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1
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Abidi SNF, Chan S, Seidel K, Lafkas D, Vermeulen L, Peale F, Siebel CW. The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation. eLife 2024; 13:RP98747. [PMID: 39585329 PMCID: PMC11588336 DOI: 10.7554/elife.98747] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2024] Open
Abstract
The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear. While there is evidence to suggest that Notch1 is the primary Notch receptor involved in regulating the differentiation process, the ligand remains unknown. Using monoclonal therapeutic antibodies designed to specifically inhibit of each of the Notch ligands or receptors, we have identified the Jag2/Notch1 signaling axis as the primary regulator of sebocyte differentiation in mouse homeostatic skin. Mature sebocytes are lost upon specific inhibition of the Jag2 ligand or Notch1 receptor, resulting in the accumulation of proliferative stem/progenitor cells in the SG. Strikingly, this phenotype is reversible, as these stem/progenitor cells re-enter differentiation when the inhibition of Notch activity is lifted. Thus, Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation.
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Affiliation(s)
| | - Sara Chan
- Department of Research Pathology, GenentechSan FranciscoUnited States
| | - Kerstin Seidel
- Department of Discovery Oncology, GenentechSan FranciscoUnited States
| | - Daniel Lafkas
- Department of Discovery Oncology, GenentechSan FranciscoUnited States
| | - Louis Vermeulen
- Department of Discovery Oncology, GenentechSan FranciscoUnited States
| | - Frank Peale
- Department of Research Pathology, GenentechSan FranciscoUnited States
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2
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Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol 2024; 25:599-616. [PMID: 38528155 DOI: 10.1038/s41580-024-00715-1] [Citation(s) in RCA: 245] [Impact Index Per Article: 245.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2024] [Indexed: 03/27/2024]
Abstract
Wound healing is a complex process that involves the coordinated actions of many different tissues and cell lineages. It requires tight orchestration of cell migration, proliferation, matrix deposition and remodelling, alongside inflammation and angiogenesis. Whereas small skin wounds heal in days, larger injuries resulting from trauma, acute illness or major surgery can take several weeks to heal, generally leaving behind a fibrotic scar that can impact tissue function. Development of therapeutics to prevent scarring and successfully repair chronic wounds requires a fuller knowledge of the cellular and molecular mechanisms driving wound healing. In this Review, we discuss the current understanding of the different phases of wound healing, from clot formation through re-epithelialization, angiogenesis and subsequent scar deposition. We highlight the contribution of different cell types to skin repair, with emphasis on how both innate and adaptive immune cells in the wound inflammatory response influence classically studied wound cell lineages, including keratinocytes, fibroblasts and endothelial cells, but also some of the less-studied cell lineages such as adipocytes, melanocytes and cutaneous nerves. Finally, we discuss newer approaches and research directions that have the potential to further our understanding of the mechanisms underpinning tissue repair.
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Affiliation(s)
- Oscar A Peña
- School of Biochemistry, University of Bristol, Bristol, UK.
| | - Paul Martin
- School of Biochemistry, University of Bristol, Bristol, UK.
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3
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Dermitzakis I, Kampitsi DD, Manthou ME, Evangelidis P, Vakirlis E, Meditskou S, Theotokis P. Ontogeny of Skin Stem Cells and Molecular Underpinnings. Curr Issues Mol Biol 2024; 46:8118-8147. [PMID: 39194698 DOI: 10.3390/cimb46080481] [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: 06/27/2024] [Revised: 07/21/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
Skin stem cells (SCs) play a pivotal role in supporting tissue homeostasis. Several types of SCs are responsible for maintaining and regenerating skin tissue. These include bulge SCs and others residing in the interfollicular epidermis, infundibulum, isthmus, sebaceous glands, and sweat glands. The emergence of skin SCs commences during embryogenesis, where multipotent SCs arise from various precursor populations. These early events set the foundation for the diverse pool of SCs that will reside in the adult skin, ready to respond to tissue repair and regeneration demands. A network of molecular cues regulates skin SC behavior, balancing quiescence, self-renewal, and differentiation. The disruption of this delicate equilibrium can lead to SC exhaustion, impaired wound healing, and pathological conditions such as skin cancer. The present review explores the intricate mechanisms governing the development, activation, and differentiation of skin SCs, shedding light on the molecular signaling pathways that drive their fate decisions and skin homeostasis. Unraveling the complexities of these molecular drivers not only enhances our fundamental knowledge of skin biology but also holds promise for developing novel strategies to modulate skin SC fate for regenerative medicine applications, ultimately benefiting patients with skin disorders and injuries.
