSCs) are depicted. Challenges and perspectives toward the therapeutic use of bioengineered HFs for hair loss disorder are also discussed.
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Affiliation(s)
- Chinnavuth Vatanashevanopakorn
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Siriraj Center for Regenerative Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Thanutchaporn Sartyoungkul
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Siriraj Center for Regenerative Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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22
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Jia Q, Zhang S, Wang D, Liu J, Luo X, Liu Y, Li X, Sun F, Xia G, Zhang L. Regulatory Effects of FGF9 on Dermal Papilla Cell Proliferation in Small-Tailed Han Sheep. Genes (Basel) 2023; 14:genes14051106. [PMID: 37239467 DOI: 10.3390/genes14051106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/12/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Fibroblast growth factor 9 (FGF9) is crucial for the growth and development of hair follicles (HFs); however, its role in sheep wool growth is unknown. Here, we clarified the role of FGF9 in HF growth in the small-tailed Han sheep by quantifying FGF9 expression in skin tissue sections collected at different periods. Moreover, we evaluated the effects of FGF9 protein supplementation on hair shaft growth in vitro and FGF9 knockdown on cultured dermal papilla cells (DPCs). The relationship between FGF9 and the Wnt/β-catenin signaling pathway was examined, and the underlying mechanisms of FGF9-mediated DPC proliferation were investigated. The results show that FGF9 expression varies throughout the HF cycle and participates in wool growth. The proliferation rate and cell cycle of FGF9-treated DPCs substantially increase compared to that of the control group, and the mRNA and protein expression of CTNNB1, a Wnt/β-catenin signaling pathway marker gene, is considerably lower than that in the control group. The opposite occurs in FGF9-knockdown DPCs. Moreover, other signaling pathways are enriched in the FGF9-treated group. In conclusion, FGF9 accelerates the proliferation and cell cycle of DPCs and may regulate HF growth and development through the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Qi Jia
- Institute of Animal Biotechnology, Jilin Academy of Agricultural Sciences, Gongzhuling 136100, China
- College of Agriculture, Yanbian University, Yanji 130021, China
| | - Shuangshuang Zhang
- Institute of Animal Biotechnology, Jilin Academy of Agricultural Sciences, Gongzhuling 136100, China
- College of Agriculture, Yanbian University, Yanji 130021, China
| | - Dan Wang
- College of Agriculture, Yanbian University, Yanji 130021, China
| | - Jianqiang Liu
- Institute of Animal Biotechnology, Jilin Academy of Agricultural Sciences, Gongzhuling 136100, China
| | - Xinhui Luo
- Institute of Animal Biotechnology, Jilin Academy of Agricultural Sciences, Gongzhuling 136100, China
| | - Yu Liu
- Institute of Animal Biotechnology, Jilin Academy of Agricultural Sciences, Gongzhuling 136100, China
| | - Xin Li
- Institute of Animal Biotechnology, Jilin Academy of Agricultural Sciences, Gongzhuling 136100, China
| | - Fuliang Sun
- College of Agriculture, Yanbian University, Yanji 130021, China
| | - Guangjun Xia
- College of Agriculture, Yanbian University, Yanji 130021, China
| | - Lichun Zhang
- Institute of Animal Biotechnology, Jilin Academy of Agricultural Sciences, Gongzhuling 136100, China
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23
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Li KN, Chovatiya G, Ko DY, Sureshbabu S, Tumbar T. Blood endothelial ALK1-BMP4 signaling axis regulates adult hair follicle stem cell activation. EMBO J 2023; 42:e112196. [PMID: 36994549 PMCID: PMC10183823 DOI: 10.15252/embj.2022112196] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/31/2023] Open
Abstract
Blood vessels can play dual roles in tissue growth by transporting gases and nutrients and by regulating tissue stem cell activity via signaling. Correlative evidence implicates skin endothelial cells (ECs) as signaling niches of hair follicle stem cells (HFSCs), but functional demonstration from gene depletion of signaling molecules in ECs is missing to date. Here, we show that depletion of the vasculature-factor Alk1 increases BMP4 secretion from ECs, which delays HFSC activation. Furthermore, while previous evidence suggests a lymphatic vessel role in adult HFSC activation possibly through tissue drainage, a blood vessel role has not yet been addressed. Genetic perturbation of the ALK1-BMP4 axis in all ECs or the lymphatic ECs specifically unveils inhibition of HFSC activation by blood vessels. Our work suggests a broader relevance of blood vessels, adding adult HFSCs to the EC functional repertoire as signaling niches for the adult stem cells.
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Affiliation(s)
- Kefei Nina Li
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
| | - Gopal Chovatiya
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
| | - Daniel Youngjoo Ko
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
| | - Sripad Sureshbabu
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
| | - Tudorita Tumbar
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
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24
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Papakonstantinou M, Siotos C, Gasteratos KC, Spyropoulou GA, Gentile P. Autologous Platelet-Rich Plasma Treatment for Androgenic Alopecia: A Systematic Review and Meta-Analysis of Clinical Trials. Plast Reconstr Surg 2023; 151:739e-747e. [PMID: 36729475 DOI: 10.1097/prs.0000000000010076] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Androgenic alopecia (AGA) is a common condition associated with hair loss in both men and women (female pattern hair loss), causing considerable psychological distress. Ongoing research focuses on novel safe, cost-effective, and efficient treatments with the best patient outcomes. Autologous platelet-rich plasma (PRP) has become increasingly popular in the treatment of AGA compared with hair transplantation techniques. The present study aims to evaluate the outcomes of PRP as a treatment for AGA/female pattern hair loss. METHODS A computerized literature search was conducted on PubMed, clinicaltrials.gov , and Cochrane Library for articles published until November of 2020. The online screening process was performed by two independent reviewers with the Covidence tool against set inclusion/exclusion criteria. The protocol was reported following the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines, and it was registered at the International Prospective Register of Systematic Reviews of the National Institute for Health and Care Research. Meta-analyses were performed by using the random effects model with the RevMan software. RESULTS The initial search yielded 49 randomized controlled clinical trials. Eleven randomized controlled clinical trials were included in the study based on a priori criteria. PRP injections significantly increased the number of hair follicles, hair thickness, and density compared with placebo interventions. Also, the patients reported high overall satisfaction with the PRP treatment. Only temporary minor side effects were noted, including localized pain, bleeding, and itching. CONCLUSIONS Autologous PRP significantly improves alopecia in select patients. Future research should focus on optimizing PRP treatment protocols and minimizing possible adverse reactions. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, II.
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Affiliation(s)
| | - Charalampos Siotos
- Division of Plastic and Reconstructive Surgery, Rush University Medical Center
| | - Konstantinos C Gasteratos
- Elmezzi Graduate School of Molecular Medicine, Feinstein Institutes for Medical Research, Northwell Health
| | | | - Pietro Gentile
- Division of Plastic and Reconstructive Surgery, Papageorgiou General Hospital of Thessaloniki
- Surgical Science Department, University "Tor Vergata."
