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Gherardini J, Rouillé T, Stone RC, Fehrholz M, Funk W, Rodríguez-Feliz J, Bauman AJ, Bíró T, Chéret J, Paus R. Human scalp hair follicles can 'taste': chemosensory signalling via the bitter taste receptor TAS2R4 inhibits hair growth ex vivo. Br J Dermatol 2025; 192:1083-1095. [PMID: 40097020 DOI: 10.1093/bjd/ljaf060] [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: 09/24/2024] [Revised: 02/14/2025] [Accepted: 02/14/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Taste receptors (TRs) exert many 'nongustatory' chemosensory functions beyond the sensation of taste. Recently, human keratinocytes have been found to express some bitter TRs, whose physiological functions remain unknown. As it has been discovered that human scalp hair follicles (HFs) use olfactory receptors to regulate their growth, we hypothesized that some bitter TRs may exert a similar function. OBJECTIVES To explore whether human scalp HFs express the bitter TR TAS2R4 and whether its stimulation with cognate agonists or its selective knockdown affects key human HF functions and, if yes, how. METHODS TAS2R4 mRNA and protein expression were assessed in situ, and organ-cultured scalp HFs were stimulated with the TAS2R4-agonistic natural sweetener rebaudioside A (Reb A) in the presence or absence of TAS2R4 small interfering RNA. Subsequently, changes in hair growth, growth factor expression and HF gene expression were assessed ex vivo. RESULTS TAS2R4 mRNA and protein were mainly expressed in the outer root sheath and matrix of human anagen VI scalp HFs. Stimulating these with Reb A ex vivo initially inhibited hair matrix keratinocyte proliferation, followed by enhanced intrafollicular production of catagen-promoting transforming growth factor (TGF)-β2. This led to TGF-β-driven premature catagen entry, which could be antagonized by TGF-β-neutralizing antibodies. Premature catagen induction was also seen with other known TAS2R4 agonists, while TAS2R4 knockdown in the -presence of Reb A promoted hair growth, documenting that the observed effects of Reb A on the HF depend on TAS2R4-mediated signalling. Gene expression profiling (RNA sequencing) revealed differential transcriptional signatures consistent with TAS2R4-mediated changes in cell cycle control and TGF-β pathway signalling. CONCLUSIONS Our study found that human scalp HFs engage in chemosensation via bitter TRs to regulate their growth, matrix keratinocyte proliferation, growth factor production and overall gene expression. Specifically, we demonstrated that a simple tastant like Reb A can promote the anagen-catagen switch of human scalp HFs and their production of TGF-β2, and modulate HF keratinocyte proliferation and intrafollicular gene transcription in a TAS2R4-dependent manner. This expands our understanding of bitter TR-mediated chemosensation in human skin and suggests a novel, drug-free strategy to inhibiting unwanted hair growth (e.g. in hirsutism and hypertrichosis) by targeting TAS2R4 (e.g. via topical Reb A).
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Affiliation(s)
- Jennifer Gherardini
- CUTANEON - Skin & Hair Innovations GmbH, Hamburg and Berlin, Germany
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Thomas Rouillé
- QIMA Life Sciences-QIMA Monasterium GmbH, Münster, Germany
| | - Rivka C Stone
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Wolfgang Funk
- Clinic for Plastic, Aesthetic and Reconstructive Surgery, Dr. Funk, Munich, Germany
| | | | | | - Tamás Bíró
- CUTANEON - Skin & Hair Innovations GmbH, Hamburg and Berlin, Germany
| | - Jérémy Chéret
- CUTANEON - Skin & Hair Innovations GmbH, Hamburg and Berlin, Germany
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ralf Paus
- CUTANEON - Skin & Hair Innovations GmbH, Hamburg and Berlin, Germany
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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Karimi N, Dinçsoy AB. The Role of Mesenchymal Stem Cell-Derived Exosomes in Skin Regeneration, Tissue Repair, and the Regulation of Hair Follicle Growth. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1479:1-17. [PMID: 39841379 DOI: 10.1007/5584_2024_839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2025]
Abstract
Skin regeneration, repair, and the promotion of hair growth are intricate and dynamic processes essential for preserving the overall health, functionality, and appearance of both skin and hair. These processes involve a coordinated interplay of cellular activities and molecular signaling pathways that ensure the maintenance and restoration of skin integrity and hair vitality. Recent advancements in regenerative medicine have underscored the significant role of mesenchymal stem cell (MSC)-derived exosomes as key mediators in these processes. Exosomes, emerging as a promising cell-free therapy in tissue engineering, hold substantial potential due to their ability to influence various biological functions. This review explores the mechanisms by which MSC-derived exosomes facilitate skin regeneration and repair, and hair growth, their therapeutic applications, and the future research directions in this emerging field.
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Affiliation(s)
- Nazli Karimi
- Department of Physiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
| | - Adnan Berk Dinçsoy
- Department of Physiology, Faculty of Medicine, Muğla Sıtkı Koçman University, Muğla, Turkey
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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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Lee DHY, Tsang JY, Li JJX, Lau SL, Tam F, Loong TC, Tse GM. Cytokeratin 15 is a novel and independent predictor of poor outcome in luminal B HER2-negative breast carcinomas. Pathology 2024; 56:834-841. [PMID: 38909003 DOI: 10.1016/j.pathol.2024.03.009] [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: 08/28/2023] [Revised: 02/28/2024] [Accepted: 03/18/2024] [Indexed: 06/24/2024]
Abstract
Cytokeratin 15 (CK15) has been described as a stem cell marker in human organs and its expression is seen in breast tissue. CK15 expression is associated with aggressive features in endometrial and oesophageal cancers, but data on the breast are lacking. This study aims to investigate the clinicopathological associations and prognostic significance of CK15 in breast carcinomas. A multi-institute cohort of breast carcinomas were retrieved. Clinicopathological and outcome data were obtained and compared with immunohistochemical expression CK15 and a panel of biomarkers. In total, 1,476 cases were included, with an expression rate of 3.5%, preferentially expressed in luminal subtypes (p=0.024), with luminal B carcinomas being the highest (4.7%), as opposed to basal-like (1%) and HER2-overexpressed carcinomas (0%). Except for nodal stage (p=0.013) and nodal metastasis (p=0.048), oestrogen (p=0.035) and progesterone receptor (p=0.001) positivity, there were no associations with other clinicopathological parameters. A trend was observed with shorter breast cancer specific survival (BCSS) in CK15-positive luminal B carcinomas (p=0.062). On further subgroup multivariate analysis of luminal B HER2-negative carcinomas, CK15 expression exhibited robust correlation with shorter BCSS (HR=9.004, p=0.001) and disease-free survival (HR=7.085, p<0.001). Restricted to luminal breast carcinomas, specifically luminal B HER2-negative, CK15 is demonstrated to be a robust independent predictor of higher risk of recurrence and shorter survival, with potential as a clinical prognostic marker and an exclusive stem cell marker for this subgroup of carcinomas.
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Affiliation(s)
- Dennis H Y Lee
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Julia Y Tsang
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Joshua J X Li
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Sin Leung Lau
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Fiona Tam
- Department of Pathology, Kwong Wah Hospital, Hong Kong
| | | | - Gary M Tse
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
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Bazid HAS, Marae AH, Farag B, Abdallah RA. The value of immunohistochemical expression of SOX9 and CD34 in alopecia areata. J Immunoassay Immunochem 2024; 45:452-466. [PMID: 39041618 DOI: 10.1080/15321819.2024.2383676] [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: 07/24/2024]
Abstract
BACKGROUND Alopecia areata (AA), an immune-mediated disorder, is marked by temporary, nonscarring hair loss. The bulge area is protected from immune attacks by immune privilege; however, recent studies demonstrated immune cells infiltrating the bulge area. OBJECTIVE This study aims to investigate the immunohistochemical expression of the sex-determining region Y-box 9 (SOX9) and cluster of differentiation 34 (CD34) in AA patients as markers of hair follicle stem cells (HFSCs) and progenitor cells, respectively. METHODS Immunohistochemical staining of SOX9 and CD34 was applied on skin samples of 20 AA patients and 20 healthy controls. RESULTS SOX9 and CD34 were significantly lower in lesional samples of cases compared to perilesional and control skin biopsies. Furthermore, SOX9 level was negatively correlated with the severity of alopecia tool score (SALT score) among the studied AA patients. Moreover, lowered SOX9 expression was present in patients with recurrent attacks. CONCLUSIONS The significant reduction of stem cell markers (SOX9 and CD34) in our studied AA cases signifies the pathological affection of HFSCs and their progeny in AA. This is thought to cause a loss of competence in generating new hair in some AA cases, which needs to be validated in further research. LIMITATIONS OF THE STUDY This study has a small sample size.
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Affiliation(s)
- Heba A S Bazid
- Dermatology and Andrology Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
| | - Alaa H Marae
- Dermatology and Andrology Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
| | - Bassant Farag
- Dermatology and Andrology Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
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Pye D, Scholey R, Ung S, Dawson M, Shahmalak A, Purba TS. Activation of the integrated stress response in human hair follicles. PLoS One 2024; 19:e0303742. [PMID: 38900734 PMCID: PMC11189182 DOI: 10.1371/journal.pone.0303742] [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: 01/19/2024] [Accepted: 04/30/2024] [Indexed: 06/22/2024] Open
Abstract
Unravelling how energy metabolism and stress responses are regulated in human scalp hair follicles could reveal novel insights into the controls of hair growth and provide new targets to manage hair loss disorders. The Mitochondrial Pyruvate Carrier (MPC) imports pyruvate, produced via glycolysis, into the mitochondria, fuelling the TCA cycle. Previous work has shown that MPC inhibition promotes lactate generation, which activates murine epithelial hair follicle stem cells (eHFSCs). However, by pharmacologically targeting the MPC in short-term human hair follicle ex vivo organ culture experiments using UK-5099, we induced metabolic stress-responsive proliferative arrest throughout the human hair follicle epithelium, including within Keratin 15+ eHFSCs. Through transcriptomics, MPC inhibition was shown to promote a gene expression signature indicative of disrupted FGF, IGF, TGFβ and WNT signalling, mitochondrial dysfunction, and activation of the integrated stress response (ISR), which can arrest cell cycle progression. The ISR, mediated by the transcription factor ATF4, is activated by stressors including amino acid deprivation and ER stress, consistent with MPC inhibition within our model. Using RNAScope, we confirmed the upregulation of both ATF4 and the highly upregulated ATF4-target gene ADM2 on human hair follicle tissue sections in situ. Moreover, treatment with the ISR inhibitor ISRIB attenuated both the upregulation of ADM2 and the proliferative block imposed via MPC inhibition. Together, this work reveals how the human hair follicle, as a complex and metabolically active human tissue system, can dynamically adapt to metabolic stress.