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Affiliation(s)
- Iasonas Dermitzakis
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Despoina Dimitria Kampitsi
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Maria Eleni Manthou
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Paschalis Evangelidis
- Hematology Unit-Hemophilia Centre, 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Efstratios Vakirlis
- First Department of Dermatology and Venereology, School of Medicine, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece
| | - Soultana Meditskou
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Paschalis Theotokis
- Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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Morgan HJ, Olivero C, Shorning BY, Gibbs A, Phillips AL, Ananthan L, Lim AXH, Martuscelli L, Borgogna C, De Andrea M, Hufbauer M, Goodwin R, Akgül B, Gariglio M, Patel GK. HPV8-induced STAT3 activation led keratinocyte stem cell expansion in human actinic keratoses. JCI Insight 2024; 9:e177898. [PMID: 38916963 PMCID: PMC11383611 DOI: 10.1172/jci.insight.177898] [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: 11/28/2023] [Accepted: 06/20/2024] [Indexed: 06/27/2024] Open
Abstract
Despite epidermal turnover, the skin is host to a complex array of microbes, including viruses, such as HPV, which must infect and manipulate skin keratinocyte stem cells (KSCs) to survive. This crosstalk between the virome and KSC populations remains largely unknown. Here, we investigated the effect of HPV8 on KSCs using various mouse models. We observed that the HPV8 early region gene E6 specifically caused Lrig1+ hair follicle junctional zone KSC proliferation and expansion, which would facilitate viral transmission. Within Lrig1+ KSCs specifically, HPV8 E6 bound intracellular p300 to phosphorylate the STAT3 transcriptional regulatory node. This induced ΔNp63 expression, resulting in KSC expansion into the overlying epidermis. HPV8 was associated with 70% of human actinic keratoses. Together, these results define the "hit-and-run" mechanism for HPV8 in human actinic keratosis as an expansion of KSCs, which lack melanosome protection and are thus susceptible to sun light-induced malignant transformation.
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Affiliation(s)
- Huw J Morgan
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Carlotta Olivero
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Boris Y Shorning
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Alex Gibbs
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Alexandra L Phillips
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Lokapriya Ananthan
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Annabelle Xiao Hui Lim
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Licia Martuscelli
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Cinzia Borgogna
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Marco De Andrea
- Viral Pathogenesis Unit, Department of Public Health and Pediatric Sciences, University of Turin Medical School, Turin, Italy
- Intrinsic Immunity Unit, Translational Research Centre for Autoimmune and Allergic Diseases, University of Eastern Piedmont, Novara, Italy
| | - Martin Hufbauer
- Institute of Virology, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany
| | - Richard Goodwin
- Department of Dermatology, Aneurin Bevan University Health Board, Royal Gwent Hospital, Newport, United Kingdom
| | - Baki Akgül
- Institute of Virology, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany
| | - Marisa Gariglio
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Girish K Patel
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
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Liu Y, Gao H, Chen H, Ji S, Wu L, Zhang H, Wang Y, Fu X, Sun X. Sebaceous gland organoid engineering. BURNS & TRAUMA 2024; 12:tkae003. [PMID: 38699464 PMCID: PMC11063650 DOI: 10.1093/burnst/tkae003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/27/2023] [Indexed: 05/05/2024]
Abstract
Sebaceous glands (SGs), as holocrine-secreting appendages, lubricate the skin and play a central role in the skin barrier. Large full-thickness skin defects cause overall architecture disruption and SG loss. However, an effective strategy for SG regeneration is lacking. Organoids are 3D multicellular structures that replicate key anatomical and functional characteristics of in vivo tissues and exhibit great potential in regenerative medicine. Recently, considerable progress has been made in developing reliable procedures for SG organoids and existing SG organoids recapitulate the main morphological, structural and functional features of their in vivo counterparts. Engineering approaches empower researchers to manipulate cell behaviors, the surrounding environment and cell-environment crosstalk within the culture system as needed. These techniques can be applied to the SG organoid culture system to generate functionally more competent SG organoids. This review aims to provide an overview of recent advancements in SG organoid engineering. It highlights some potential strategies for SG organoid functionalization that are promising to forge a platform for engineering vascularized, innervated, immune-interactive and lipogenic SG organoids. We anticipate that this review will not only contribute to improving our understanding of SG biology and regeneration but also facilitate the transition of the SG organoid from laboratory research to a feasible clinical application.