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25
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Lambertini M, Ricci C, Corti B, Veronesi G, Quaglino P, Ribero S, Pellacani G, Hrvatin Stancic B, Campione E, Dika E. Follicular colonization in melanocytic nevi and melanoma: A literature review. J Cutan Pathol 2023. [PMID: 36820529 DOI: 10.1111/cup.14415] [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: 11/22/2022] [Revised: 02/11/2023] [Accepted: 02/21/2023] [Indexed: 02/24/2023]
Abstract
The lentiginous spread of melanocytes into the hair follicle can be observed in a number of benign melanocytic neoplasms such as in nevi but also in sun-induced melanocytic hyperplasia and melanoma. The follicular colonization by melanocytes in melanoma is classified into three distinct patterns: primary follicular melanoma, melanoma with folliculotropism, and invasive melanoma arising from melanoma in situ with folliculotropism. The role of follicular colonization in melanoma pathologic staging is still a matter of debate though the description of the latter has been recommended by the International Collaboration on Cancer Reporting. In this review, we will discuss the role of follicular colonization in melanoma and melanocytic nevi as well as the facts and controversies regarding this topic.
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Affiliation(s)
- Martina Lambertini
- Melanoma Centre, Dermatology, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
- Dermatology, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Costantino Ricci
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- Pathology Unit, Maggiore Hospital, AUSL Bologna, Bologna, Italy
| | - Barbara Corti
- Pathology Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
| | - Giulia Veronesi
- Melanoma Centre, Dermatology, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
- Dermatology, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Pietro Quaglino
- Dermatology Clinic, Department of medical sciences, University of Turin, Turin, Italy
| | - Simone Ribero
- Dermatology Clinic, Department of medical sciences, University of Turin, Turin, Italy
| | - Giovanni Pellacani
- Dermatology Clinic, Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza Medical School, Sapienza University of Rome, Rome, Italy
| | - Bor Hrvatin Stancic
- Dermatovenerology Department, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Elena Campione
- Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Emi Dika
- Melanoma Centre, Dermatology, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
- Dermatology, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy
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26
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Oak ASW, Cotsarelis G. Wound-Induced Hair Neogenesis: A Portal to the Development of New Therapies for Hair Loss and Wound Regeneration. Cold Spring Harb Perspect Biol 2023; 15:a041239. [PMID: 36123030 PMCID: PMC9899649 DOI: 10.1101/cshperspect.a041239] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Adult mammals retain the remarkable ability to regenerate hair follicles after wounding. Wound-induced hair neogenesis (WIHN) in many ways recapitulates embryogenesis. The origin of the stem cells that give rise to a nascent hair follicle after wounding and the role of mesenchymal cells and signaling pathways responsible for this regenerative phenomenon are slowly being elucidated. WIHN provides a potential therapeutic window for manipulating cell fate by the introduction of factors during the wound healing process to enhance hair follicle formation.
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Affiliation(s)
- Allen S W Oak
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - George Cotsarelis
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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27
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Jeong S, Na Y, Nam HM, Sung GY. Skin-on-a-chip strategies for human hair follicle regeneration. Exp Dermatol 2023; 32:13-23. [PMID: 36308297 DOI: 10.1111/exd.14699] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/20/2022] [Accepted: 10/28/2022] [Indexed: 01/06/2023]
Abstract
The number of hair loss patients increases every year, and hair loss treatment has several limitations, so research on hair is attracting attention recently. However, most current hair follicle research models are limited by their inability to replicate several key functions of the hair follicle microenvironment. To complement this, an in vitro culture system similar to the in vivo environment must be constructed. It is necessary to develop a hair-on-a-chip that implements a fully functional hair follicle model by reproducing the main characteristics of hair follicle morphogenesis and cycle. In this review, we summarize the gradation of hair follicle morphogenesis and the roles and mechanisms of molecular signals involved in the hair follicle cycle. In addition, we discuss research results of various in vitro organoid products and organ-on-a-chip-based hair follicle tissue chips for the treatment of alopecia and present future research and development directions.
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Affiliation(s)
- Subin Jeong
- Interdisciplinary Program of Nano-Medical Device Engineering, Hallym University, Chuncheon, South Korea.,Integrative Materials Research Institute, Hallym University, Chuncheon, South Korea
| | - Yoojin Na
- Interdisciplinary Program of Nano-Medical Device Engineering, Hallym University, Chuncheon, South Korea.,Integrative Materials Research Institute, Hallym University, Chuncheon, South Korea
| | - Hyeon-Min Nam
- Integrative Materials Research Institute, Hallym University, Chuncheon, South Korea.,Major in Materials Science and Engineering, Hallym University, Chuncheon, South Korea
| | - Gun Yong Sung
- Interdisciplinary Program of Nano-Medical Device Engineering, Hallym University, Chuncheon, South Korea.,Integrative Materials Research Institute, Hallym University, Chuncheon, South Korea.,Major in Materials Science and Engineering, Hallym University, Chuncheon, South Korea
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28
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Sung JH. Effective and economical cell therapy for hair regeneration. Biomed Pharmacother 2023; 157:113988. [PMID: 36370520 DOI: 10.1016/j.biopha.2022.113988] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 11/01/2022] [Accepted: 11/05/2022] [Indexed: 11/11/2022] Open
Abstract
We reviewed and summarized the latest reports on the characteristics of stem cells and follicular cells that are under development for hair loss treatment. Compared with conventional medicine, cell therapy could be effective in the long term with a single treatment while having mild adverse effects. Adipose-derived stem cells (ASCs) have the advantages of easy access and large isolation amount compared with dermal papilla cells (DPCs) and dermal sheath cup cells (DSCs), and promote hair growth through the paracrine effect. ASCs have a poor potential in hair neogenesis, therefore, methods to enhance trichogenecity of ASCs should be developed. DSCs can be isolated from the peribulbar dermal sheath cup, while having immune tolerance, and hair inductivity. Therefore, DSCs were first developed and finished the phase II clinical trial; however, the hair growth was not satisfactory. Considering that a single injection of DSCs is effective for at least 9 months in the clinical setting, they can be an alternative therapy for hair regeneration. Though DPCs are not yet studied in clinical trials, we should pay attention to DPCs, as hair loss is associated with gradual reduction of DPCs and DP cell numbers fluctuate over the hair cycle. DPCs could make new hair follicles with epidermal cells, and have an immunomodulatory function to enable allogeneic transplantation. In addition, we can expand large quantities of DPCs with hair inductivity using spheroid culture, hypoxia condition, and growth factor supplement. 'Off-the-shelf' DPC therapy could be effective and economical, and therefore promising for hair regeneration.
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Affiliation(s)
- Jong-Hyuk Sung
- Epi Biotech Co., Ltd., Incheon, South Korea; College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea.