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Affiliation(s)
- Derek Pye
- Division Musculoskeletal and Dermatological Sciences, Centre for Dermatology Research, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biosciences, The University of Manchester, Manchester, United Kingdom
| | - Rachel Scholey
- Bioinformatics Core Facility, University of Manchester, Manchester, United Kingdom
| | - Sin Ung
- Division Musculoskeletal and Dermatological Sciences, Centre for Dermatology Research, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biosciences, The University of Manchester, Manchester, United Kingdom
| | - Madoc Dawson
- Division Musculoskeletal and Dermatological Sciences, Centre for Dermatology Research, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biosciences, The University of Manchester, Manchester, United Kingdom
| | | | - Talveen S. Purba
- Division Musculoskeletal and Dermatological Sciences, Centre for Dermatology Research, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biosciences, The University of Manchester, Manchester, United Kingdom
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7
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Iqbal S, Karim MR, Mohammad S, Mathiyalagan R, Morshed MN, Yang DC, Bae H, Rupa EJ, Yang DU. Multiomics Analysis of the PHLDA Gene Family in Different Cancers and Their Clinical Prognostic Value. Curr Issues Mol Biol 2024; 46:5488-5510. [PMID: 38921000 PMCID: PMC11201736 DOI: 10.3390/cimb46060328] [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: 04/14/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/27/2024] Open
Abstract
The PHLDA (pleckstrin homology-like domain family) gene family is popularly known as a potential biomarker for cancer identification, and members of the PHLDA family have become considered potentially viable targets for cancer treatments. The PHLDA gene family consists of PHLDA1, PHLDA2, and PHLDA3. The predictive significance of PHLDA genes in cancer remains unclear. To determine the role of pleckstrin as a prognostic biomarker in human cancers, we conducted a systematic multiomics investigation. Through various survival analyses, pleckstrin expression was evaluated, and their predictive significance in human tumors was discovered using a variety of online platforms. By analyzing the protein-protein interactions, we also chose a collection of well-known functional protein partners for pleckstrin. Investigations were also carried out on the relationship between pleckstrins and other cancers regarding mutations and copy number alterations. The cumulative impact of pleckstrin and their associated genes on various cancers, Gene Ontology (GO), and pathway analyses were used for their evaluation. Thus, the expression profiles of PHLDA family members and their prognosis in various cancers may be revealed by this study. During this multiomics analysis, we found that among the PHLDA family, PHLDA1 may be a therapeutic target for several cancers, including kidney, colon, and brain cancer, while PHLDA2 can be a therapeutic target for cancers of the colon, esophagus, and pancreas. Additionally, PHLDA3 may be a useful therapeutic target for ovarian, renal, and gastric cancer.
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Affiliation(s)
- Safia Iqbal
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea; (S.I.); (M.R.K.); (M.N.M.); (D.-C.Y.)
| | - Md. Rezaul Karim
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea; (S.I.); (M.R.K.); (M.N.M.); (D.-C.Y.)
| | - Shahnawaz Mohammad
- Graduate School of Biotechnology, College of Life Science, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea; (S.M.); (R.M.)
| | - Ramya Mathiyalagan
- Graduate School of Biotechnology, College of Life Science, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea; (S.M.); (R.M.)
| | - Md. Niaj Morshed
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea; (S.I.); (M.R.K.); (M.N.M.); (D.-C.Y.)
| | - Deok-Chun Yang
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea; (S.I.); (M.R.K.); (M.N.M.); (D.-C.Y.)
- Department of Oriental Medicinal Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea;
| | - Hyocheol Bae
- Department of Oriental Medicinal Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea;
| | - Esrat Jahan Rupa
- College of Korean Medicine, Woosuk University, Wanju-gun 55338, Jeollabuk-do, Republic of Korea
| | - Dong Uk Yang
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Republic of Korea; (S.I.); (M.R.K.); (M.N.M.); (D.-C.Y.)
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Wang X, Pan C, Zheng L, Wang J, Zou Q, Sun P, Zhou K, Zhao A, Cao Q, He W, Wang Y, Cheng R, Yao Z, Zhang S, Zhang H, Li M. ADAM17 variant causes hair loss via ubiquitin ligase TRIM47-mediated degradation. JCI Insight 2024; 9:e177588. [PMID: 38771644 PMCID: PMC11383180 DOI: 10.1172/jci.insight.177588] [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: 11/14/2023] [Accepted: 05/15/2024] [Indexed: 05/23/2024] Open
Abstract
Hypotrichosis is a genetic disorder characterized by a diffuse and progressive loss of scalp and/or body hair. Nonetheless, the causative genes for several affected individuals remain elusive, and the underlying mechanisms have yet to be fully elucidated. Here, we discovered a dominant variant in a disintegrin and a metalloproteinase domain 17 (ADAM17) gene caused hypotrichosis with woolly hair. Adam17 (p.D647N) knockin mice mimicked the hair abnormality in patients. ADAM17 (p.D647N) mutation led to hair follicle stem cell (HFSC) exhaustion and caused abnormal hair follicles, ultimately resulting in alopecia. Mechanistic studies revealed that ADAM17 binds directly to E3 ubiquitin ligase tripartite motif-containing protein 47 (TRIM47). ADAM17 variant enhanced the association between ADAM17 and TRIM47, leading to an increase in ubiquitination and subsequent degradation of ADAM17 protein. Furthermore, reduced ADAM17 protein expression affected the Notch signaling pathway, impairing the activation, proliferation, and differentiation of HFSCs during hair follicle regeneration. Overexpression of Notch intracellular domain rescued the reduced proliferation ability caused by Adam17 variant in primary fibroblast cells.
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Affiliation(s)
- Xiaoxiao Wang
- Department of Dermatology, Xinhua Hospital, and
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chaolan Pan
- Department of Dermatology, Xinhua Hospital, and
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Luyao Zheng
- Department of Dermatology, Xinhua Hospital, and
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Dermatology, Anhui Provincial Children's Hospital, Hefei, China
| | - Jianbo Wang
- Department of Dermatology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, and Henan University People's Hospital, Zhengzhou, China
| | - Quan Zou
- Department of Dermatology, Xinhua Hospital, and
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Peiyi Sun
- Department of Dermatology, Xinhua Hospital, and
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Kaili Zhou
- Department of Dermatology, Xinhua Hospital, and
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Anqi Zhao
- Department of Dermatology, Xinhua Hospital, and
- Department of Dermatology, The Children's Hospital of Fudan University, Shanghai, China
| | - Qiaoyu Cao
- Department of Dermatology, Xinhua Hospital, and
- Department of Dermatology, The Children's Hospital of Fudan University, Shanghai, China
| | - Wei He
- Department of Dermatology, The Children's Hospital of Fudan University, Shanghai, China
| | - Yumeng Wang
- Department of Dermatology, Xinhua Hospital, and
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ruhong Cheng
- Department of Dermatology, Xinhua Hospital, and
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhirong Yao
- Department of Dermatology, Xinhua Hospital, and
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Si Zhang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hui Zhang
- Department of Dermatology, Xinhua Hospital, and
| | - Ming Li
- Department of Dermatology, Xinhua Hospital, and
- Department of Dermatology, The Children's Hospital of Fudan University, Shanghai, China
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Kiselev A, Park S. Immune niches for hair follicle development and homeostasis. Front Physiol 2024; 15:1397067. [PMID: 38711955 PMCID: PMC11070776 DOI: 10.3389/fphys.2024.1397067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 04/09/2024] [Indexed: 05/08/2024] Open
Abstract
The hair follicle is a dynamic mini-organ that has specialized cycles and architectures with diverse cell types to form hairs. Previous studies for several decades have investigated morphogenesis and signaling pathways during embryonic development and adult hair cycles in both mouse and human skin. In particular, hair follicle stem cells and mesenchymal niches received major attention as key players, and their roles and interactions were heavily revealed. Although resident and circulating immune cells affect cellular function and interactions in the skin, research on immune cells has mainly received attention on diseases rather than development or homeostasis. Recently, many studies have suggested the functional roles of diverse immune cells as a niche for hair follicles. Here, we will review recent findings about immune niches for hair follicles and provide insight into mechanisms of hair growth and diseases.
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Affiliation(s)
- Artem Kiselev
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI, United States
- Division of Dermatology, Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, United States
- Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, MI, United States
| | - Sangbum Park
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI, United States
- Division of Dermatology, Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, United States
- Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, MI, United States
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Bertolini M, Gherardini J, Chéret J, Alam M, Sulk M, Botchkareva NV, Biro T, Funk W, Grieshaber F, Paus R. Mechanical epilation exerts complex biological effects on human hair follicles and perifollicular skin: An ex vivo study approach. Int J Cosmet Sci 2024; 46:175-198. [PMID: 37923568 DOI: 10.1111/ics.12923] [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: 07/06/2023] [Revised: 10/04/2023] [Accepted: 10/12/2023] [Indexed: 11/07/2023]
Abstract
OBJECTIVE Electrical epilation of unwanted hair is a widely used hair removal method, but it is largely unknown how this affects the biology of human hair follicles (HF) and perifollicular skin. Here, we have begun to explore how mechanical epilation changes selected key biological read-out parameters ex vivo within and around the pilosebaceous unit. METHODS Human full-thickness scalp skin samples were epilated ex vivo using an electro-mechanical device, organ-cultured for up to 6 days in serum-free, supplemented medium, and assessed at different time points by quantitative (immuno-)histomorphometry for selected relevant read-out parameters in epilated and sham-epilated control samples. RESULTS Epilation removed most of the hair shafts, often together with fragments of the outer and inner root sheath and hair matrix. This was associated with persistent focal thinning of the HF basal membrane, decreased melanin content of the residual HF epithelium, and increased HF keratinocyte apoptosis, including in the bulge, yet without affecting the number of cytokeratin 15+ HF epithelial stem cells. Sebocyte apoptosis in the peripheral zone was increased, albeit without visibly altering sebum production. Epilation transiently perturbed HF immune privilege, and increased the expression of ICAM-1 in the bulge and bulb mesenchyme, and the number of perifollicular MHC class II+ cells as well as mast cells around the distal epithelium and promoted mast cell degranulation around the suprabulbar and bulbar area. Moreover, compared to controls, several key players of neurogenic skin inflammation, itch, and/or thermosensation (TRPV1, TRPA1, NGF, and NKR1) were differentially expressed in post-epilation skin. CONCLUSION These data generated in denervated, organ-cultured human scalp skin demonstrate that epilation-induced mechanical HF trauma elicits surprisingly complex biological responses. These may contribute to the delayed re-growth of thinner and lighter hair shafts post-epilation and temporary post-epilation discomfort. Our findings also provide pointers regarding the development of topically applicable agents that minimize undesirable sequelae of epilation.
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Affiliation(s)
- Marta Bertolini
- Monasterium Laboratory Skin and Hair Research Solutions GmbH, Münster, Germany
| | - Jennifer Gherardini
- Monasterium Laboratory Skin and Hair Research Solutions GmbH, Münster, Germany
- Dr Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Jérémy Chéret
- Monasterium Laboratory Skin and Hair Research Solutions GmbH, Münster, Germany
- Dr Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Majid Alam
- Department of Dermatology and Venereology, Qatar Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Mathias Sulk
- Department of Dermatology, University of Münster, Münster, Germany
| | - Natalia V Botchkareva
- Department of Dermatology, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Tamas Biro
- Monasterium Laboratory Skin and Hair Research Solutions GmbH, Münster, Germany
| | - Wolfgang Funk
- Clinic for Plastic, Aesthetic and Reconstructive Surgery, Dr. Dr. med. Funk, Munich, Germany
| | | | - Ralf Paus
- Monasterium Laboratory Skin and Hair Research Solutions GmbH, Münster, Germany
- Dr Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- CUTANEON - Skin & Hair Innovations, Hamburg, Germany
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11
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Jiang Y, Perez-Moreno M. Translational frontiers: insight from lymphatics in skin regeneration. Front Physiol 2024; 15:1347558. [PMID: 38487264 PMCID: PMC10937408 DOI: 10.3389/fphys.2024.1347558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/01/2024] [Indexed: 03/17/2024] Open
Abstract
The remarkable regenerative ability of the skin, governed by complex molecular mechanisms, offers profound insights into the skin repair processes and the pathogenesis of various dermatological conditions. This understanding, derived from studies in human skin and various model systems, has not only deepened our knowledge of skin regeneration but also facilitated the development of skin substitutes in clinical practice. Recent research highlights the crucial role of lymphatic vessels in skin regeneration. Traditionally associated with fluid dynamics and immune modulation, these vessels are now recognized for interacting with skin stem cells and coordinating regeneration. This Mini Review provides an overview of recent advancements in basic and translational research related to skin regeneration, focusing on the dynamic interplay between lymphatic vessels and skin biology. Key highlights include the critical role of stem cell-lymphatic vessel crosstalk in orchestrating skin regeneration, emerging translational approaches, and their implications for skin diseases. Additionally, the review identifies research gaps and proposes potential future directions, underscoring the significance of this rapidly evolving research arena.