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Affiliation(s)
- Yiqiong Liu
- Research Center for Tissue Repair and Regeneration affliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, P. R. China
| | - Huanhuan Gao
- Research Center for Tissue Repair and Regeneration affliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, P. R. China
| | - Huating Chen
- Research Center for Tissue Repair and Regeneration affliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, P. R. China
| | - Shuaifei Ji
- Research Center for Tissue Repair and Regeneration affliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, P. R. China
| | - Lu Wu
- Research Center for Tissue Repair and Regeneration affliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, P. R. China
| | - Hongliang Zhang
- Research Center for Tissue Repair and Regeneration affliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, P. R. China
| | - Yujia Wang
- Queen Mary School of Nanchang University, Nanchang University, Nanchang, Jiangxi 330006, P. R. China
| | - Xiaobing Fu
- Research Center for Tissue Repair and Regeneration affliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, P. R. China
| | - Xiaoyan Sun
- Research Center for Tissue Repair and Regeneration affliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, P. R. China
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6
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Lee JH, Choi S. Deciphering the molecular mechanisms of stem cell dynamics in hair follicle regeneration. Exp Mol Med 2024; 56:110-117. [PMID: 38182654 PMCID: PMC10834421 DOI: 10.1038/s12276-023-01151-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/24/2023] [Accepted: 11/01/2023] [Indexed: 01/07/2024] Open
Abstract
Hair follicles, which are connected to sebaceous glands in the skin, undergo cyclic periods of regeneration, degeneration, and rest throughout adult life in mammals. The crucial function of hair follicle stem cells is to maintain these hair growth cycles. Another vital aspect is the activity of melanocyte stem cells, which differentiate into melanin-producing melanocytes, contributing to skin and hair pigmentation. Sebaceous gland stem cells also have a pivotal role in maintaining the skin barrier by regenerating mature sebocytes. These stem cells are maintained in a specialized microenvironment or niche and are regulated by internal and external signals, determining their dynamic behaviors in homeostasis and hair follicle regeneration. The activity of these stem cells is tightly controlled by various factors secreted by the niche components around the hair follicles, as well as immune-mediated damage signals, aging, metabolic status, and stress. In this study, we review these diverse stem cell regulatory and related molecular mechanisms of hair regeneration and disease conditions. Molecular insights would provide new perspectives on the disease mechanisms as well as hair and skin disorder treatment.
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Affiliation(s)
- Jung Hyun Lee
- Department of Dermatology, School of Medicine, University of Washington, Seattle, WA, 98109, USA
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA
| | - Sekyu Choi
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
- Medical Science and Engineering, School of Convergence Science and Technology, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
- Institute for Convergence Research and Education in Advanced Technology (I_CREATE), Yonsei University, Incheon, 21983, Republic of Korea.
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7
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Novis T, Takiya CM. Skin Resident Stem Cells. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:205-249. [DOI: 10.1016/b978-0-443-15289-4.00005-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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8
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Bai R, Guo Y, Liu W, Song Y, Yu Z, Ma X. The Roles of WNT Signaling Pathways in Skin Development and Mechanical-Stretch-Induced Skin Regeneration. Biomolecules 2023; 13:1702. [PMID: 38136575 PMCID: PMC10741662 DOI: 10.3390/biom13121702] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/10/2023] [Accepted: 11/14/2023] [Indexed: 12/24/2023] Open
Abstract
The WNT signaling pathway plays a critical role in a variety of biological processes, including development, adult tissue homeostasis maintenance, and stem cell regulation. Variations in skin conditions can influence the expression of the WNT signaling pathway. In light of the above, a deeper understanding of the specific mechanisms of the WNT signaling pathway in different physiological and pathological states of the skin holds the potential to significantly advance clinical treatments of skin-related diseases. In this review, we present a comprehensive analysis of the molecular and cellular mechanisms of the WNT signaling pathway in skin development, wound healing, and mechanical stretching. Our review sheds new light on the crucial role of the WNT signaling pathway in the regulation of skin physiology and pathology.