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29
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Guo K, Wang L, Zhong Y, Gao S, Jing R, Ye J, Zhang K, Fu M, Hu Z, Zhao W, Xu N. Cucurbitacin promotes hair growth in mice by inhibiting the expression of fibroblast growth factor 18. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1104. [PMID: 36388783 PMCID: PMC9652544 DOI: 10.21037/atm-22-4423] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 10/08/2022] [Indexed: 08/03/2023]
Abstract
BACKGROUND The inhibition of fibroblast growth factor 18 (FGF18) promotes the transition of hair follicles (HFs) from the telogen phase to the anagen phase. Cucurbitacin has been shown to have a good effect in promoting hair cell growth. This study explored the potential effect of cucurbitacin on hair growth and its effect on FGF18 expression in mice. METHODS Male C57BL/6J mice were randomly divided into the following two groups: (I) the vehicle group; and (II) the cucurbitacin group. Matrix cream and cucurbitacin cream were applied to the depilated skin on the back of the vehicle group mice and the cucurbitacin group mice, respectively. On days 3, 6, 9, 12, 15, and 18, the hair growth in the depilated dorsal skin of the mice was recorded with a digital camera and a HF detector, and the HF cycle status of the mice was observed by hematoxylin and eosin (H&E) staining. In addition, the level of FGF18 messenger ribonucleic acid (mRNA) in the dorsal skin was measured on days 15 and 18 by quantitative real-time polymerase chain reaction (qRT-PCR), while the level of FGF18 protein was measured by western blot and immunofluorescence staining. RESULTS The dorsal skin to which the cucurbitacin cream was applied began to darken on day 6 and grew hairs on day 9, which was 3 days earlier than the dorsal skin to which the matrix cream was applied. The H&E staining revealed a transition from the telogen phase to the anagen phase 3 days earlier for the cucurbitacin cream-treated skin than the matrix cream-treated skin. In addition, the skin treated with cucurbitacin cream also showed a significant decrease in FGF18 mRNA as seen by qRT-PCR, and reduced FGF18 protein levels as detected by western blot and immunofluorescence staining compared to the skin treated with matrix cream only. CONCLUSIONS Cucurbitacin significantly reduced the levels of FGF18 mRNA and protein in the dorsal skin of mice to accelerate the HFs to enter the anagen phase earlier, thereby promoting the regeneration of hair. Thus, cucurbitacin can be considered a new and valuable agent for the development of anti-hair loss products.
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Affiliation(s)
- Keke Guo
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, China
| | - Lusheng Wang
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, China
| | - Yulan Zhong
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, China
| | - Shuang Gao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Rongrong Jing
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, China
| | - Jiabin Ye
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, China
| | - Kaini Zhang
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, China
| | - Mengli Fu
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, China
| | - Zhenlin Hu
- School of Medicine, Shanghai University, Shanghai, China
| | - Wengang Zhao
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Nuo Xu
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, China
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30
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Ghuwalewala S, Lee SA, Jiang K, Baidya J, Chovatiya G, Kaur P, Shalloway D, Tumbar T. Binary organization of epidermal basal domains highlights robustness to environmental exposure. EMBO J 2022; 41:e110488. [PMID: 35949182 PMCID: PMC9475544 DOI: 10.15252/embj.2021110488] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 11/09/2022] Open
Abstract
Adulte interfollicular epidermis (IFE) renewal is likely orchestrated by physiological demands of its complex tissue architecture comprising spatial and cellular heterogeneity. Mouse tail and back skin display two kinds of basal IFE spatial domains that regenerate at different rates. Here, we elucidate the molecular and cellular states of basal IFE domains by marker expression and single-cell transcriptomics in mouse and human skin. We uncover two paths of basal cell differentiation that in part reflect the IFE spatial domain organization. We unravel previously unrecognized similarities between mouse tail IFE basal domains defined as scales and interscales versus human rete ridges and inter-ridges, respectively. Furthermore, our basal IFE transcriptomics and gene targeting in mice provide evidence supporting a physiological role of IFE domains in adaptation to differential UV exposure. We identify Sox6 as a novel UV-induced and interscale/inter-ridge preferred basal IFE-domain transcription factor, important for IFE proliferation and survival. The spatial, cellular, and molecular organization of IFE basal domains underscores skin adaptation to environmental exposure and its unusual robustness in adult homeostasis.
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Affiliation(s)
| | - Seon A Lee
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
| | - Kevin Jiang
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
| | - Joydeep Baidya
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
| | - Gopal Chovatiya
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
| | - Pritinder Kaur
- Curtin Medical School/Curtin Health Innovation Research InstituteCurtin UniversityPerthWAAustralia
| | - David Shalloway
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
| | - Tudorita Tumbar
- Department of Molecular Biology and GeneticsCornell UniversityIthacaNYUSA
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31
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Sunkara RR, Mehta D, Sarate RM, Waghmare SK. BMP-AKT-GSK3β signalling restores hair follicle stem cells decrease associated with loss of Sfrp1. Stem Cells 2022; 40:802-817. [PMID: 35689817 DOI: 10.1093/stmcls/sxac041] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 04/05/2022] [Indexed: 11/15/2022]
Abstract
Wnt signaling plays a pivotal role in regulating activation, proliferation, stem cell renewal and differentiation of hair follicle stem cells (HFSCs). Secreted frizzled related protein-1 (Sfrp1), a Wnt antagonist is up regulated in the HFSCs; however, its role in the HFSCs regulation is still obscure. Here, we show that Sfrp1 loss showed a depletion of HFSCs, enhanced HFSC proliferation and faster hair follicle cycle at PD21 to PD28, HFSC markers such as Lgr5 and Axin2 were decreased in both the Sfrp1 +/- and Sfrp1 -/- HFSCs. In addition, the second hair follicle cycle was also faster as compared to WT. Importantly, Sfrp1 -/- showed a restoration of HFSC by 2 nd telogen (PD49), while Sfrp1+/- did not show restoration with still having a decreased HFSC. Infact, restoration of HFSCs was due to a pronounced down-regulation of β-CATENIN activity mediated through a cross-talk of BMP-AKT-GSK3β signalling in Sfrp1-/- as compared to Sfrp1+/-, where down regulation was less pronounced. In cultured keratinocytes, Sfrp1 loss resulted in enhanced proliferation and clonogenicity, which were reversed by treating with either BMPR1A or GSK3β inhibitor thereby confirming BMP-AKT-GSK3β signaling involved in β-CATENIN regulation in both the Sfrp1 +/- and Sfrp1 -/- mice. Our study reveals a novel function of Sfrp1 by unravelling an in vivo molecular mechanism that regulate the HFSCs pool mediated through a hitherto unknown cross-talk of BMP-AKT-GSK3β signalling that maintain stem cell pool balance, which in turn maintain skin tissue homeostasis.
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Affiliation(s)
- Raghava R Sunkara
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Darshan Mehta
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Rahul M Sarate
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Sanjeev K Waghmare
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
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32
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Lorenzo-Martín LF, Menacho-Márquez M, Fernández-Parejo N, Rodríguez-Fdez S, Pascual G, Abad A, Crespo P, Dosil M, Benitah SA, Bustelo XR. The Rho guanosine nucleotide exchange factors Vav2 and Vav3 modulate epidermal stem cell function. Oncogene 2022; 41:3341-3354. [PMID: 35534539 PMCID: PMC9187518 DOI: 10.1038/s41388-022-02341-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 12/21/2022]
Abstract
It is known that Rho GTPases control different aspects of the biology of skin stem cells (SSCs). However, little information is available on the role of their upstream regulators under normal and tumorigenic conditions in this process. To address this issue, we have used here mouse models in which the activity of guanosine nucleotide exchange factors of the Vav subfamily has been manipulated using both gain- and loss-of-function strategies. These experiments indicate that Vav2 and Vav3 regulate the number, functional status, and responsiveness of hair follicle bulge stem cells. This is linked to gene expression programs related to the reinforcement of the identity and the quiescent state of normal SSCs. By contrast, in the case of cancer stem cells, they promote transcriptomal programs associated with the identity, activation state, and cytoskeletal remodeling. These results underscore the role of these Rho exchange factors in the regulation of normal and tumor epidermal stem cells.