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Affiliation(s)
| | - Mirna Perez-Moreno
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
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12
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Luna-Arias JP, Castro-Muñozledo F. Participation of the TBP-associated factors (TAFs) in cell differentiation. J Cell Physiol 2024; 239:e31167. [PMID: 38126142 DOI: 10.1002/jcp.31167] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/04/2023] [Accepted: 11/27/2023] [Indexed: 12/23/2023]
Abstract
The understanding of the mechanisms that regulate gene expression to establish differentiation programs and determine cell lineages, is one of the major challenges in Developmental Biology. Besides the participation of tissue-specific transcription factors and epigenetic processes, the role of general transcription factors has been ignored. Only in recent years, there have been scarce studies that address this issue. Here, we review the studies on the biological activity of some TATA-box binding protein (TBP)-associated factors (TAFs) during the proliferation of stem/progenitor cells and their involvement in cell differentiation. Particularly, the accumulated evidence suggests that TAF4, TAF4b, TAF7L, TAF8, TAF9, and TAF10, among others, participate in nervous system development, adipogenesis, myogenesis, and epidermal differentiation; while TAF1, TAF7, TAF15 may be involved in the regulation of stem cell proliferative abilities and cell cycle progression. On the other hand, evidence suggests that TBP variants such as TBPL1 and TBPL2 might be regulating some developmental processes such as germ cell maturation and differentiation, myogenesis, or ventral specification during development. Our analysis shows that it is necessary to study in greater depth the biological function of these factors and its participation in the assembly of specific transcription complexes that contribute to the differential gene expression that gives rise to the great diversity of cell types existing in an organism. The understanding of TAFs' regulation might lead to the development of new therapies for patients which suffer from mutations, alterations, and dysregulation of these essential elements of the transcriptional machinery.
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Affiliation(s)
- Juan Pedro Luna-Arias
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México City, Mexico
| | - Federico Castro-Muñozledo
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México City, Mexico
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13
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Zhou Y, Seo J, Tu S, Nanmo A, Kageyama T, Fukuda J. Exosomes for hair growth and regeneration. J Biosci Bioeng 2024; 137:1-8. [PMID: 37996318 DOI: 10.1016/j.jbiosc.2023.11.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/01/2023] [Accepted: 11/02/2023] [Indexed: 11/25/2023]
Abstract
Exosomes are lipid bilayer vesicles, 30-200 nm in diameter, that are produced by cells and play essential roles in cell-cell communication. Exosomes have been studied in several medical fields including dermatology. Hair loss, a major disorder that affects people and sometimes causes mental stress, urgently requires more effective treatment. Because the growth and cycling of hair follicles are governed by interactions between hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs), a better understanding of the mechanisms responsible for hair growth and cycling through exosomes may provide new insights into novel treatments for hair loss. In this review, we focused on the comprehensive knowledge and recent studies on exosomes in the field of hair development and regeneration. We classified exosomes of several cellular origins for the treatment of hair loss. Exosomes and their components, such as microRNAs, are promising drugs for effective hair loss treatment.
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Affiliation(s)
- Yinghui Zhou
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan
| | - Jieun Seo
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan; Institute of Advanced Sciences, 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
| | - Shan Tu
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan
| | - Ayaka Nanmo
- 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; Institute of Advanced Sciences, 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
| | - Junji Fukuda
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501, Japan; Institute of Advanced Sciences, 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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14
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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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15
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Popescu I, Constantin M, Solcan G, Ichim DL, Rata DM, Horodincu L, Solcan C. Composite Hydrogels with Embedded Silver Nanoparticles and Ibuprofen as Wound Dressing. Gels 2023; 9:654. [PMID: 37623109 PMCID: PMC10454181 DOI: 10.3390/gels9080654] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/02/2023] [Accepted: 08/11/2023] [Indexed: 08/26/2023] Open
Abstract
The wound healing process is often slowed down as a result of complications from bacterial infections and inflammatory reactions. Therefore, it is necessary to develop dressings with fast antibacterial and anti-inflammatory activity that shorten the wound healing period by promoting cell migration and proliferation. Chitosan (CS)-based hydrogels have been widely studied for their antibacterial and wound healing capabilities. Herein, we developed a composite hydrogel based on CS and PVA embedding silver nanoparticles (AgNPs) with antibacterial properties and ibuprofen (Ib) as an anti-inflammatory agent. The hydrogel prepared by double physical cross-linking, with oxalic acid and by freeze-thawing, loaded with 0.225 wt.% AgNPs and 0.264 wt.% Ib, displayed good mechanical properties (compressive modulus = 132 kPa), a high swelling degree and sustained drug delivery (in simulated skin conditions). Moreover, the hydrogel showed strong antibacterial activity against S. aureus and K. pneumoniae due to the embedded AgNPs. In vivo, this hydrogel accelerated the wound regeneration process through the enhanced expression of TNF alpha IP8, by activating downstream cascades and supporting the healing process of inflammation; Cox2, which enhances the migration and proliferation of cells involved in re-epithelization and angiogenesis; MHCII, which promotes immune cooperation between local cells, eliminating dead tissue and controlling infection; the intense expression of Col I as a major marker in the tissue granulation process; and αSMA, which marks the presence of myofibroblasts involved in wound closure and indicates ongoing re-epithelization. The results reveal the potential healing effect of CS/PVA/AgNPs/Ib hydrogels and suggest their potential use as wound dressings.
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Affiliation(s)
- Irina Popescu
- “Petru Poni” Institute of Macromolecular Chemistry, Grigore Ghica Voda Alley 41A, 700487 Iasi, Romania; (I.P.); (M.C.)
| | - Marieta Constantin
- “Petru Poni” Institute of Macromolecular Chemistry, Grigore Ghica Voda Alley 41A, 700487 Iasi, Romania; (I.P.); (M.C.)
| | - Gheorghe Solcan
- Faculty of Veterinary Medicine, “Ion Ionescu de la Brad” Iasi University of Life Sciences, 700489 Iasi, Romania; (G.S.); (L.H.)
| | - Daniela Luminita Ichim
- Faculty of Medical Dentistry, “Apollonia” University of Iasi, 700511 Iasi, Romania; (D.L.I.); (D.M.R.)
| | - Delia Mihaela Rata
- Faculty of Medical Dentistry, “Apollonia” University of Iasi, 700511 Iasi, Romania; (D.L.I.); (D.M.R.)
| | - Loredana Horodincu
- Faculty of Veterinary Medicine, “Ion Ionescu de la Brad” Iasi University of Life Sciences, 700489 Iasi, Romania; (G.S.); (L.H.)
| | - Carmen Solcan
- Faculty of Veterinary Medicine, “Ion Ionescu de la Brad” Iasi University of Life Sciences, 700489 Iasi, Romania; (G.S.); (L.H.)
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16
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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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17
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Nicu C, Jackson J, Shahmalak A, Pople J, Ansell D, Paus R. Adiponectin negatively regulates pigmentation, Wnt/β-catenin and HGF/c-Met signalling within human scalp hair follicles ex vivo. Arch Dermatol Res 2023; 315:603-612. [PMID: 34854998 DOI: 10.1007/s00403-021-02291-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 08/22/2021] [Accepted: 09/24/2021] [Indexed: 12/15/2022]
Abstract
Adiponectin reportedly stimulates proliferation and elongation of human scalp hair follicles (HFs) ex vivo. In the current study, we investigated how adiponectin oligomers produced by perifollicular dermal white adipose tissue (dWAT), a potent source of adiponectin isoforms, influence human HF proliferation and pigmentation. To do so, we treated microdissected, organ-cultured HFs in the presence or absence of dWAT with a recombinant human adiponectin oligomer mix, or inhibited dWAT-derived adiponectin using a neutralizing antibody. Multiplex qPCR (Fluidigm) revealed that adiponectin oligomers downregulated pigmentation genes KITLG, PMEL and TYRP1 and Wnt genes AXIN2, LEF1 and WNT10B. In situ hybridization showed that adiponectin downregulated AXIN2 and LEF1, and up-regulated DKK1 within the dermal papilla (DP), a highly unusual transcriptional profile for a putative hair growth-promoting agent. Adiponectin oligomers also downregulated protein expression of the HGF receptor c-Met within the matrix and DP. However, adiponectin did not alter hair matrix keratinocyte proliferation within 48 h ex vivo, irrespective of the presence/absence of dWAT; HF pigmentation (Masson-Fontana histochemistry, tyrosinase activity) was also unchanged. In contrast, neutralizing adiponectin isoforms within HF + dWAT increased proliferation, melanin content and tyrosinase activity but resulted in fewer melanocytes and melanocytic dendrites, as assessed by gp100 immunostaining. These seemingly contradictory effects suggest that adiponectin exerts complex effects upon human HF biology, likely in parallel with the pro-pigmentation effects of dWAT- and DP-derived HGF. Our data suggest that dWAT-derived ratios of adiponectin isoforms and the cleaved, globular version of adiponectin may in fact determine how adiponectin impacts upon follicular pigmentation and growth.
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Affiliation(s)
- Carina Nicu
- Centre for Dermatology Research, University of Manchester, Manchester and NIHR Manchester Biomedical Research Centre, Manchester, UK.
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Jennifer Jackson
- Centre for Dermatology Research, University of Manchester, Manchester and NIHR Manchester Biomedical Research Centre, Manchester, UK
| | | | - Jenny Pople
- Unilever R&D Colworth, Colworth Science Park, Bedford, UK
| | - David Ansell
- Centre for Dermatology Research, University of Manchester, Manchester and NIHR Manchester Biomedical Research Centre, Manchester, UK
- Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, Bradford, UK
| | - Ralf Paus
- Centre for Dermatology Research, University of Manchester, Manchester and NIHR Manchester Biomedical Research Centre, Manchester, UK
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
- Monasterium Laboratory, Münster, Germany
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18
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Colin-Pierre C, Untereiner V, Sockalingum GD, Ramont L, Brézillon S. Investigation of Glypican-4 and -6 by Infrared Spectral Imaging during the Hair Growth Cycle. Int J Mol Sci 2023; 24:ijms24054291. [PMID: 36901723 PMCID: PMC10002317 DOI: 10.3390/ijms24054291] [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: 11/23/2022] [Revised: 01/13/2023] [Accepted: 02/14/2023] [Indexed: 02/24/2023] Open
Abstract
The expression of glypicans in different hair follicle (HF) compartments is still poorly understood. Heparan sulfate proteoglycans (HSPGs) distribution in HF is classically investigated by conventional histology, biochemical analysis, and immunohistochemistry. Our previous study proposed a novel approach to assess hair histology and glypican-1 (GPC1) distribution changes in the HF at different phases of the hair growth cycle using infrared spectral imaging (IRSI). We show in the present manuscript for the first time complementary data on the distribution of glypican-4 (GPC4) and glypican-6 (GPC6) in HF at different phases of the hair growth cycle using IR imaging. Findings were supported by Western blot assays focusing on the GPC4 and GPC6 expression in HFs. Like all proteoglycan features, the glypicans are characterized by a core protein to which sulfated and/or unsulfated glycosaminoglycan (GAG) chains are covalently linked. Our study demonstrates the capacity of IRSI to identify the different HF tissue structures and to highlight protein, proteoglycan (PG), GAG, and sulfated GAG distribution in these structures. The comparison between anagen, catagen, and telogen phases shows the qualitative and/or quantitative evolution of GAGs, as supported by Western blot. Thus, in one analysis, IRSI can simultaneously reveal the location of proteins, PGs, GAGs and sulfated GAGs in HFs in a chemical and label-free manner. From a dermatological point of view, IRSI may constitute a promising technique to study alopecia.
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Affiliation(s)
- Charlie Colin-Pierre
- Laboratoire de Biochimie Médicale et Biologie Moléculaire, Université de Reims Champagne-Ardenne, 51097 Reims, France
- Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, CNRS UMR 7369, 51097 Reims, France
- BASF Beauty Care Solutions France SAS, 54425 Pulnoy, France
| | | | - Ganesh D. Sockalingum
- Université de Reims Champagne-Ardenne, BioSpecT EA7506, UFR de Pharmacie, 51097 Reims, France
- Correspondence: (G.D.S.); (S.B.)
| | - Laurent Ramont
- Laboratoire de Biochimie Médicale et Biologie Moléculaire, Université de Reims Champagne-Ardenne, 51097 Reims, France
- Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, CNRS UMR 7369, 51097 Reims, France
- Service Biochimie-Pharmacologie-Toxicologie, CHU de Reims, 51097 Reims, France
| | - Stéphane Brézillon
- Laboratoire de Biochimie Médicale et Biologie Moléculaire, Université de Reims Champagne-Ardenne, 51097 Reims, France
- Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, CNRS UMR 7369, 51097 Reims, France
- Correspondence: (G.D.S.); (S.B.)