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Affiliation(s)
- Ruoxue Bai
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Yaotao Guo
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
- Department of The Cadet Team 6, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China
| | - Wei Liu
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Yajuan Song
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Zhou Yu
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Xianjie Ma
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
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9
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Veniaminova NA, Jia YY, Hartigan AM, Huyge TJ, Tsai SY, Grachtchouk M, Nakagawa S, Dlugosz AA, Atwood SX, Wong SY. Distinct mechanisms for sebaceous gland self-renewal and regeneration provide durability in response to injury. Cell Rep 2023; 42:113121. [PMID: 37715952 PMCID: PMC10591672 DOI: 10.1016/j.celrep.2023.113121] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 07/01/2023] [Accepted: 08/25/2023] [Indexed: 09/18/2023] Open
Abstract
Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single-cell RNA sequencing, we uncovered both direct and indirect paths by which resident SG progenitors ordinarily differentiate into sebocytes, including transit through a Krt5+PPARγ+ transitional basal cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair-follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR2 signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.
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Affiliation(s)
- Natalia A Veniaminova
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yunlong Y Jia
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA
| | - Adrien M Hartigan
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Thomas J Huyge
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shih-Ying Tsai
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Marina Grachtchouk
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Seitaro Nakagawa
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Dermatology, Department of Cutaneous Immunology and Microbiology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Andrzej A Dlugosz
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Scott X Atwood
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
| | - Sunny Y Wong
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
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10
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Raja E, Clarin MTRDC, Yanagisawa H. Matricellular Proteins in the Homeostasis, Regeneration, and Aging of Skin. Int J Mol Sci 2023; 24:14274. [PMID: 37762584 PMCID: PMC10531864 DOI: 10.3390/ijms241814274] [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: 08/31/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Matricellular proteins are secreted extracellular proteins that bear no primary structural functions but play crucial roles in tissue remodeling during development, homeostasis, and aging. Despite their low expression after birth, matricellular proteins within skin compartments support the structural function of many extracellular matrix proteins, such as collagens. In this review, we summarize the function of matricellular proteins in skin stem cell niches that influence stem cells' fate and self-renewal ability. In the epidermal stem cell niche, fibulin 7 promotes epidermal stem cells' heterogeneity and fitness into old age, and the transforming growth factor-β-induced protein ig-h3 (TGFBI)-enhances epidermal stem cell growth and wound healing. In the hair follicle stem cell niche, matricellular proteins such as periostin, tenascin C, SPARC, fibulin 1, CCN2, and R-Spondin 2 and 3 modulate stem cell activity during the hair cycle and may stabilize arrector pili muscle attachment to the hair follicle during piloerections (goosebumps). In skin wound healing, matricellular proteins are upregulated, and their functions have been examined in various gain-and-loss-of-function studies. However, much remains unknown concerning whether these proteins modulate skin stem cell behavior, plasticity, or cell-cell communications during wound healing and aging, leaving a new avenue for future studies.
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Affiliation(s)
- Erna Raja
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; (E.R.); (M.T.R.D.C.C.)
| | - Maria Thea Rane Dela Cruz Clarin
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; (E.R.); (M.T.R.D.C.C.)
- Ph.D. Program in Humanics, School of Integrative and Global Majors (SIGMA), University of Tsukuba, Tsukuba 305-8577, Japan
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan; (E.R.); (M.T.R.D.C.C.)