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Affiliation(s)
- L Francisco Lorenzo-Martín
- Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007, Salamanca, Spain.,Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 37007, Salamanca, Spain
| | - Mauricio Menacho-Márquez
- Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007, Salamanca, Spain.,Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 37007, Salamanca, Spain
| | - Natalia Fernández-Parejo
- Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007, Salamanca, Spain.,Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain
| | - Sonia Rodríguez-Fdez
- Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007, Salamanca, Spain.,Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain
| | | | - Antonio Abad
- Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007, Salamanca, Spain.,Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 37007, Salamanca, Spain
| | - Piero Crespo
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 37007, Salamanca, Spain.,Instituto de Biomedicina y Biotecnología de Cantabria, CSIC-University of Cantabria, 39011, Santander, Spain
| | - Mercedes Dosil
- Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007, Salamanca, Spain.,Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 37007, Salamanca, Spain
| | | | - Xosé R Bustelo
- Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007, Salamanca, Spain. .,Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain. .,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 37007, Salamanca, Spain.
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Liu Y, Yang S, Zeng Y, Tang Z, Zong X, Li X, Yang C, Liu L, Tong X, Zhou L, Wang D. Dysregulated behaviour of hair follicle stem cells triggers alopecia and provides potential therapeutic targets. Exp Dermatol 2022; 31:986-992. [PMID: 35524394 DOI: 10.1111/exd.14600] [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: 02/19/2022] [Revised: 04/10/2022] [Accepted: 05/03/2022] [Indexed: 11/26/2022]
Abstract
Due to a steady increase in the number of individuals suffering from alopecia, this condition has recently received increasing attention. Alopecia can be caused by various pathological, environmental or psychological factors, eventually resulting in abnormalities in hair follicle (HF) structures or HF regeneration disorders, especially dysregulated hair follicle stem cell (HFSC) behaviour. HFSC behaviour includes activation, proliferation and differentiation. Appropriate HFSC behaviour sustains a persistent hair cycle (HC). HFSC behaviour is mainly influenced by HFSC metabolism, ageing, and the microenvironment. In this review, we summarize recent findings on how HFSC metabolism, ageing and the microenvironment give rise to hair growth disorders, as well as related genes and signalling pathways. Recent research on the application of stem cell-based hair tissue engineering and regenerative medicine to treat alopecia is also summarized. Determining how dysregulated HFSC behaviour underlies alopecia would be helpful in identifying potential therapeutic targets.
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Affiliation(s)
- Yuanhong Liu
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Shengbo Yang
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yilan Zeng
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ziting Tang
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiule Zong
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xuemei Li
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Caifeng Yang
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Lulu Liu
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoliang Tong
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Lu Zhou
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Dan Wang
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
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Elsebay SAG, Nada HF, Sultan NSS, El-Waseef DAEDA. Comparative histological and immunohistochemical study on the effect of platelet rich plasma/minoxidil, alone or in combination, on hair growth in a rat model of androgenic alopecia. Tissue Cell 2022; 75:101726. [DOI: 10.1016/j.tice.2021.101726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/29/2021] [Accepted: 12/31/2021] [Indexed: 10/19/2022]
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Liu Q, Lv C, Jiang Y, Luo K, Gao Y, Liu J, Zhang X, Mohammad Omar J, Jin S. From hair to liver: emerging application of hair follicle mesenchymal stem cell transplantation reverses liver cirrhosis by blocking the TGF-β/Smad signaling pathway to inhibit pathological HSC activation. PeerJ 2022; 10:e12872. [PMID: 35186473 PMCID: PMC8855721 DOI: 10.7717/peerj.12872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/11/2022] [Indexed: 01/10/2023] Open
Abstract
Liver cirrhosis (LC) involves multiple systems throughout the body, and patients with LC often die of multiple organ failure. However, few drugs are useful to treat LC. Hair follicle mesenchymal stem cells (HF-MSCs) are derived from the dermal papilla and the bulge area of hair follicles and are pluripotent stem cells in the mesoderm with broad prospects in regenerative medicine. As an emerging seed cell type widely used in skin wound healing and plastic surgery, HF-MSCs show considerable prospects in the treatment of LC due to their proliferation and multidirectional differentiation capabilities. We established an LC model in C57BL/6J mice by administering carbon tetrachloride (CCl4) and injected HF-MSCs through the tail vein to explore the therapeutic effects and potential mechanisms of HF-MSCs on LC. Here, we found that HF-MSCs improved liver function and ameliorated the liver pathology of LC. Notably, PKH67-labeled HF-MSCs were detected in the injured liver and expressed the hepatocyte-specific markers cytokeratin 18 (CK18) and albumin (ALB). In addition, in contrast to that in the LC group, the α-SMA expression showed a decreasing trend in the treatment group in vitro and in vivo, indicating that the pathological activation of hepatic stellate cells (HSCs) was inhibited by HF-MSC treatment. Moreover, the levels of transforming growth factor β (TGF-β1) and p-Smad3, a signaling molecule downstream of TGF-β1, were increased in mice with LC, while HF-MSC treatment reversed these changes in vivo and in vitro. Based on these findings, HF-MSCs may reverse LC by blocking the TGF-β/Smad pathway and inhibiting the pathological activation of HSCs, which may provide evidence for the application of HF-MSCs to treat LC.
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Affiliation(s)
- Qi Liu
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chengqian Lv
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanan Jiang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy of Harbin Medical University, Harbin, China,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Kunpeng Luo
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yang Gao
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jingyang Liu
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xu Zhang
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jan Mohammad Omar
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shizhu Jin
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Mestrallet G, Carosella ED, Martin MT, Rouas-Freiss N, Fortunel NO, LeMaoult J. Immunosuppressive Properties of Epidermal Keratinocytes Differ According to Their Immaturity Status. Front Immunol 2022; 13:786859. [PMID: 35222373 PMCID: PMC8878806 DOI: 10.3389/fimmu.2022.786859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 01/14/2022] [Indexed: 12/04/2022] Open
Abstract
Preservation of a functional keratinocyte stem cell pool is essential to ensure the long-term maintenance of epidermis integrity, through continuous physiological renewal and regeneration in case of injury. Protecting stem cells from inflammation and immune reactions is thus a critical issue that needs to be explored. Here, we show that the immature CD49fhigh precursor cell fraction from interfollicular epidermis keratinocytes, comprising stem cells and progenitors, is able to inhibit CD4+ T-cell proliferation. Of note, both the stem cell-enriched CD49fhigh/EGFRlow subpopulation and the less immature CD49fhigh/EGFRhigh progenitors ensure this effect. Moreover, we show that HLA-G and PD-L1 immune checkpoints are overexpressed in CD49fhigh precursors, as compared to CD49flow differentiated keratinocytes. This potency may limit immune reactions against immature precursors including stem cells, and protect them from exacerbated inflammation. Further exploring this correlation between immuno-modulation and immaturity may open perspectives in allogenic cell therapies.