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19
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Silver Nanoparticles Biocomposite Films with Antimicrobial Activity: In Vitro and In Vivo Tests. Int J Mol Sci 2022; 23:ijms231810671. [PMID: 36142584 PMCID: PMC9503464 DOI: 10.3390/ijms231810671] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Overuse of antimicrobials by the population has contributed to genetic modifications in bacteria and development of antimicrobial resistance, which is very difficult to combat nowadays. To solve this problem, it is necessary to develop new systems for the administration of antimicrobial active principles. Biocomposite systems containing silver nanoparticles can be a good medical alternative. In this context, the main objective of this study was to obtain a complex system in the form of a biocomposite film with antimicrobial properties based on chitosan, poly (vinyl alcohol) and silver nanoparticles. This new system was characterized from a structural and morphological point of view. The swelling degree, the mechanical properties and the efficiency of loading and release of an anti-inflammatory drug were also evaluated. The obtained biocomposite films are biocompatibles, this having been demonstrated by in vitro tests on HDFa cell lines, and have antimicrobial activity against S. aureus. The in vivo tests, carried out on rabbit subjects, highlighted the fact that signs of reduced fibrosis were specific to the C2P4.10.Ag1-IBF film sample, demonstrated by: intense expression of TNFAIP8 factors; as an anti-apoptotic marker, MHCII that favors immune cooperation among local cells; αSMA, which marks the presence of myofibroblasts involved in approaching the interepithelial spaces for epithelialization; and reduced expression of the Cox2 indicator of inflammation, Col I.
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20
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LGR5 is a conserved marker of hair follicle stem cells in multiple species and is present early and throughout follicle morphogenesis. Sci Rep 2022; 12:9104. [PMID: 35650234 PMCID: PMC9160037 DOI: 10.1038/s41598-022-13056-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 05/19/2022] [Indexed: 11/29/2022] Open
Abstract
Hair follicle stem cells are key for driving growth and homeostasis of the hair follicle niche, have remarkable regenerative capacity throughout hair cycling, and display fate plasticity during cutaneous wound healing. Due to the need for a transgenic reporter, essentially all observations related to LGR5-expressing hair follicle stem cells have been generated using transgenic mice, which have significant differences in anatomy and physiology from the human. Using a transgenic pig model, a widely accepted model for human skin and human skin repair, we demonstrate that LGR5 is a marker of hair follicle stem cells across species in homeostasis and development. We also report the strong similarities and important differences in expression patterns, gene expression profiles, and developmental processes between species. This information is important for understanding the fundamental differences and similarities across species, and ultimately improving human hair follicle regeneration, cutaneous wound healing, and skin cancer treatment.
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21
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Mysore V, Alexander S, Nepal S, Venkataram A. Regenerative Medicine Treatments for Androgenetic Alopecia. Indian J Plast Surg 2022; 54:514-520. [PMID: 34984094 PMCID: PMC8719950 DOI: 10.1055/s-0041-1739257] [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: 05/25/2021] [Accepted: 09/05/2021] [Indexed: 11/16/2022] Open
Abstract
Regenerative medicine and the role of stem cells are being studied for applications in nearly every field of medicine. The pluripotent nature of stem cells underlies their vast potential for treatment of androgenic alopecia. Several advances in recent years have heightened interest in this field, chief among them are the evolution of simpler techniques to isolate regenerative elements and stems cells. These techniques are easy, outpatient procedures with immediate injection, often single session with harvest, and minimal manipulation (usually physical). This paper seeks to critically review the existing data and determine the current evidence and their role in practice.
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Affiliation(s)
- Venkataram Mysore
- The Venkat Center for Skin ENT and Plastic Surgery, Bangalore, India
| | - Sajin Alexander
- Department of Dermatology, Sony Memorial Hospital, Erumely, Kottayam, Kerala, India
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22
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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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23
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Zari S. Short-Term Efficacy of Autologous Cellular Micrografts in Male and Female Androgenetic Alopecia: A Retrospective Cohort Study. Clin Cosmet Investig Dermatol 2021; 14:1725-1736. [PMID: 34824538 PMCID: PMC8610382 DOI: 10.2147/ccid.s334807] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/28/2021] [Indexed: 01/01/2023]
Abstract
Purpose Autologous cellular micrografts (ACM) is a novel treatment method in hair loss, and few data are available regarding its efficacy. The present study was carried out to assess the short-term clinical efficacy of a single application of ACM in the treatment of male and female androgenetic alopecia (AGA). Materials and Methods This was a single-center retrospective study involving 140 consecutive adults with confirmed AGA, who received a single session of ACM (Regenera Activa®). Efficacy was evaluated 1–6 months after treatment, by analyzing the change of trichometry parameters, which were assessed using TrichoScan digital image analysis. Results Depending on the scalp region, there was increase in mean hair density by 4.5–7.12 hair/cm2, average hair thickness by 0.96–1.88 μm, % thick hair by 1.74–3.26%, and mean number of follicular units by 1.30–2.77, resulting in an increase of cumulative hair thickness by 0.48–0.56 unit. Additionally, the frontal region showed a significant decrease in % thin hair (−1.81%, p = 0.037) and yellow dots (−1.93 N/cm2, p = 0.003). A favorable response was observed in 66.4% of the participants in the frontal region. Further, a gender-specific effect of treatment was observed. Conclusion ACM is a promising treatment in AGA with a short-term favorable response observed in up to approximately two-thirds of patients.
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Affiliation(s)
- Shadi Zari
- Department of Dermatology, Faculty of Medicine, University of Jeddah, Jeddah, Saudi Arabia
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24
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Figlak K, Williams G, Bertolini M, Paus R, Philpott MP. Human hair follicles operate an internal Cori cycle and modulate their growth via glycogen phosphorylase. Sci Rep 2021; 11:20761. [PMID: 34675331 PMCID: PMC8531296 DOI: 10.1038/s41598-021-99652-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 09/08/2021] [Indexed: 12/03/2022] Open
Abstract
Hair follicles (HFs) are unique, multi-compartment, mini-organs that cycle through phases of active hair growth and pigmentation (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen). Anagen HFs have high demands for energy and biosynthesis precursors mainly fulfilled by aerobic glycolysis. Histochemistry reports the outer root sheath (ORS) contains high levels of glycogen. To investigate a functional role for glycogen in the HF we quantified glycogen by Periodic-Acid Schiff (PAS) histomorphometry and colorimetric quantitative assay showing ORS of anagen VI HFs contained high levels of glycogen that decreased in catagen. qPCR and immunofluorescence microscopy showed the ORS expressed all enzymes for glycogen synthesis and metabolism. Using human ORS keratinocytes (ORS-KC) and ex vivo human HF organ culture we showed active glycogen metabolism by nutrient starvation and use of a specific glycogen phosphorylase (PYGL) inhibitor. Glycogen in ORS-KC was significantly increased by incubation with lactate demonstrating a functional Cori cycle. Inhibition of PYGL significantly stimulated the ex vivo growth of HFs and delayed onset of catagen. This study defines translationally relevant and therapeutically targetable new features of HF metabolism showing that human scalp HFs operate an internal Cori cycle, synthesize glycogen in the presence of lactate and modulate their growth via PYGL activity.
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Affiliation(s)
- Katarzyna Figlak
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK
| | | | | | - Ralf Paus
- Monasterium Laboratory, Münster, Germany.,Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Dermatology Research Centre, University of Manchester, and NIHR Biomedical Research Centre, Manchester, UK
| | - Michael P Philpott
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
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25
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Suzuki T, Ito T, Gilhar A, Tokura Y, Reich K, Paus R. The hair follicle-psoriasis axis: Shared regulatory mechanisms and therapeutic targets. Exp Dermatol 2021; 31:266-279. [PMID: 34587317 DOI: 10.1111/exd.14462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 09/09/2021] [Accepted: 09/24/2021] [Indexed: 12/17/2022]
Abstract
It has long been known that there is a special affinity of psoriasis for the scalp: Here, it occurs most frequently, lesions terminate sharply in frontal skin beyond the hair line and are difficult to treat. Yet, surprisingly, scalp psoriasis only rarely causes alopecia, even though the pilosebaceous unit clearly is affected. Here, we systematically explore the peculiar, insufficiently investigated connection between psoriasis and growing (anagen) terminal scalp hair follicles (HFs), with emphasis on shared regulatory mechanism and therapeutic targets. Interestingly, several drugs and stressors that can trigger/aggravate psoriasis can inhibit hair growth (e.g. beta-blockers, chloroquine, carbamazepine, interferon-alpha, perceived stress). Instead, several anti-psoriatic agents can stimulate hair growth (e.g. cyclosporine, glucocorticoids, dithranol, UV irradiation), while skin/HF trauma (Köbner phenomenon/depilation) favours the development of psoriatic lesions and induces anagen in "quiescent" (telogen) HFs. On this basis, we propose two interconnected working models: (a) the existence of a bidirectional "hair follicle-psoriasis axis," along which keratinocytes of anagen scalp HFs secrete signals that favour the development and maintenance of psoriatic scalp lesions and respond to signals from these lesions, and (b) that anagen induction and psoriatic lesions share molecular "switch-on" mechanisms, which invite pharmacological targeting, once identified. Therefore, we advocate a novel, cross-fertilizing and integrative approach to psoriasis and hair research that systematically characterizes the "HF-psoriasis axis," focused on identification and therapeutic targeting of selected, shared signalling pathways in the future management of both, psoriasis and hair growth disorders.
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Affiliation(s)
- Takahiro Suzuki
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Taisuke Ito
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Amos Gilhar
- Skin Research Laboratory, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Yoshiki Tokura
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.,Allergic Disease Research Center, Chutoen General Medical Center, Kakegawa, Japan
| | - Kristian Reich
- Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Monasterium Laboratory, Münster, Germany
| | - Ralf Paus
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.,Monasterium Laboratory, Münster, Germany.,Centre for Dermatology Research, University of Manchester, Manchester, UK.,NIHR Manchester Biomedical Research Center, Manchester, UK
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26
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Spurlock B, Parker D, Basu MK, Hjelmeland A, GC S, Liu S, Siegal GP, Gunter A, Moran A, Mitra K. Fine-tuned repression of Drp1-driven mitochondrial fission primes a 'stem/progenitor-like state' to support neoplastic transformation. eLife 2021; 10:e68394. [PMID: 34545812 PMCID: PMC8497058 DOI: 10.7554/elife.68394] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 09/08/2021] [Indexed: 12/13/2022] Open
Abstract
Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model, we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem/progenitor cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed 'stem/progenitor-like state' to accelerate neoplastic transformation, and more complete reduction of Drp1 protein prevents it. Therefore, our data highlights a 'goldilocks' level of Drp1 repression supporting stem/progenitor state dependent neoplastic transformation.