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11
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Veniaminova NA, Jia Y, Hartigan AM, Huyge TJ, Tsai SY, Grachtchouk M, Nakagawa S, Dlugosz AA, Atwood SX, Wong SY. Distinct mechanisms for sebaceous gland self-renewal and regeneration provide durability in response to injury. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.05.539454. [PMID: 37205445 PMCID: PMC10187279 DOI: 10.1101/2023.05.05.539454] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single cell RNA-sequencing, we uncovered both direct and indirect paths by which these resident SG progenitors ordinarily differentiate into sebocytes, including transit through a PPARγ+Krt5+ transitional cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.
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Affiliation(s)
- Natalia A. Veniaminova
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yunlong Jia
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA
| | - Adrien M. Hartigan
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Thomas J. Huyge
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shih-Ying Tsai
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Marina Grachtchouk
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Seitaro Nakagawa
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Andrzej A. Dlugosz
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Scott X. Atwood
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA
| | - Sunny Y. Wong
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Lead Contact:
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12
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Lim SBH, Wei S, Tan AHM, van Steensel MAM, Lim X. Lrig1-expressing epidermal progenitors require SCD1 to maintain the dermal papilla niche. Sci Rep 2023; 13:4027. [PMID: 36899019 PMCID: PMC10006094 DOI: 10.1038/s41598-023-30411-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 02/22/2023] [Indexed: 03/12/2023] Open
Abstract
Niche cells are widely known to regulate stem/progenitor cells in many mammalian tissues. In the hair, dermal papilla niche cells are well accepted to regulate hair stem/progenitor cells. However, how niche cells themselves are maintained is largely unknown. We present evidence implicating hair matrix progenitors and the lipid modifying enzyme, Stearoyl CoA Desaturase 1, in the regulation of the dermal papilla niche during the anagen-catagen transition of the mouse hair cycle. Our data suggest that this takes place via autocrine Wnt signalling and paracrine Hedgehog signalling. To our knowledge, this is the first report demonstrating a potential role for matrix progenitor cells in maintaining the dermal papilla niche.
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Affiliation(s)
- Sophia Beng Hui Lim
- Institute of Medical Biology (IMB) / Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A*STAR), 11 Mandalay Road, Clinical Sciences Building #17-01, Singapore, 308232, Republic of Singapore
- NUS Graduate School, National University of Singapore, Singapore, 119077, Republic of Singapore
| | - Shang Wei
- Institute of Medical Biology (IMB) / Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A*STAR), 11 Mandalay Road, Clinical Sciences Building #17-01, Singapore, 308232, Republic of Singapore
| | - Andy Hee-Meng Tan
- Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Centros, Singapore, 138668, Republic of Singapore
| | - Maurice A M van Steensel
- Institute of Medical Biology (IMB) / Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A*STAR), 11 Mandalay Road, Clinical Sciences Building #17-01, Singapore, 308232, Republic of Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore, 308232, Republic of Singapore
| | - Xinhong Lim
- Institute of Medical Biology (IMB) / Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A*STAR), 11 Mandalay Road, Clinical Sciences Building #17-01, Singapore, 308232, Republic of Singapore.
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13
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Zouboulis CC, Coenye T, He L, Kabashima K, Kobayashi T, Niemann C, Nomura T, Oláh A, Picardo M, Quist SR, Sasano H, Schneider MR, Törőcsik D, Wong SY. Sebaceous immunobiology - skin homeostasis, pathophysiology, coordination of innate immunity and inflammatory response and disease associations. Front Immunol 2022; 13:1029818. [PMID: 36439142 PMCID: PMC9686445 DOI: 10.3389/fimmu.2022.1029818] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 10/17/2022] [Indexed: 08/01/2023] Open
Abstract
This review presents several aspects of the innovative concept of sebaceous immunobiology, which summarizes the numerous activities of the sebaceous gland including its classical physiological and pathophysiological tasks, namely sebum production and the development of seborrhea and acne. Sebaceous lipids, which represent 90% of the skin surface lipids in adolescents and adults, are markedly involved in the skin barrier function and perifollicular and dermal innate immune processes, leading to inflammatory skin diseases. Innovative experimental techniques using stem cell and sebocyte models have clarified the roles of distinct stem cells in sebaceous gland physiology and sebocyte function control mechanisms. The sebaceous gland represents an integral part of the pilosebaceous unit and its status is connected to hair follicle morphogenesis. Interestingly, professional inflammatory cells contribute to sebocyte differentiation and homeostasis, whereas the regulation of sebaceous gland function by immune cells is antigen-independent. Inflammation is involved in the very earliest differentiation changes of the pilosebaceous unit in acne. Sebocytes behave as potent immune regulators, integrating into the innate immune responses of the skin. Expressing inflammatory mediators, sebocytes also contribute to the polarization of cutaneous T cells towards the Th17 phenotype. In addition, the immune response of the perifollicular infiltrate depends on factors produced by the sebaceous glands, mostly sebaceous lipids. Human sebocytes in vitro express functional pattern recognition receptors, which are likely to interact with bacteria in acne pathogenesis. Sex steroids, peroxisome proliferator-activated receptor ligands, neuropeptides, endocannabinoids and a selective apoptotic process contribute to a complex regulation of sebocyte-induced immunological reaction in numerous acquired and congenital skin diseases, including hair diseases and atopic dermatitis.