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Affiliation(s)
- Guillaume Mestrallet
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Evry, France
- Université Paris-Saclay, Saint-Aubin, France
| | - Edgardo D. Carosella
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, Paris, France
- U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Michele T. Martin
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Evry, France
- Université Paris-Saclay, Saint-Aubin, France
| | - Nathalie Rouas-Freiss
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, Paris, France
- U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Nicolas O. Fortunel
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Evry, France
- Université Paris-Saclay, Saint-Aubin, France
- *Correspondence: Joel LeMaoult, ; Nicolas O. Fortunel,
| | - Joel LeMaoult
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, Paris, France
- U976 HIPI Unit, IRSL, Université Paris, Paris, France
- *Correspondence: Joel LeMaoult, ; Nicolas O. Fortunel,
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Verhaegen ME, Harms PW, Van Goor JJ, Arche J, Patrick MT, Wilbert D, Zabawa H, Grachtchouk M, Liu CJ, Hu K, Kelly MC, Chen P, Saunders TL, Weidinger S, Syu LJ, Runge JS, Gudjonsson JE, Wong SY, Brownell I, Cieslik M, Udager AM, Chinnaiyan AM, Tsoi LC, Dlugosz AA. Direct cellular reprogramming enables development of viral T antigen-driven Merkel cell carcinoma in mice. J Clin Invest 2022; 132:152069. [PMID: 35143422 PMCID: PMC8970662 DOI: 10.1172/jci152069] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 02/08/2022] [Indexed: 11/17/2022] Open
Abstract
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer that frequently carries an integrated Merkel cell polyomavirus (MCPyV) genome and expresses viral transforming antigens (TAgs). MCC tumor cells also express signature genes detected in skin-resident, postmitotic Merkel cells, including atonal bHLH transcription factor 1 (ATOH1), which is required for Merkel cell development from epidermal progenitors. We now report the use of in vivo cellular reprogramming, using ATOH1, to drive MCC development from murine epidermis. We generated mice that conditionally expressed MCPyV TAgs and ATOH1 in epidermal cells, yielding microscopic collections of proliferating MCC-like cells arising from hair follicles. Immunostaining of these nascent tumors revealed p53 accumulation and apoptosis, and targeted deletion of transformation related protein 53 (Trp53) led to development of gross skin tumors with classic MCC histology and marker expression. Global transcriptome analysis confirmed the close similarity of mouse and human MCCs, and hierarchical clustering showed conserved upregulation of signature genes. Our data establish that expression of MCPyV TAgs in ATOH1-reprogrammed epidermal cells and their neuroendocrine progeny initiates hair follicle–derived MCC tumorigenesis in adult mice. Moreover, progression to full-blown MCC in this model requires loss of p53, mimicking the functional inhibition of p53 reported in human MCPyV-positive MCCs.
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Affiliation(s)
- Monique E Verhaegen
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - Paul W Harms
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - Julia J Van Goor
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - Jacob Arche
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - Matthew T Patrick
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - Dawn Wilbert
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - Haley Zabawa
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - Marina Grachtchouk
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - Chia-Jen Liu
- Department of Pathology, University of Michigan, Ann Arbor, United States of America
| | - Kevin Hu
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, United States of America
| | - Michael C Kelly
- Department of Cell Biology, Emory University School of Medicine, Atlanta, United States of America
| | - Ping Chen
- Department of Cell Biology, Emory University School of Medicine, Atlanta, United States of America
| | - Thomas L Saunders
- Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America
| | - Stephan Weidinger
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Li-Jyun Syu
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - John S Runge
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - Johann E Gudjonsson
- Department of Dermatology, University of Michigan, Ann Arbor, United States of America
| | - Sunny Y Wong
- Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, United States of America
| | - Isaac Brownell
- Dermatology Branch, National Cancer Institute, Bethesda, United States of America
| | - Marcin Cieslik
- Department of Pathology, University of Michigan, Ann Arbor, United States of America
| | - Aaron M Udager
- Department of Pathology, University of Michigan, Ann Arbor, United States of America
| | - Arul M Chinnaiyan
- Department of Pathology, University of Michigan, Ann Arbor, United States of America
| | - Lam C Tsoi
- Department of Biostatistics, University of Michigan, Ann Arbor, United States of America
| | - Andrzej A Dlugosz
- Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, United States of America
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ECM1 modified HF-MSCs targeting HSC attenuate liver cirrhosis by inhibiting the TGF-β/Smad signaling pathway. Cell Death Dis 2022; 8:51. [PMID: 35136027 PMCID: PMC8827057 DOI: 10.1038/s41420-022-00846-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/05/2022] [Accepted: 01/20/2022] [Indexed: 12/13/2022]
Abstract
Hair follicle-derived mesenchymal stem cells (HF-MSCs) show considerable therapeutic potential for liver cirrhosis (LC). To improve the effectiveness of naïve HF-MSC treatments on LC, we used bioinformatic tools to identify an exogenous gene targeting HSCs among the differentially expressed genes (DEGs) in LC to modify HF-MSCs. Extracellular matrix protein 1 (ECM1) was identified as a DEG that was significantly downregulated in the cirrhotic liver. Then, ECM1-overexpressing HF-MSCs (ECM1-HF-MSCs) were transplanted into mice with LC to explore the effectiveness and correlated mechanism of gene-overexpressing HF-MSCs on LC. The results showed that ECM1-HF-MSCs significantly improved liver function and liver pathological injury in LC after cell therapy relative to the other treatment groups. Moreover, we found that ECM1-HF-MSCs homed to the injured liver and expressed the hepatocyte-specific surface markers ALB, CK18, and AFP. In addition, hepatic stellate cell (HSC) activation was significantly inhibited in the cell treatment groups in vivo and in vitro, especially in the ECM1-HF-MSC group. Additionally, TGF-β/Smad signal inhibition was the most significant in the ECM1-HF-MSC group in vivo and in vitro. The findings indicate that the genetic modification of HF-MSCs with bioinformatic tools may provide a broad perspective for precision treatment of LC.
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39
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Singh S, Muthuvel K. Role of Hair Transplantation in Scarring Alopecia-To Do or Not to Do. Indian J Plast Surg 2022; 54:501-506. [PMID: 34984092 PMCID: PMC8719951 DOI: 10.1055/s-0041-1739246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Alopecia in the scalp region leads to psychosocial embarrassment for an individual. Alopecia could be due to several reasons, including genetic, hormonal, traumatic and infections. Cicatricial alopecias (CAs) are considered as trichological emergency, since their progression is rapid and always results in permanent hair loss. The pathogenesis, disease progression and prognosis of CA are poorly understood, and the treatment process is still evolving. An early diagnosis must be established, and aggressive treatment protocol should be followed in the management of scarring alopecia. This article presents various aspects of CA and determines whether hair transplant (HT) should be done in this condition.