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Affiliation(s)
- Brian Spurlock
- Department of Genetics, University of Alabama at BirminghamBirminghamUnited States
| | - Danitra Parker
- Department of Genetics, University of Alabama at BirminghamBirminghamUnited States
| | - Malay Kumar Basu
- Departments of Pathology, University of Alabama at BirminghamBirminghamUnited States
| | - Anita Hjelmeland
- Department of Cell Development and Integrative Biology, University of Alabama at BirminghamBirminghamUnited States
| | - Sajina GC
- Department of Cell Development and Integrative Biology, University of Alabama at BirminghamBirminghamUnited States
| | - Shanrun Liu
- Department of Genetics, University of Alabama at BirminghamBirminghamUnited States
| | - Gene P Siegal
- Departments of Pathology, Surgery, Genetics and Cell and Developmental Biology, University of Alabama at BirminghamBirminghamUnited States
| | - Alan Gunter
- Department of Genetics, University of Alabama at BirminghamBirminghamUnited States
| | - Aida Moran
- Department of Genetics, University of Alabama at BirminghamBirminghamUnited States
| | - Kasturi Mitra
- Department of Genetics, University of Alabama at BirminghamBirminghamUnited States
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27
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A Cell Membrane-Level Approach to Cicatricial Alopecia Management: Is Caveolin-1 a Viable Therapeutic Target in Frontal Fibrosing Alopecia? Biomedicines 2021; 9:biomedicines9050572. [PMID: 34069454 PMCID: PMC8159142 DOI: 10.3390/biomedicines9050572] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/05/2021] [Accepted: 05/17/2021] [Indexed: 12/12/2022] Open
Abstract
Irreversible destruction of the hair follicle (HF) in primary cicatricial alopecia and its most common variant, frontal fibrosing alopecia (FFA), results from apoptosis and pathological epithelial-mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs), in conjunction with the collapse of bulge immune privilege (IP) and interferon-gamma-mediated chronic inflammation. The scaffolding protein caveolin-1 (Cav1) is a key component of specialized cell membrane microdomains (caveolae) that regulates multiple signaling events, and even though Cav1 is most prominently expressed in the bulge area of human scalp HFs, it has not been investigated in any cicatricial alopecia context. Interestingly, in mice, Cav1 is involved in the regulation of (1) key HF IP guardians (TGF-β and α-MSH signaling), (2) IP collapse inducers/markers (IFNγ, substance P and MICA), and (3) EMT. Therefore, we hypothesize that Cav1 may be an unrecognized, important player in the pathobiology of cicatricial alopecias, and particularly, in FFA, which is currently considered as the most common type of primary lymphocytic scarring alopecia in the world. We envision that localized therapeutic inhibition of Cav1 in management of FFA (by cholesterol depleting agents, i.e., cyclodextrins/statins), could inhibit and potentially reverse bulge IP collapse and pathological EMT. Moreover, manipulation of HF Cav1 expression/localization would not only be relevant for management of cicatricial alopecia, but FFA could also serve as a model disease for elucidating the role of Cav1 in other stem cell- and/or IP collapse-related pathologies.
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28
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Lousada MB, Lachnit T, Edelkamp J, Rouillé T, Ajdic D, Uchida Y, Di Nardo A, Bosch TCG, Paus R. Exploring the human hair follicle microbiome. Br J Dermatol 2021; 184:802-815. [PMID: 32762039 DOI: 10.1111/bjd.19461] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2020] [Indexed: 12/31/2022]
Abstract
Human hair follicles (HFs) carry complex microbial communities that differ from the skin surface microbiota. This likely reflects that the HF epithelium differs from the epidermal barrier in that it provides a moist, less acidic, and relatively ultraviolet light-protected environment, part of which is immune-privileged, thus facilitating microbial survival. Here we review the current understanding of the human HF microbiome and its potential physiological and pathological functions, including in folliculitis, acne vulgaris, hidradenitis suppurativa, alopecia areata and cicatricial alopecias. While reviewing the main human HF bacteria (such as Propionibacteria, Corynebacteria, Staphylococci and Streptococci), viruses, fungi and parasites as human HF microbiome constituents, we advocate a broad view of the HF as an integral part of the human holobiont. Specifically, we explore how the human HF may manage its microbiome via the regulated production of antimicrobial peptides (such as cathelicidin, psoriasin, RNAse7 and dermcidin) by HF keratinocytes, how the microbiome may impact on cytokine and chemokine release from the HF, and examine hair growth-modulatory effects of antibiotics, and ask whether the microbiome affects hair growth in turn. We highlight major open questions and potential novel approaches to the management of hair diseases by targeting the HF microbiome.
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Affiliation(s)
- M B Lousada
- Monasterium Laboratory, Münster, Germany
- Zoological Institute, Christian-Albrechts University Kiel, Kiel, Germany
| | - T Lachnit
- Zoological Institute, Christian-Albrechts University Kiel, Kiel, Germany
| | - J Edelkamp
- Monasterium Laboratory, Münster, Germany
| | - T Rouillé
- Monasterium Laboratory, Münster, Germany
| | - D Ajdic
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Y Uchida
- Monasterium Laboratory, Münster, Germany
| | - A Di Nardo
- Department of Dermatology, University of California, San Diego, CA, USA
| | - T C G Bosch
- Zoological Institute, Christian-Albrechts University Kiel, Kiel, Germany
| | - R Paus
- Monasterium Laboratory, Münster, Germany
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
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29
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Jimenez F, Alam M, Vogel JE, Avram M. Hair Transplantation: Basic Overview. J Am Acad Dermatol 2021; 85:803-814. [PMID: 33905785 DOI: 10.1016/j.jaad.2021.03.124] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 03/02/2021] [Accepted: 03/16/2021] [Indexed: 10/21/2022]
Abstract
Modern hair restoration surgery is based on a technique known as follicular unit transplantation in which follicular units (FUs) are the exclusive structures used as hair grafts. In Part 1 of this two-part review, we describe how the techniques employed in hair transplantation have evolved into their present forms. Anatomic concepts of specific relevance for dermatologists are discussed, including the distribution and ex-vivo morphology of scalp FUs. Male androgenetic alopecia and female pattern hair loss are the most common reasons for hair loss consultations with dermatologists and will be the primary focus of this review. However, as not all hair disorders are suitable for transplantation, this review will also describe which scalp conditions are amenable to surgery and which are not. In addition, guidelines are provided to help dermatologists better define good or bad candidates for hair transplantation. Finally, other conditions for which hair transplantation surgery is indicated are reviewed.
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Affiliation(s)
- Francisco Jimenez
- Mediteknia Dermatology and Hair Transplant Clinic, Universidad Fernando Pessoa Canarias, Gran Canaria, Spain.
| | - Majid Alam
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar, Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - James E Vogel
- Associate Professor of Surgery, Department of Plastic Surgery, The Johns Hopkins Hospital and School of Medicine, Baltimore, MD, USA
| | - Marc Avram
- Clinical Professor of Dermatology Weill Cornell Medical School; Private practice, New York, NY, USA
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30
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Stone RC, Aviv A, Paus R. Telomere Dynamics and Telomerase in the Biology of Hair Follicles and their Stem Cells as a Model for Aging Research. J Invest Dermatol 2021; 141:1031-1040. [PMID: 33509633 DOI: 10.1016/j.jid.2020.12.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/28/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023]
Abstract
In this review, we propose that telomere length dynamics play an important but underinvestigated role in the biology of the hair follicle (HF), a prototypic, cyclically remodeled miniorgan that shows an intriguing aging pattern in humans. Whereas the HF pigmentary unit ages quickly, its epithelial stem cell (ESC) component and regenerative capacity are surprisingly aging resistant. Telomerase-deficient mice with short telomeres display an aging phenotype of hair graying and hair loss that is attributed to impaired HF ESC mobilization. Yet, it remains unclear whether the function of telomerase and telomeres in murine HF biology translate to the human system. Therefore, we propose new directions for future telomere research of the human HF. Such research may guide the development of novel treatments for selected disorders of human hair growth or pigmentation (e.g., chemotherapy-induced alopecia, telogen effluvium, androgenetic alopecia, cicatricial alopecia, graying). It might also increase the understanding of the global role of telomeres in aging-related human disease.
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Affiliation(s)
- Rivka C Stone
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
| | - Abraham Aviv
- The Center of Human Development and Aging, Rutgers New Jersey Medical School, Newark, New Jersey, USA
| | - Ralf Paus
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA; Centre for Dermatology Research, University of Manchester, Manchester, United Kingdom; Monasterium Laboratory, Münster, Germany
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31
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Purba TS, Berriche L, Paus R. Compartmentalised metabolic programmes in human anagen hair follicles: New targets to modulate epithelial stem cell behaviour, keratinocyte proliferation and hair follicle immune status? Exp Dermatol 2021; 30:645-651. [PMID: 33548088 DOI: 10.1111/exd.14300] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/12/2021] [Accepted: 02/02/2021] [Indexed: 01/09/2023]
Abstract
Human scalp hair follicles (HF) preferentially engage in glycolysis followed by lactate production in the presence of oxygen (i.e. the Warburg effect). Through the spatiotemporally controlled expression of key metabolic proteins, we hypothesise that the Warburg effect and other HF metabolic programmes are compartmentalised by region in order to regulate regional cell fate and phenotypes, such as epithelial stem cell quiescence in the bulge or keratinocyte proliferation in the hair matrix. We further propose that metabolic conditions in the HF are organised in accordance with the lactate shuttle, hypothesised to occur in other tissue systems and tumours, but never before described in the HF. Specifically, we argue that lactate is produced and exported by glycolytic GLUT1+ lower outer root sheath (ORS) keratinocytes. We further propose that lactate is then utilised by neighbouring highly proliferative matrix keratinocytes to fuel oxidative metabolism via MCT1-mediated uptake. Furthermore, as lactate has been described to be immunomodulatory, its production and accumulation could enhance immune tolerance in the HF bulb. Here we delineate how to experimentally probe this hypothesis, define major open questions and present preliminary immunohistological evidence in support of metabolic compartmentalisation and lactate shuttling. Overall, we argue that basic and translational hair research needs to rediscover the importance of lactate in human HF biology, well beyond its recognised role in murine HF epithelial stem cells, and should explore how HF metabolism can be therapeutically targeted to modulate hair growth and the immunological HF microenvironment as a novel strategy for managing hair loss disorders.
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Affiliation(s)
- Talveen S Purba
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Leïla Berriche
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK.,Claude Bernard Lyon 1, Lyon, France
| | - Ralf Paus
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK.,Monasterium Laboratory, Münster, Germany.,Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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32
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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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33
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Colin-Pierre C, Untereiner V, Sockalingum GD, Berthélémy N, Danoux L, Bardey V, Mine S, Jeanmaire C, Ramont L, Brézillon S. Hair Histology and Glycosaminoglycans Distribution Probed by Infrared Spectral Imaging: Focus on Heparan Sulfate Proteoglycan and Glypican-1 during Hair Growth Cycle. Biomolecules 2021; 11:biom11020192. [PMID: 33573119 PMCID: PMC7912031 DOI: 10.3390/biom11020192] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/22/2021] [Accepted: 01/22/2021] [Indexed: 01/30/2023] Open
Abstract
The expression of glypicans in different hair follicle (HF) compartments and their potential roles during hair shaft growth are still poorly understood. Heparan sulfate proteoglycan (HSPG) distribution in HFs is classically investigated by conventional histology, biochemical analysis, and immunohistochemistry. In this report, a novel approach is proposed to assess hair histology and HSPG distribution changes in HFs at different phases of the hair growth cycle using infrared spectral imaging (IRSI). The distribution of HSPGs in HFs was probed by IRSI using the absorption region relevant to sulfation as a spectral marker. The findings were supported by Western immunoblotting and immunohistochemistry assays focusing on the glypican-1 expression and distribution in HFs. This study demonstrates the capacity of IRSI to identify the different HF tissue structures and to highlight protein, proteoglycan (PG), glycosaminoglycan (GAG), and sulfated GAG distribution in these structures. The comparison between anagen, catagen, and telogen phases shows the qualitative and/or quantitative evolution of GAGs as supported by Western immunoblotting. Thus, IRSI can simultaneously reveal the location of proteins, PGs, GAGs, and sulfated GAGs in HFs in a reagent- and label-free manner. From a dermatological point of view, IRSI shows its potential as a promising technique to study alopecia.
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Affiliation(s)
- Charlie Colin-Pierre
- Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, 51097 Reims, France; (C.C.-P.); (L.R.)
- CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, 51097 Reims, France
- BASF Beauty Care Solutions France SAS, 54425 Pulnoy, France; (N.B.); (L.D.); (V.B.); (S.M.); (C.J.)
| | | | - Ganesh D. Sockalingum
- Université de Reims Champagne-Ardenne, BioSpecT EA7506, UFR de Pharmacie, 51097 Reims, France;
| | - Nicolas Berthélémy
- BASF Beauty Care Solutions France SAS, 54425 Pulnoy, France; (N.B.); (L.D.); (V.B.); (S.M.); (C.J.)
| | - Louis Danoux
- BASF Beauty Care Solutions France SAS, 54425 Pulnoy, France; (N.B.); (L.D.); (V.B.); (S.M.); (C.J.)
| | - Vincent Bardey
- BASF Beauty Care Solutions France SAS, 54425 Pulnoy, France; (N.B.); (L.D.); (V.B.); (S.M.); (C.J.)
| | - Solène Mine
- BASF Beauty Care Solutions France SAS, 54425 Pulnoy, France; (N.B.); (L.D.); (V.B.); (S.M.); (C.J.)
| | - Christine Jeanmaire
- BASF Beauty Care Solutions France SAS, 54425 Pulnoy, France; (N.B.); (L.D.); (V.B.); (S.M.); (C.J.)
| | - Laurent Ramont
- Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, 51097 Reims, France; (C.C.-P.); (L.R.)
- CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, 51097 Reims, France
- CHU de Reims, Service Biochimie-Pharmacologie-Toxicologie, 51097 Reims, France
| | - Stéphane Brézillon
- Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, 51097 Reims, France; (C.C.-P.); (L.R.)
- CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, 51097 Reims, France
- Correspondence:
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Tp63-expressing adult epithelial stem cells cross lineages boundaries revealing latent hairy skin competence. Nat Commun 2020; 11:5645. [PMID: 33159086 PMCID: PMC7648065 DOI: 10.1038/s41467-020-19485-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 10/15/2020] [Indexed: 12/30/2022] Open
Abstract
The formation of hair follicles, a landmark of mammals, requires complex mesenchymal–epithelial interactions and it is commonly believed that embryonic epidermal cells are the only cells that can respond to hair follicle morphogenetic signals in vivo. Here, we demonstrate that epithelial stem cells of non-skin origin (e.g. that of cornea, oesophagus, vagina, bladder, prostate) that express the transcription factor Tp63, a master gene for the development of epidermis and its appendages, can respond to skin morphogenetic signals. When exposed to a newborn skin microenvironment, these cells express hair-follicle lineage markers and contribute to hair follicles, sebaceous glands and/or epidermis renewal. Our results demonstrate that lineage restriction is not immutable and support the notion that all Tp63-expressing epithelial stem cells, independently of their embryonic origin, have latent skin competence explaining why aberrant hair follicles or sebaceous glands are sometimes observed in non-skin tissues (e.g. in cornea, vagina or thymus). Adult stem cells are thought to be fate restricted to lineages distinct to their tissue of origin. Here, the authors demonstrate that Tp63 expressing epithelial stem cells from several disparate tissues can respond to skin morphogenetic signals and contribute to hair follicles, sebaceous glands and/or epidermis.
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Halley-Stott RP, Adeola HA, Khumalo NP. Destruction of the stem cell Niche, Pathogenesis and Promising Treatment Targets for Primary Scarring Alopecias. Stem Cell Rev Rep 2020; 16:1105-1120. [PMID: 32789558 DOI: 10.1007/s12015-020-09985-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The Primary Scarring Alopecias are characterised by the irreversible destruction and fibrosis of hair follicles, leading to permanent and often disfiguring loss of hair. The pathophysiology of these diseases is not well understood. However, follicular-fibrosis and loss of the stem-cell niche appears to be a common theme. This review explores the pathogenesis of primary scarring alopecias, asking what happens to the stem cells of the hair follicle and how they may contribute to the progression of these diseases. Bulge-resident cells are lost (leading to loss of capacity for hair growth) from the follicle either by inflammatory-mediate apoptosis or through epigenetic reprogramming to assume a mesenchymal-like identity. What proportion of bulge cells is lost to which process is unknown and probably differs depending on the individual PCA and its specific inflammatory cell infiltrate. The formation of fibroblast-like cells from follicular stem cells may also mean that the cells of the bulge have a direct role in the pathogenesis. The identification of specific cells involved in the pathogenesis of these diseases could provide unique diagnostic and therapeutic opportunities to prevent disease progression by preventing EMT and specific pro-fibrotic signals.
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Affiliation(s)
- Richard P Halley-Stott
- Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town, South Africa.
| | - Henry A Adeola
- Hair and Skin Research Laboratory, Groote Schuur Hospital, Cape Town, South Africa
| | - Nonhlanhla P Khumalo
- Hair and Skin Research Laboratory, Groote Schuur Hospital, Cape Town, South Africa
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Zaki AKA, Almundarij TI, Abo-Aziza FAM. Comparative characterization and osteogenic / adipogenic differentiation of mesenchymal stem cells derived from male rat hair follicles and bone marrow. CELL REGENERATION (LONDON, ENGLAND) 2020; 9:13. [PMID: 32778979 PMCID: PMC7417469 DOI: 10.1186/s13619-020-00051-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/06/2020] [Indexed: 01/11/2023]
Abstract
Clinical applications of cell therapy and tissue regeneration under different conditions need a multiplicity of adult stem cell sources. Up to date, little is available on the comparative isolation, characterization, proliferation, rapid amplification, and osteogenic/adipogenic differentiation of rat mesenchymal stem cells (MSCs) isolated from living bulge cells of the hair follicle (HF) and bone marrow (BM) from the same animal. This work hopes to use HF-MSCs as an additional adult stem cell source for research and application. After reaching 80% confluence, the cell counting, viability %, and yields of HF-MSCs and BM-MSCs were nearly similar. The viability % was 91.41 ± 2.98 and 93.11 ± 3.06 while the cells yield of initial seeding was 33.15 ± 2.76 and 34.22 ± 3.99 and of second passage was 28.76 ± 1.01 and 29.56 ± 3.11 for HF-MSCs and BM-MSCs respectively. Clusters of differentiation (CDs) analysis revealed that HF-MSCs were positively expressed CD34, CD73 and CD200 and negatively expressed CD45. BM-MSCs were positively expressed CD73 and CD200 and negatively expressed of CD34 and CD45. The proliferation of HF-MSCs and BM-MSCs was determined by means of incorporation of Brd-U, population doubling time (PDT) assays and the quantity of formazan release. The percentage of Brd-U positive cells and PDT were relatively similar in both types of cells. The proliferation, as expressed by the quantity of formazan assay in confluent cells, revealed that the quantity of release by BM-MSCs was slightly higher than HF-MSCs. Adipogenic differentiated BM-MSCs showed moderate accumulation of oil red-O stained lipid droplets when compared to that of HF-MSCs which exhibited high stain. The total lipid concentration was significantly higher in adipogenic differentiated HF-MSCs than BM-MSCs (P < 0.05). It was found that activity of bone alkaline phosphatase and calcium concentration were significantly higher (P < 0.01 and P < 0.05 respectively) in osteogenic differentiated BM-MSCs than that of HF-MSCs. The present findings demonstrate that the HF-MSCs are very similar in most tested characteristics to BM-MSCs with the exception of differentiation. Additionally; no issues have been reported during the collection of HF-MSCs. Therefore, the HF may represent a suitable and accessible source for adult stem cells and can be considered an ideal cell source for adipogenesis research.
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Affiliation(s)
- Abdel Kader A Zaki
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia.
- Department of Physiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
| | - Tariq I Almundarij
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Faten A M Abo-Aziza
- Department of Parasitology and Animal Diseases, Veterinary Research Division, National Research Centre, Cairo, Egypt
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Katou-Ichikawa C, Nishina H, Tanaka M, Takenaka S, Izawa T, Kuwamura M, Yamate J. Participation of Somatic Stem Cells, Labeled by a Unique Antibody (A3) Recognizing both N-glycan and Peptide, to Hair Follicle Cycle and Cutaneous Wound Healing in Rats. Int J Mol Sci 2020; 21:ijms21113806. [PMID: 32471256 PMCID: PMC7312608 DOI: 10.3390/ijms21113806] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 05/25/2020] [Indexed: 11/16/2022] Open
Abstract
A monoclonal antibody (A3) was generated by using rat malignant fibrous histiocytoma (MFH) cells as the antigen. Generally, MFH is considered to be a sarcoma derived from undifferentiated mesenchymal cells. Molecular biological analyses using the lysate of rat MFH cells revealed that A3 is a conformation specific antibody recognizing both N-glycan and peptide. A3-labeled cells in bone marrow were regarded as somatic stem cells, because the cells partly coexpressed CD90 and CD105 (both immature mesenchymal markers). In the hair follicle cycle, particularly the anagen, the immature epithelial cells (suprabasal cells) near the bulge and some immature mesenchymal cells in the disassembling dermal papilla and regenerating connective tissue sheath/hair papilla reacted to A3. In the cutaneous wound-healing process, A3-labeled epithelial cells participated in re-epithelialization in the wound bed, and apparently, the labeled cells were derived from the hair bulge; in addition, A3-labeled immature mesenchymal cells in the connective tissue sheath of hair follicles at the wound edge showed the expansion of the A3 immunolabeling. A3-labeled immature epithelial and mesenchymal cells contributed to morphogenesis in the hair cycle and tissue repair after a cutaneous wound. A3 could become a unique antibody to identify somatic stem cells capable of differentiating both epithelial and mesenchymal cells in rat tissues.
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Affiliation(s)
- Chisa Katou-Ichikawa
- Laboratory of Veterinary Pathology, Osaka Prefecture University, Izumisano City, Osaka 598-0048, Japan; (C.K.-I.); (H.N.); (M.T.); (T.I.); (M.K.)
| | - Hironobu Nishina
- Laboratory of Veterinary Pathology, Osaka Prefecture University, Izumisano City, Osaka 598-0048, Japan; (C.K.-I.); (H.N.); (M.T.); (T.I.); (M.K.)
| | - Miyuu Tanaka
- Laboratory of Veterinary Pathology, Osaka Prefecture University, Izumisano City, Osaka 598-0048, Japan; (C.K.-I.); (H.N.); (M.T.); (T.I.); (M.K.)
| | - Shigeo Takenaka
- Department of Clinical Nutrition, Osaka Prefecture University, Habikino City, Osaka 583-8555, Japan;
| | - Takeshi Izawa
- Laboratory of Veterinary Pathology, Osaka Prefecture University, Izumisano City, Osaka 598-0048, Japan; (C.K.-I.); (H.N.); (M.T.); (T.I.); (M.K.)
| | - Mitsuru Kuwamura
- Laboratory of Veterinary Pathology, Osaka Prefecture University, Izumisano City, Osaka 598-0048, Japan; (C.K.-I.); (H.N.); (M.T.); (T.I.); (M.K.)
| | - Jyoji Yamate
- Laboratory of Veterinary Pathology, Osaka Prefecture University, Izumisano City, Osaka 598-0048, Japan; (C.K.-I.); (H.N.); (M.T.); (T.I.); (M.K.)
- Correspondence:
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Abstract
Today, about 50% of men and 15-30% of women suffer from hair loss as well as the associated psychological impact. Drug therapy, especially through topical administration, is the main treatment strategy for stimulating hair regrowth. However, challenges exist due to the skin barrier that hinders drug penetration. To this end, many efforts have been made to enhance drug penetration efficiency. This review focuses on the advancement of the transdermal drug delivery strategies for hair loss therapy reported in the last five years, especially those via nanoformulations for topical administration and microneedles for transdermal delivery. In addition, physical or chemical penetration enhancers are also introduced, which are often applied with the drug delivery systems to achieve a synergy effect.