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Affiliation(s)
- Christos C. Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany
| | - Tom Coenye
- Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium
| | - Li He
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tetsuro Kobayashi
- Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, Japan
| | - Catherin Niemann
- Center for Molecular Medicine Cologne, CMMC Research Institute, University of Cologne, Cologne, Germany
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Takashi Nomura
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Attila Oláh
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Mauro Picardo
- San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
| | - Sven R. Quist
- Department of Dermatology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Hironobu Sasano
- Department of Pathology, Tohoku University School of Medicine, Sendai, Japan
| | - Marlon R. Schneider
- Institute of Veterinary Physiology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany
| | - Daniel Törőcsik
- Department of Dermatology, Faculty of Medicine, University of Debrecen and ELKH-DE Allergology Research Group, Debrecen, Hungary
| | - Sunny Y. Wong
- Departments of Dermatology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, United States
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14
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Hosseini M, Koehler KR, Shafiee A. Biofabrication of Human Skin with Its Appendages. Adv Healthc Mater 2022; 11:e2201626. [PMID: 36063498 PMCID: PMC11469047 DOI: 10.1002/adhm.202201626] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/30/2022] [Indexed: 01/28/2023]
Abstract
Much effort has been made to generate human skin organ in the laboratory. Yet, the current models are limited due to the lack of many critical biological and structural features of the skin. Importantly, these in vitro models lack appendages and fail to recapitulate the whole human skin construction. Thus, engineering a human skin with the capacity to generate all components, including appendages, is a major challenge. This review intends to provide an update on the recent efforts underway to regenerate appendage-bearing skin organs based on scaffold-free and scaffold-based bioengineering approaches. Although the mouse skin equivalents containing hair follicles, sebaceous glands, and sweat glands have been established in vitro, there has been limited success in humans. A combination of biofabricated matrices and cell aggregates, such as organoids, can pave the way for generating skin substitutes with human-like biological, structural, and physical features. Accordingly, the formation of human skin organoids and reconstruction of vascularized skin equipped with immune cells prompt calls for more scientific research. The generation of appendage-bearing skin substitutes can be applied in practice for wound healing, hair restoration, and scar treatment.