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Affiliation(s)
- Sukhbir Singh
- Department of Plastic Surgery, Resplendent the Cosmetic Studio, New Delhi, India
| | - Kumaresan Muthuvel
- Department of Dermatology, Cutis Skin Clinic and Hair Transplant Centre, Coimbatore, Tamil Nadu, India
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40
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Abreu CM, Marques AP. Recreation of a hair follicle regenerative microenvironment: Successes and pitfalls. Bioeng Transl Med 2022; 7:e10235. [PMID: 35079623 PMCID: PMC8780054 DOI: 10.1002/btm2.10235] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 05/15/2021] [Accepted: 05/18/2021] [Indexed: 12/19/2022] Open
Abstract
The hair follicle (HF) is an exquisite skin appendage endowed with cyclical regenerative capacity; however, de novo follicle formation does not naturally occur. Consequently, patients suffering from extensive skin damage or hair loss are deprived of the HF critical physiological and/or aesthetic functions, severally compromising skin function and the individual's psychosocial well-being. Translation of regenerative strategies has been prevented by the loss of trichogenic capacity that relevant cell populations undergo in culture and by the lack of suitable human-based in vitro testing platforms. Here, we provide a comprehensive overview of the major difficulties associated with HF regeneration and the approaches used to overcome these drawbacks. We describe key cellular requirements and discuss the importance of the HF extracellular matrix and associated signaling for HF regeneration. Finally, we summarize the strategies proposed so far to bioengineer human HF or hair-bearing skin models and disclose future trends for the field.
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Affiliation(s)
- Carla M. Abreu
- 3B's Research Group, I3Bs ‐ Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineAvePark–Parque de Ciência e Tecnologia, University of MinhoGuimarãesPortugal
- ICVS/3B's–PT Government Associate LaboratoryGuimarãesPortugal
| | - Alexandra P. Marques
- 3B's Research Group, I3Bs ‐ Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineAvePark–Parque de Ciência e Tecnologia, University of MinhoGuimarãesPortugal
- ICVS/3B's–PT Government Associate LaboratoryGuimarãesPortugal
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41
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Genedy RM, Badran FK, Tayae EM, Sabra HN. Lesson to Learn From Cellular infiltrate in Scalp Biopsy of Alopecia Areata. Am J Dermatopathol 2021; 43:e158-e164. [PMID: 33606369 DOI: 10.1097/dad.0000000000001929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Alopecia areata (AA) is a common cause of hair loss. It is mediated by T lymphocytes. Scalp biopsy findings in AA differ according to the disease phase and activity. OBJECTIVES To study the cellular infiltrate in the transverse section of scalp biopsy of AA at different disease stages and in relation to disease activity. METHODS The study was performed on 40 subjects with AA. A 4-mm punch biopsy was obtained from an AA scalp lesion. Biopsies were sectioned horizontally; 2 anatomical levels were studied (mid dermal and deep dermal levels). RESULTS Ninety-five percent of AA showed noncicatrical alopecia. A significant relation was found between the course of AA and the terminal:vellus ratio. Peribulbar lymphocytic infiltration was seen in 70% of cases. Mast cells were observed in 87.5% of cases, including fibrous tract and around the arrector pili muscles. Eosinophils were detected in the scalp biopsy of 22.5% of cases. Course and activity of AA were significantly related to the peribulbar lymphocytic cell infiltration but not to mast cells and eosinophils. CONCLUSION Although a peribulbar lymphocytic infiltrate is the classical finding of AA, it is absent in the chronic phase. Mast cells are commonly found in the scalp biopsy of AA and could explain the potential therapeutic effect of antihistamines.
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Affiliation(s)
- Rasha Mahmoud Genedy
- Department of Dermatology and Venereology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Fairouz Khalil Badran
- Department of Dermatology and Venereology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Eman Mohamed Tayae
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University Egypt, Alexandria, Egypt; and
| | - Heba Nasrallah Sabra
- Department of Dermatology and Venereology, Ministry of Health Hospitals, Alexandria, Egypt
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42
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Li S. Theoretical derivation and clinical dose-response quantification of a unified multi-activation (UMA) model of cell survival from a logistic equation. BJR Open 2021; 3:20210040. [PMID: 34877459 PMCID: PMC8611684 DOI: 10.1259/bjro.20210040] [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: 06/18/2021] [Revised: 08/19/2021] [Accepted: 08/24/2021] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE To theoretically derive a unified multiactivation (UMA) model of cell survival after ionising radiation that can accurately assess doses and responses in radiotherapy and X-ray imaging. METHODS A unified formula with only two parameters in fitting of a cell survival curve (CSC) is first derived from an assumption that radiation-activated cell death pathways compose the first- and second-order reaction kinetics. A logit linear regression of CSC data is used for precise determination of the two model parameters. Intrinsic radiosensitivity, biologically effective dose (BED), equivalent dose to the traditional 2 Gy fractions (EQD2), tumour control probability, normal-tissue complication probability, BED50 and steepness (Γ50) at 50% of tumour control probability (or normal-tissue complication probability) are analytical functions of the model and treatment (or imaging) parameters. RESULTS The UMA model has almost perfectly fit typical CSCs over the entire dose range with R2≥0.99. Estimated quantities for stereotactic body radiotherapy of early stage lung cancer and the skin reactions from X-ray imaging agree with clinical results. CONCLUSION The proposed UMA model has theoretically resolved the catastrophes of the zero slope at zero dose for multiple target model and the bending curve at high dose for the linear quadratic model. More importantly, it analytically predicts dose-responses to various dose-fraction schemes in radiotherapy and to low dose X-ray imaging based on these preclinical CSCs. ADVANCES IN KNOWLEDGE The discovery of a unified formula of CSC over the entire dose range may reveal a common mechanism of the first- and second-order reaction kinetics among multiple CD pathways activated by ionising radiation at various dose levels.
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Affiliation(s)
- Shidong Li
- Department of Radiation Oncology, Temple University Hospital, Philadelphia, PA, USA
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43
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Hair Growth Stimulation Effect of Centipeda minima Extract: Identification of Active Compounds and Anagen-Activating Signaling Pathways. Biomolecules 2021; 11:biom11070976. [PMID: 34356600 PMCID: PMC8301965 DOI: 10.3390/biom11070976] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/24/2021] [Accepted: 06/29/2021] [Indexed: 01/02/2023] Open
Abstract
Centipeda minima (L.) A. Braun & Asch is a well-studied plant in Chinese medicine that is used for the treatment of several diseases. A recent study has revealed the effects of extract of Cetipeda minima (CMX) standardized by brevilin A in inducing hair growth. However, the mechanism of action of CMX in human hair follicle dermal papilla cells (HFDPCs) has not yet been identified. We aimed to investigate the molecular basis underlying the effect of CMX on hair growth in HFDPCs. CMX induced the proliferation of HFDPCs, and the transcript-level expression of Wnt family member 5a (Wnt5a), frizzled receptor (FZDR), and vascular endothelial growth factor (VEGF) was upregulated. These results correlated with an increase in the expression of growth-related factors, such as VEGF and IGF-1. Immunoblotting and immunocytochemistry further revealed that the phosphorylation of ERK and JNK was enhanced by CMX in HFDPCs, and β-catenin accumulated significantly in a dose-dependent manner. Therefore, CMX substantially induced the expression of Wnt signaling-related proteins, such as GSK phosphorylation and β-catenin. This study supports the hypothesis that CMX promotes hair growth and secretion of growth factors via the Wnt/β-catenin, ERK, and JNK signaling pathways. In addition, computational predictions of drug-likeness, together with ADME property predictions, revealed the satisfactory bioavailability score of CMX compounds, exhibiting high gastrointestinal absorption. We suggest that CMX could be used as a promising treatment for hair regeneration and minimization of hair loss.