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Affiliation(s)
- Guang Yang
- Key Laboratory of Science & Technology of Eco-Textile, Donghua University, Ministry of Education, Shanghai 201620, China.,College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, North Ren Min Road No. 2999, Shanghai 201620, China
| | - Guojun Chen
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, California 90095, United States.,California NanoSystems Institute, Jonsson Comprehensive Cancer Center, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, Los Angeles, California 90095, United States
| | - Zhen Gu
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, California 90095, United States.,California NanoSystems Institute, Jonsson Comprehensive Cancer Center, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, Los Angeles, California 90095, United States
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Ramovs V, Krotenberg Garcia A, Song JY, de Rink I, Kreft M, Goldschmeding R, Sonnenberg A. Integrin α3β1 in hair bulge stem cells modulates CCN2 expression and promotes skin tumorigenesis. Life Sci Alliance 2020; 3:3/7/e202000645. [PMID: 32423907 PMCID: PMC7240742 DOI: 10.26508/lsa.202000645] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 05/06/2020] [Accepted: 05/06/2020] [Indexed: 12/18/2022] Open
Abstract
Although hair bulge stem cells are not the cancer cells-of-origin, they contribute to two-stage DMBA/TPA skin carcinogenesis in an α3β1-dependent manner. Epidermal-specific deletion of integrin α3β1 almost completely prevents the formation of papillomas during 7,12-Dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage skin carcinogenesis. This dramatic decrease in tumorigenesis was thought to be due to an egress and premature differentiation of α3β1-depleted hair bulge (HB) stem cells (SCs), previously considered to be the cancer cells-of-origin in the DMBA/TPA model. Using a reporter mouse line with inducible deletion of α3β1 in HBs, we show that HB SCs remain confined to their niche regardless of the presence of α3β1 and are largely absent from skin tumors. However, tumor formation was significantly decreased in mice deficient for α3β1 in HB SCs. RNA sequencing of HB SCs isolated from short-term DMBA/TPA–treated skin showed α3β1-dependent expression of the matricellular protein connective tissue growth factor (CCN2), which was confirmed in vitro, where CCN2 promoted colony formation and 3D growth of transformed keratinocytes. Together, these findings show that HBs contribute to skin tumorigenesis in an α3β1-dependent manner and suggest a role of HB SCs in creating a permissive environment for tumor growth through the modulation of CCN2 secretion.
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Affiliation(s)
- Veronika Ramovs
- Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ana Krotenberg Garcia
- Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ji-Ying Song
- Department of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Iris de Rink
- Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Maaike Kreft
- Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Roel Goldschmeding
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Arnoud Sonnenberg
- Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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40
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Li S, Hu M, Lorenz HP. Treatment of Full-Thickness Skin Wounds with Blood-Derived CD34 + Precursor Cells Enhances Healing with Hair Follicle Regeneration. Adv Wound Care (New Rochelle) 2020; 9:264-276. [PMID: 32226650 DOI: 10.1089/wound.2019.0974] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 04/23/2019] [Indexed: 10/26/2022] Open
Abstract
Objective: Epidermal CD34+ stem cells located in the hair follicle (HF) bulge area are capable of inducing HF neogenesis and enhancing wound healing after transplantation. In this study, we observed CD34+ cells derived from blood directly participate in dermal regeneration during full-thickness excisional wound healing. Approach: We isolated and in vitro expanded a subset of hematopoietic stem cell (HSC)-like precursor cells from the peripheral blood of adult mice with the surface markers: CD34+, leucine rich repeat containing G protein-coupled receptor 5 (LGR5)+, CD44+, c-kit+, lineage negative (lin-), and E-cadherin-. These blood-derived precursor cells (BDPCs), can be further differentiated into epithelial-like cells (eBDPCs) and secret fibroblast growth factor 9 (Fgf9) protein. Result: When transplanted into full-thickness skin wounds, eBDPC treatment produced accelerated healing and enhanced skin structure regeneration with less dermal scar formation. Also, HF neogenesis (HFN) was observed with incorporation of labeled BDPCs in the wound area. Innovation:Nondermal-derived CD34+ cells (BDPCs) from the adult unmobilized peripheral blood are capable of in vitro expansion and differentiation.Successful establishment of an in vitro technical platform for BDPCs expansion and differentiation.The in vitro expanded and differentiated epithelial-like cells (eBDPCs) enhance wound healing and directly contribute to skin regeneration and HFN. Conclusion: BDPCs isolated and expanded from adult peripheral blood may provide a possible new cell-based treatment strategy for HF neogenesis and skin wound regeneration.
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Affiliation(s)
- Shaowei Li
- Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California
- APstem Therapeutics, Inc., Fremont, California
| | - Min Hu
- Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California
- APstem Therapeutics, Inc., Fremont, California
| | - H. Peter Lorenz
- Division of Plastic Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California
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41
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He N, Su R, Wang Z, Zhang Y, Li J. Exploring differentially expressed genes between anagen and telogen secondary hair follicle stem cells from the Cashmere goat (Capra hircus) by RNA-Seq. PLoS One 2020; 15:e0231376. [PMID: 32298297 PMCID: PMC7162518 DOI: 10.1371/journal.pone.0231376] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 03/23/2020] [Indexed: 12/17/2022] Open
Abstract
Hair follicle stem cells (HFSCs) have been shown to be essential in the development and regeneration of hair follicles (HFs). The Inner Mongolia Cashmere goat (Capra hircus) has two types of HFs, primary and secondary, with cashmere being produced from the secondary hair follicle. To identify the genes associated with cashmere growth, transcriptome profiling of anagen and telogen secondary HFSCs was performed by RNA-Seq. The RNA-Seq analysis generated over 58 million clean reads from each group, with 2717 differentially expressed genes (DEGs) detected between anagen and telogen, including 1500 upregulated and 1217 downregulated DEGs. A large number of DEGs were predominantly associated with cell part, cellular process, binding, biological regulation and organelle. In addition, the PI3K-Akt, MAPK, Ras and Rap1 signaling pathways may be involved in the growth of HFSCs cultured in vitro. The RNA-Seq results showed that the well-defined HFSC signature genes and cell cycle-associated genes showed no significant differences between anagen and telogen HFSCs, indicating a relatively quiescent cellular state of the HFSCs cultured in vitro. These results are useful for future studies of complex molecular mechanisms of hair follicle cycling in cashmere goats.
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Affiliation(s)
- Nimantana He
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia, China
- Agriculture Research Center, Chifeng University, Chifeng, Inner Mongolia, China
| | - Rui Su
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia, China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Hohhot, Inner Mongolia Autonomous Region, China
- Key Laboratory of Mutton Sheep Genetics and Breeding, Ministry of Agriculture, Hohhot, China
- Engineering Research Center for Goat Genetics and Breeding, Hohhot, Inner Mongolia Autonomous Region, China
| | - Zhiying Wang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia, China
- Engineering Research Center for Goat Genetics and Breeding, Hohhot, Inner Mongolia Autonomous Region, China
| | - Yanjun Zhang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia, China
- Engineering Research Center for Goat Genetics and Breeding, Hohhot, Inner Mongolia Autonomous Region, China
| | - Jinquan Li
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, Inner Mongolia, China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Hohhot, Inner Mongolia Autonomous Region, China
- Key Laboratory of Mutton Sheep Genetics and Breeding, Ministry of Agriculture, Hohhot, China
- Engineering Research Center for Goat Genetics and Breeding, Hohhot, Inner Mongolia Autonomous Region, China
- * E-mail:
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Bertolini M, Ramot Y, Gherardini J, Heinen G, Chéret J, Welss T, Giesen M, Funk W, Paus R. Theophylline exerts complex anti-ageing and anti-cytotoxicity effects in human skin ex vivo. Int J Cosmet Sci 2019; 42:79-88. [PMID: 31633195 DOI: 10.1111/ics.12589] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 10/17/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Theophylline is a phosphodiesterase inhibitor that is being used clinically for asthma therapy. In addition, it is recognized as a cosmetic agent with possible anti-ageing and anti-oxidative properties. Nevertheless, how it affects human skin is still poorly examined. METHODS Theophylline (10 or 100 µM) was administered to the culture medium of full-thickness human skin ex vivo for 24 or 72 h. RESULTS Theophylline stimulated protein expression of the anti-oxidant metallothionein-1 and mRNA levels of collagen I and III. Assessment of fibrillin-1 immunohistology revealed enhanced structural stability of dermal microfibrils. Theophylline also exerted extracellular matrix-protective effects by decreasing MMP-2 and MMP-9 mRNA levels, partially antagonizing the effects of menadione, the potent, toxic ROS donor. In addition, it decreased menadione-stimulated epidermal keratinocytes apoptosis. Interestingly, theophylline also increased the level of intracutaneously produced melatonin, that is the most potent ROS-protective and DNA damage repair neuromediator, and tendentially increased protein expression of MT1, the melatonin receptor. Theophylline also increased the expression of keratin 15, the stem cell marker, in the epidermal basal layer but did not change mitochondrial activity or epidermal pigmentation. CONCLUSION This ex vivo pilot study in human skin shows that theophylline possesses several interesting complex skin-protective properties. It encourages further examination of theophylline as a topical candidate for anti-ageing treatment.
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Affiliation(s)
- M Bertolini
- Monasterium Laboratory GmbH, 48149 , Muenster, Germany
| | - Y Ramot
- Department of Dermatology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, 9112001 , Jerusalem, Israel
| | - J Gherardini
- Monasterium Laboratory GmbH, 48149 , Muenster, Germany
| | - G Heinen
- Henkel AG & Co. KGaA, 40589 , Düsseldorf, Germany
| | - J Chéret
- Monasterium Laboratory GmbH, 48149 , Muenster, Germany.,Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 33136 , Miami, FL, USA
| | - T Welss
- Henkel AG & Co. KGaA, 40589 , Düsseldorf, Germany
| | - M Giesen
- Henkel AG & Co. KGaA, 40589 , Düsseldorf, Germany
| | - W Funk
- Clinic for Plastic, Aesthetic and Reconstructive Surgery, Dr. Dr. med. Funk, 81739, Munich, Germany
| | - R Paus
- Monasterium Laboratory GmbH, 48149 , Muenster, Germany.,Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 33136 , Miami, FL, USA.,Centre for Dermatology Research, University of Manchester, M13 9PL, Manchester, UK
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Ramot Y, Bertolini M, Boboljova M, Uchida Y, Paus R. PPAR-γ signalling as a key mediator of human hair follicle physiology and pathology. Exp Dermatol 2019; 29:312-321. [PMID: 31769892 DOI: 10.1111/exd.14062] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 11/20/2019] [Accepted: 11/22/2019] [Indexed: 02/07/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are abundantly expressed in human skin, with PPAR-γ being the most intensively investigated isoform. In various ex vivo and in vivo models, PPAR-γ-mediated signalling has recently surfaced as an essential element of hair follicle (HF) development, growth and stem cell biology. Moreover, the availability of novel, topically applicable PPAR-γ modulators with a favourable toxicological profile has extended the range of potential applications in clinical dermatology. In this review, we synthesize where this field currently stands and sketch promising future research avenues, focussing on the role of PPAR-γ-mediated signalling in the biology and pathology of human scalp HFs, with special emphasis on scarring alopecias such as lichen planopilaris and frontal fibrosing alopecia as model human epithelial stem cell diseases. In particular, we discuss whether and how pharmacological modulation of PPAR-γ signalling may be employed for the management of hair growth disorders, for example, in scarring alopecia (by reducing HF inflammation as well as by promoting the survival and suppressing pathological epithelial-mesenchymal transition of keratin 15 + epithelial stem cells in the bulge) and in hirsutism/hypertrichosis (by promoting catagen development). Moreover, we explore the potential role of PPAR-γ in androgenetic alopecia, HF energy metabolism and HF ageing, and consider clinical perspectives that emanate from the limited data available on this so far. As this field of translational human hair research is still in its infancy, many open questions exist, for which we briefly delineate selected experimental approaches that promise to generate instructive answers in the near future.