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Ankawa R, Goldberger N, Yosefzon Y, Koren E, Yusupova M, Rosner D, Feldman A, Baror-Sebban S, Buganim Y, Simon DJ, Tessier-Lavigne M, Fuchs Y. Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration. Dev Cell 2021; 56:1900-1916.e5. [PMID: 34197726 DOI: 10.1016/j.devcel.2021.06.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 12/14/2020] [Accepted: 06/09/2021] [Indexed: 12/17/2022]
Abstract
Stem cells (SCs) play a key role in homeostasis and repair. While many studies have focused on SC self-renewal and differentiation, little is known regarding the molecular mechanism regulating SC elimination and compensation upon loss. Here, we report that Caspase-9 deletion in hair follicle SCs (HFSCs) attenuates the apoptotic cascade, resulting in significant temporal delays. Surprisingly, Casp9-deficient HFSCs accumulate high levels of cleaved caspase-3 and are improperly cleared due to an essential caspase-3/caspase-9 feedforward loop. These SCs are retained in an apoptotic-engaged state, serving as mitogenic signaling centers by continuously releasing Wnt3 and instructing proliferation. Investigating the underlying mechanism, we reveal a caspase-3/Dusp8/p38 module responsible for Wnt3 induction, which operates in both normal and Casp9-deleted HFSCs. Notably, Casp9-deleted mice display accelerated wound repair and de novo hair follicle regeneration. Taken together, we demonstrate that apoptotic cells represent a dynamic SC niche, from which emanating signals drive SC proliferation and tissue regeneration.
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Affiliation(s)
- Roi Ankawa
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Nitzan Goldberger
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Yahav Yosefzon
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Elle Koren
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Marianna Yusupova
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Daniel Rosner
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Alona Feldman
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Shulamit Baror-Sebban
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, the Hebrew University of Jerusalem, Hadassah Medical School, Jerusalem, Israel
| | - Yosef Buganim
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, the Hebrew University of Jerusalem, Hadassah Medical School, Jerusalem, Israel
| | - David J Simon
- Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA
| | | | - Yaron Fuchs
- Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel.
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45
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Li S, Chen J, Chen F, Wang C, Guo X, Wang C, Fan Y, Wang Y, Peng Y, Li W. Liposomal honokiol promotes hair growth via activating Wnt3a/β-catenin signaling pathway and down regulating TGF-β1 in C57BL/6N mice. Biomed Pharmacother 2021; 141:111793. [PMID: 34098216 DOI: 10.1016/j.biopha.2021.111793] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/22/2021] [Accepted: 05/29/2021] [Indexed: 12/15/2022] Open
Abstract
Liposomal honokiol isolated from the genus Magnolia has been found to have antiangiogenic, anti-inflammatory and antitumor properties. However, there has no report on its role in hair growth. Hair follicles are life-long cycled organelles that go through from anagen, catagen and telogen stages and are regulated by diverse signaling pathways, including Wnt/β-catenin, Notch, Epidermal growth factor (EGF) and Sonic hegehog (SHH). Wnt signals are essential for the initiation of hair follicle placode development and a new potential target of hair loss treatment. This study was designed to investigate the effect of liposomal honokiol (Lip-honokiol) on inducing hair anagen. We identified the hair grew out in advance in the shaving area of C57BL/6N mice after the treatment of liposomal honokiol (Lip-honokiol) by daily abdominal injection. We first demonstrated that Lip-Honokiol activated the Wnt3a/β-catenin pathway and downregulated the transforming growth factor-β1 (TGF-β1) to promote hair growth in mice via immunohistochemistry and immunofluorescence staining. These findings suggest that Lip-honokiol activated the Wnt/β-catenin pathway and accelerated the transfer from the telogen to anagen stage and finally promoted the hair growth.
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Affiliation(s)
- Shenglan Li
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
| | - Jinyi Chen
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
| | - Feng Chen
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
| | - Ce Wang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
| | - Xiaodi Guo
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
| | - Can Wang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
| | - Yaqiong Fan
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
| | - Yali Wang
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
| | - Yichen Peng
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
| | - Wenbin Li
- Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
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Flores A, Choi S, Hsu YC, Lowry WE. Inhibition of pyruvate oxidation as a versatile stimulator of the hair cycle in models of alopecia. Exp Dermatol 2021; 30:448-456. [PMID: 33739490 DOI: 10.1111/exd.14307] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 02/05/2021] [Accepted: 02/15/2021] [Indexed: 12/25/2022]
Abstract
Hair follicle stem cells (HFSCs) are known to be responsible for the initiation of a new hair cycle, but typically remain quiescent for very long periods. In alopecia, or hair loss disorders, follicles can be refractory to activation for years or even permanently. Alopecia can be triggered by autoimmunity, age, chemotherapeutic treatment, stress, disrupted circadian rhythm or other environmental insults. We previously showed that hair follicle stem cells and the hair cycle can be manipulated by regulation of pyruvate entry into mitochondria for subsequent oxidation to fuel the TCA cycle in normal adult mice with typical hair cycling. Here, we present new data from our efforts to develop murine models of alopecia based on environmental triggers that have been shown to do the same in human skin. We found that inhibition of pyruvate transport into mitochondria can accelerate the hair cycle even during refractory hair cycling due to age, repeated chemotherapeutic treatment and stress. Hair cycle acceleration in these alopecia models led to the formation of histologically normal hair follicles within 30-40 days of treatment without any overt signs of toxicity or deleterious effects. Therefore, we propose inhibition of pyruvate entry into mitochondria as a versatile treatment strategy for alopecia in humans.
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Affiliation(s)
- Aimee Flores
- Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA, USA.,Pelage Pharmaceuticals, Inc., Los Angeles, CA, USA
| | - Sekyu Choi
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Ya-Chieh Hsu
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - William E Lowry
- Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA, USA.,Pelage Pharmaceuticals, Inc., Los Angeles, CA, USA.,Division of Dermatology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.,Molecular Biology Institute, UCLA, Los Angeles, CA, USA.,Broad Center for Regenerative Medicine, UCLA, Los Angeles, CA, USA
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Nakajima R, Tate Y, Yan L, Kageyama T, Fukuda J. Impact of adipose-derived stem cells on engineering hair follicle germ-like tissue grafts for hair regenerative medicine. J Biosci Bioeng 2021; 131:679-685. [PMID: 33678531 DOI: 10.1016/j.jbiosc.2021.02.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/01/2021] [Accepted: 02/04/2021] [Indexed: 12/11/2022]
Abstract
Hair regenerative medicine has emerged as a promising treatment strategy for severe hair loss, such as end-stage androgenetic alopecia. Various approaches to engineering three-dimensional tissue grafts have been explored since they drive the ability to regenerate hair follicles when transplanted. In the present study, we demonstrated the assembly of human adipose-derived stem cells (hASCs) into hair follicle germ (HFG)-like aggregates for de novo hair regeneration. We mixed human dermal papilla cells (hDPCs), murine embryonic epithelial cells, and hASCs in suspension, and allowed them to form aggregates. During three days of culture, cells initially formed a single aggregate with a random distribution of the three cell types, but the epithelial and dermal papilla cells subsequently separated from each other and formed a dumbbell-shaped HFG, with hASCs localized on the hDPC aggregate side. The involvement of hASCs significantly increased gene expression associated with hair morphogenesis compared to HFGs without hASCs. The self-organization of the three cell types was observed in our scalable lab-made chip device. HFGs containing hASCs efficiently generated hair shafts upon transplantation to nude mice, while only a few shafts were generated with HFGs without hASCs. This approach may be a promising strategy for fabricating tissue grafts for hair regenerative medicine.
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Affiliation(s)
- Rikuma Nakajima
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan
| | - Yoshiki Tate
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan
| | - Lei Yan
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan
| | - Tatsuto Kageyama
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan; Kanagawa Institute of Industrial Science and Technology, 3-2-1 Sakado Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan; Japan Science and Technology Agency (JST)-PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
| | - Junji Fukuda
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan; Kanagawa Institute of Industrial Science and Technology, 3-2-1 Sakado Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan.
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48
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Sugawara K, Zákány N, Tiede S, Purba T, Harries M, Tsuruta D, Bíró T, Paus R. Human epithelial stem cell survival within their niche requires "tonic" cannabinoid receptor 1-signalling-Lessons from the hair follicle. Exp Dermatol 2021; 30:479-493. [PMID: 33523535 DOI: 10.1111/exd.14294] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/17/2020] [Accepted: 01/06/2021] [Indexed: 12/23/2022]
Abstract
The endocannabinoid system (ECS) regulates multiple aspects of human epithelial physiology, including inhibition/stimulation of keratinocyte proliferation/apoptosis, respectively. Yet, how the ECS impacts on human adult epithelial stem cell (eSC) functions remains unknown. Scalp hair follicles (HFs) offer a clinically relevant, prototypic model system for studying this directly within the native human stem cell niche. Here, we show in organ-cultured human HFs that, unexpectedly, selective activation of cannabinoid receptor-1 (CB1)-mediated signalling via the MAPK (MEK/Erk 1/2) and Akt pathways significantly increases the number and proliferation of cytokeratin CK15+ or CK19+ human HF bulge eSCs in situ, and enhances CK15 promoter activity in situ. In striking contrast, CB1-stimulation promotes apoptosis in the differentiated progeny of these eSCs (CK6+ HF keratinocytes). Instead, intrafollicular CB1 gene knockdown or CB1 antagonist treatment significantly reduces human HF eSCs numbers and stimulates their apoptosis, while CB1 knockout mice exhibit a reduced bulge eSCs pool in vivo. This identifies "tonic" CB1 signalling as a required survival stimulus for adult human HF eSCs within their niche. This novel concept must be taken into account whenever the human ECS is targeted therapeutically.
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Affiliation(s)
- Koji Sugawara
- Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | | | - Stephan Tiede
- Department of Biochemistry, Children's Hospital, University of Hamburg, Hamburg, Germany
| | - Talveen Purba
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC, NIHR Biomedical Research Centre, Manchester, UK
| | - Matthew Harries
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC, NIHR Biomedical Research Centre, Manchester, UK.,The Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester, UK
| | - Daisuke Tsuruta
- Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tamás Bíró
- Monasterium Laboratory, Münster, Germany
| | - Ralf Paus
- Monasterium Laboratory, Münster, Germany.,Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC, NIHR Biomedical Research Centre, Manchester, UK.,Dr Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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49
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Hegde A, Ananthan ASHP, Kashyap C, Ghosh S. Wound Healing by Keratinocytes: A Cytoskeletal Perspective. J Indian Inst Sci 2021. [DOI: 10.1007/s41745-020-00219-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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50
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Ceruti JM, Oppenheimer FM, Leirós GJ, Balañá ME. Androgens downregulate BMP2 impairing the inductive role of dermal papilla cells on hair follicle stem cells differentiation. Mol Cell Endocrinol 2021; 520:111096. [PMID: 33259912 DOI: 10.1016/j.mce.2020.111096] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 11/24/2020] [Accepted: 11/24/2020] [Indexed: 12/17/2022]
Abstract
Hair follicle cyclical regeneration is regulated by epithelial-mesenchymal interactions. During androgenetic alopecia (AGA), hair follicle stem cells (HFSC) differentiation is impaired by deregulation of dermal papilla cells (DPC) secreted factors. We analyzed androgen influence on BMPs expression in DPC and their effect on HFSC differentiation to hair lineage. Androgens downregulated BMP2 and BMP4 in DPC spheroids. Addition of BMP2 restored alkaline phosphatase activity, marker of hair-inductivity in DPC, and DPC-induced HFSC differentiation, both inhibited by androgens. Concomitantly, in differentiating HFSC, an upregulation of BMPRIa and BMPRII receptors and nuclear β-catenin accumulation, indicative of Wnt/β-catenin pathway activation, were detected. Our results present BMP2 as an androgen-downregulated paracrine factor that contributes to DPC inductivity and favors DPC-induced HFSC differentiation to hair lineage, possibly through a crosstalk with Wnt/β-catenin pathway. A comprehensive understanding of androgen-deregulated DPC factors and their effects on differentiating HFSC would help to improve treatments for AGA.
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Affiliation(s)
- Julieta María Ceruti
- Instituto de Ciencia y Tecnología Dr. César Milstein - (Consejo Nacional de Investigaciones Científicas y Técnicas CONICET- Fundación Pablo Cassará), Saladillo 2468, Ciudad de Buenos Aires, C1440FFX, Argentina
| | - Florencia Maia Oppenheimer
- Instituto de Ciencia y Tecnología Dr. César Milstein - (Consejo Nacional de Investigaciones Científicas y Técnicas CONICET- Fundación Pablo Cassará), Saladillo 2468, Ciudad de Buenos Aires, C1440FFX, Argentina
| | - Gustavo José Leirós
- Instituto de Ciencia y Tecnología Dr. César Milstein - (Consejo Nacional de Investigaciones Científicas y Técnicas CONICET- Fundación Pablo Cassará), Saladillo 2468, Ciudad de Buenos Aires, C1440FFX, Argentina
| | - María Eugenia Balañá
- Instituto de Ciencia y Tecnología Dr. César Milstein - (Consejo Nacional de Investigaciones Científicas y Técnicas CONICET- Fundación Pablo Cassará), Saladillo 2468, Ciudad de Buenos Aires, C1440FFX, Argentina.
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