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Affiliation(s)
- Yuval Ramot
- Department of Dermatology, Hadassah Medical Center, The Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Marta Bertolini
- Monasterium Laboratory, Skin and Hair Research Solutions GmbH, Muenster, Germany
| | - Maria Boboljova
- Monasterium Laboratory, Skin and Hair Research Solutions GmbH, Muenster, Germany
| | - Yoshikazu Uchida
- Monasterium Laboratory, Skin and Hair Research Solutions GmbH, Muenster, Germany
| | - Ralf Paus
- Monasterium Laboratory, Skin and Hair Research Solutions GmbH, Muenster, Germany.,Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Centre for Dermatology Research, University of Manchester, and NIHR Biomedical Research Centre, Manchester, UK
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44
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Hardman JA, Muneeb F, Pople J, Bhogal R, Shahmalak A, Paus R. Human Perifollicular Macrophages Undergo Apoptosis, Express Wnt Ligands, and Switch their Polarization during Catagen. J Invest Dermatol 2019; 139:2543-2546.e9. [DOI: 10.1016/j.jid.2019.04.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 04/03/2019] [Accepted: 04/06/2019] [Indexed: 02/06/2023]
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45
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A crucial role of fibroblast growth factor 2 in the differentiation of hair follicle stem cells toward endothelial cells in a STAT5-dependent manner. Differentiation 2019; 111:70-78. [PMID: 31715508 DOI: 10.1016/j.diff.2019.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 10/21/2019] [Accepted: 10/23/2019] [Indexed: 11/23/2022]
Abstract
Fibroblast growth factor (FGF2) is reported to affect the proliferation, differentiation, and survival abilities of stem cells. In this study, we hypothesize that FGF2 might promote the differentiation of hair follicle stem cell (HFSCs) into endothelial cells (ECs), in a manner dependent on STAT5 activation. We first treated human HFSCs with recombinant human FGF2 to determine the involvement of FGF2 in the differentiation of HFSCs. Then the expression of EC-specific markers including von Willebrand factor (vWF), VE-cadherin, CD31, FLT-1, KDR and Tie2 was evaluated using immunofluorescence and flow cytometry, while the expression of HFSC-specific markers such as K15, K19, Lgr5, Sox9 and Lhx2 was determined by flow cytometry. Next, in vitro tube formation was performed to confirm the function of FGF2, and low-density lipoprotein (LDL) uptake by ECs and HFSCs was studied by Dil-acetylated LDL assay. In addition, we transduced FGF2-treated HFSCs with constitutive-active or dominant-negative STAT5A adenovirus vectors. FGF2 up-regulated the expression of EC-specific markers, and promoted the differentiation of HFSCs into ECs, tube formation and LDL uptake. The phosphorylated STAT5 was translocated into the nucleus of HFSCs after FGF2 treatment, but this translocation was blocked by the dominant-negative STAT5A mutant. FGF2 increased the differentiation potential through the activation of STAT5 in vivo. Taken together, we find that FGF2 promotes the differentiation of HFSCs into ECs via activated STAT5, which gives a new perspective on the role of FGF2 in the development of ischemic vascular disease.
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Hawkshaw N, Hardman J, Alam M, Jimenez F, Paus R. Deciphering the molecular morphology of the human hair cycle: Wnt signalling during the telogen–anagen transformation. Br J Dermatol 2019; 182:1184-1193. [DOI: 10.1111/bjd.18356] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2019] [Indexed: 12/24/2022]
Affiliation(s)
- N.J. Hawkshaw
- Centre for Dermatology Research The University of Manchester and NIHR Biomedical Research Centre Manchester U.K
| | - J.A. Hardman
- Centre for Dermatology Research The University of Manchester and NIHR Biomedical Research Centre Manchester U.K
| | - M. Alam
- Mediteknia Skin and Hair Lab Las Palmas de Gran Canaria Spain
- Monasterium Laboratory Skin and Hair Research Solutions GmbH Münster Germany
- Universidad Fernando Pessoa‐Canarias Las Palmas de Gran Canaria Spain
| | - F. Jimenez
- Mediteknia Skin and Hair Lab Las Palmas de Gran Canaria Spain
- Universidad Fernando Pessoa‐Canarias Las Palmas de Gran Canaria Spain
| | - R. Paus
- Centre for Dermatology Research The University of Manchester and NIHR Biomedical Research Centre Manchester U.K
- Monasterium Laboratory Skin and Hair Research Solutions GmbH Münster Germany
- Dr Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami FL U.S.A
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Gago-Lopez N, Mellor LF, Megías D, Martín-Serrano G, Izeta A, Jimenez F, Wagner EF. Role of bulge epidermal stem cells and TSLP signaling in psoriasis. EMBO Mol Med 2019; 11:e10697. [PMID: 31556482 PMCID: PMC6835205 DOI: 10.15252/emmm.201910697] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 08/27/2019] [Accepted: 08/29/2019] [Indexed: 12/24/2022] Open
Abstract
Psoriasis is a common inflammatory skin disease involving a cross‐talk between epidermal and immune cells. The role of specific epidermal stem cell populations, including hair follicle stem cells (HF‐SCs) in psoriasis is not well defined. Here, we show reduced expression of c‐JUN and JUNB in bulge HF‐SCs in patients with scalp psoriasis. Using lineage tracing in mouse models of skin inflammation with inducible deletion of c‐Jun and JunB, we found that mutant bulge HF‐SCs initiate epidermal hyperplasia and skin inflammation. Mechanistically, thymic stromal lymphopoietin (TSLP) was identified in mutant cells as a paracrine factor stimulating proliferation of neighboring non‐mutant epidermal cells, while mutant inter‐follicular epidermal (IFE) cells are lost over time. Blocking TSLP in psoriasis‐like mice reduced skin inflammation and decreased epidermal proliferation, VEGFα expression, and STAT5 activation. These findings unravel distinct roles of HF‐SCs and IFE cells in inflammatory skin disease and provide novel mechanistic insights into epidermal cell interactions in inflammation.
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Affiliation(s)
- Nuria Gago-Lopez
- Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Liliana F Mellor
- Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Diego Megías
- Confocal Unit at Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | | | - Ander Izeta
- Tissue Engineering Group, Biodonostia Health Research Institute, San Sebastian, Spain
| | - Francisco Jimenez
- Grupo de Patología Médica, Mediteknia Dermatologic Clinic, Universidad Fernando Pessoa Canarias, Universidad Las Palmas Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Erwin F Wagner
- Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.,Department of Dermatology and Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
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Purba TS, Ng'andu K, Brunken L, Smart E, Mitchell E, Hassan N, O'Brien A, Mellor C, Jackson J, Shahmalak A, Paus R. CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane-induced alopecia. EMBO Mol Med 2019; 11:e11031. [PMID: 31512803 PMCID: PMC6783643 DOI: 10.15252/emmm.201911031] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 08/13/2019] [Accepted: 08/16/2019] [Indexed: 01/29/2023] Open
Abstract
Taxanes are a leading cause of severe and often permanent chemotherapy‐induced alopecia. As the underlying pathobiology of taxane chemotherapy‐induced alopecia remains poorly understood, we investigated how paclitaxel and docetaxel damage human scalp hair follicles in a clinically relevant ex vivo organ culture model. Paclitaxel and docetaxel induced massive mitotic defects and apoptosis in transit amplifying hair matrix keratinocytes and within epithelial stem/progenitor cell‐rich outer root sheath compartments, including within Keratin 15+ cell populations, thus implicating direct damage to stem/progenitor cells as an explanation for the severity and permanence of taxane chemotherapy‐induced alopecia. Moreover, by administering the CDK4/6 inhibitor palbociclib, we show that transit amplifying and stem/progenitor cells can be protected from paclitaxel cytotoxicity through G1 arrest, without premature catagen induction and additional hair follicle damage. Thus, the current study elucidates the pathobiology of taxane chemotherapy‐induced alopecia, highlights the paramount importance of epithelial stem/progenitor cell‐protective therapy in taxane‐based oncotherapy, and provides preclinical proof‐of‐principle in a healthy human (mini‐) organ that G1 arrest therapy can limit taxane‐induced tissue damage.
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Affiliation(s)
- Talveen S Purba
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Kayumba Ng'andu
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Lars Brunken
- Monasterium Laboratory - Skin & Hair Research Solutions GmbH, Münster, Germany
| | - Eleanor Smart
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Ellen Mitchell
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Nashat Hassan
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Aaron O'Brien
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Charlotte Mellor
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Jennifer Jackson
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | | | - Ralf Paus
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK.,Monasterium Laboratory - Skin & Hair Research Solutions GmbH, Münster, Germany.,Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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Panteleyev AA. Functional anatomy of the hair follicle: The Secondary Hair Germ. Exp Dermatol 2019; 27:701-720. [PMID: 29672929 DOI: 10.1111/exd.13666] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2018] [Indexed: 12/17/2022]
Abstract
The secondary hair germ (SHG)-a transitory structure in the lower portion of the mouse telogen hair follicle (HF)-is directly involved in anagen induction and eventual HF regrowth. Some crucial aspects of SHG functioning and ontogenetic relations with other HF parts, however, remain undefined. According to recent evidence (in contrast to previous bulge-centric views), the SHG is the primary target of anagen-inducing signalling and a source of both the outer root sheath (ORS) and ascending HF layers during the initial (morphogenetic) anagen subphase. The SHG is comprised of two functionally distinct cell populations. Its lower portion (originating from lower HF cells that survived catagen) forms all ascending HF layers, while the upper SHG (formed by bulge-derived cells) builds up the ORS. The predetermination of SHG cells to a specific morphogenetic fate contradicts their attribution to the "stem cell" category and supports SHG designation as a "germinative" or a "founder" cell population. The mechanisms of this predetermination driving transition of the SHG from "refractory" to the "competent" state during the telogen remain unknown. Functionally, the SHG serves as a barrier, protecting the quiescent bulge stem cell niche from the extensive follicular papilla/SHG signalling milieu. The formation of the SHG is a prerequisite for efficient "precommitment" of these cells and provides for easier sensing and a faster response to anagen-inducing signals. In general, the formation of the SHG is an evolutionary adaptation, which allowed the ancestors of modern Muridae to acquire a specific, highly synchronized pattern of hair cycling.
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Affiliation(s)
- Andrey A Panteleyev
- Kurchatov complex of NBICS Technologies, National Research Center "Kurchatov Institute", Moscow, Russia
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50
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Gentile P, Garcovich S. Advances in Regenerative Stem Cell Therapy in Androgenic Alopecia and Hair Loss: Wnt pathway, Growth-Factor, and Mesenchymal Stem Cell Signaling Impact Analysis on Cell Growth and Hair Follicle Development. Cells 2019; 8:466. [PMID: 31100937 PMCID: PMC6562814 DOI: 10.3390/cells8050466] [Citation(s) in RCA: 197] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/13/2019] [Accepted: 05/14/2019] [Indexed: 12/17/2022] Open
Abstract
The use of stem cells has been reported to improve hair regrowth in several therapeutic strategies, including reversing the pathological mechanisms, that contribute to hair loss, regeneration of hair follicles, or creating hair using the tissue-engineering approach. Although various promising stem cell approaches are progressing via pre-clinical models to clinical trials, intraoperative stem cell treatments with a one-step procedure offer a quicker result by incorporating an autologous cell source without manipulation, which may be injected by surgeons through a well-established clinical practice. Many authors have concentrated on adipose-derived stromal vascular cells due to their ability to separate into numerous cell genealogies, platelet-rich plasma for its ability to enhance cell multiplication and neo-angiogenesis, as well as human follicle mesenchymal stem cells. In this paper, the significant improvements in intraoperative stem cell approaches, from in vivo models to clinical investigations, are reviewed. The potential regenerative instruments and functions of various cell populaces in the hair regrowth process are discussed. The addition of Wnt signaling in dermal papilla cells is considered a key factor in stimulating hair growth. Mesenchymal stem cell-derived signaling and growth factors obtained by platelets influence hair growth through cellular proliferation to prolong the anagen phase (FGF-7), induce cell growth (ERK activation), stimulate hair follicle development (β-catenin), and suppress apoptotic cues (Bcl-2 release and Akt activation).
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Affiliation(s)
- Pietro Gentile
- Surgical Science Department, Plastic and Reconstructive Surgery Unit, University of "Tor Vergata", 00133 Rome, Italy.
| | - Simone Garcovich
- Institute of Dermatology, F. Policlinico Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
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