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Affiliation(s)
- Motaharesadat Hosseini
- School of MechanicalMedical and Process EngineeringFaculty of EngineeringQueensland University of TechnologyBrisbaneQLD4059Australia
- ARC Industrial Transformation Training Centre for Multiscale 3D Imaging, Modelling and Manufacturing (M3D)Queensland University of TechnologyBrisbaneQLD4059Australia
| | - Karl R. Koehler
- Department of Otolaryngology‐Head and Neck SurgeryHarvard Medical SchoolBostonMA02115USA
- Department of OtolaryngologyBoston Children's HospitalBostonMA02115USA
| | - Abbas Shafiee
- Herston Biofabrication InstituteMetro North Hospital and Health ServiceBrisbaneQLD4029Australia
- Royal Brisbane and Women's HospitalMetro North Hospital and Health ServiceBrisbaneQLD4029Australia
- The University of Queensland Diamantina InstituteTranslational Research InstituteThe University of QueenslandBrisbaneQLD4102Australia
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15
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Hou X, Wei Z, Zouboulis CC, Ju Q. Aging in the sebaceous gland. Front Cell Dev Biol 2022; 10:909694. [PMID: 36060807 PMCID: PMC9428133 DOI: 10.3389/fcell.2022.909694] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Sebaceous glands (SGs) originate from hair follicular stem cells and secrete lipids to lubricate the skin. The coordinated effects of intrinsic and extrinsic aging factors generate degradation of SGs at a late age. Senescence of SGs could be a mirror of the late aging of both the human body and skin. The procedure of SG aging goes over an initial SG hyperplasia at light-exposed skin areas to end with SG atrophy, decreased sebum secretion, and altered sebum composition, which is related to skin dryness, lack of brightness, xerosis, roughness, desquamation, and pruritus. During differentiation and aging of SGs, many signaling pathways, such as Wnt/β-catenin, c-Myc, aryl hydrocarbon receptor (AhR), and p53 pathways, are involved. Random processes lead to random cell and DNA damage due to the production of free radicals during the lifespan and neuroendocrine system alterations. Extrinsic factors include sunlight exposure (photoaging), environmental pollution, and cigarette smoking, which can directly activate signaling pathways, such as Wnt/β-catenin, Notch, AhR, and p53 pathways, and are probably associated with the de-differentiation and hyperplasia of SGs, or indirectly activate the abovementioned signaling pathways by elevating the inflammation level. The production of ROS during intrinsic SG aging is less, the signaling pathways are activated slowly and mildly, and sebocytes are still differentiated, yet terminal differentiation is not completed. With extrinsic factors, relevant signaling pathways are activated rapidly and fiercely, thus inhibiting the differentiation of progenitor sebocytes and even inducing the differentiation of progenitor sebocytes into keratinocytes. The management of SG aging is also mentioned.
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Affiliation(s)
- Xiaoxiao Hou
- Department of Dermatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany
- Berlin Brandenburg Center for Regenerative Therapies, Charite Universitatsmedizin Berlin, Berlin, Germany
| | - Ziyu Wei
- Genetic Skin Disease Center, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Christos C Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany
- *Correspondence: Christos C Zouboulis, ; Qiang Ju,
| | - Qiang Ju
- Department of Dermatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- *Correspondence: Christos C Zouboulis, ; Qiang Ju,
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16
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Shi R, Li S, Liu P, Guo L, Gong S, Wan Y. Effects of testosterone on skin structure and factors related to androgen conversion and binding in Hetian sheep. Trop Anim Health Prod 2022; 54:218. [PMID: 35759149 DOI: 10.1007/s11250-022-03216-5] [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: 12/23/2021] [Accepted: 06/18/2022] [Indexed: 12/06/2022]
Abstract
The effects of androgens on human skin mainly include the regulation of growth and differentiation of hair follicles and sebaceous glands. Androgens may have some physiological roles in sheep skin that are similar to those of humans, but further confirmation is needed. Therefore, Hetian sheep were chosen in this study as an animal model to explore the effects of testosterone on skin structure and factors related to androgen conversion and binding in Hetian sheep. The sheep were treated with different concentrations of testosterone for 42 days. Skin tissue sections were prepared and then subjected to hematoxylin-eosin, Sacpic, Masson's trichrome, and Oil Red O staining to observe changes in skin morphology. Changes in the content of blood-related factors were also detected using ELISA kits. The skin tissue distribution of androgen receptor was explored by immunohistochemistry and immunofluorescence assays. The results showed that testosterone significantly increases the sebaceous gland area and stimulates the formation of new sebaceous glands. Further exploration revealed that testosterone promotes the proliferation of sebaceous gland juvenile cells. However, testosterone was found to have no significant effect on hair follicle density and hair follicle structure. Testosterone increased dihydrotestosterone levels but decreased 5α-reductase 1 and 5α-reductase 2 levels. The androgen receptors were distributed in the hair follicles, sebaceous glands, and some major skin appendages of Hetian sheep. This study suggests that androgens can be effective in regulating sebum production in sheep. This study will help advance research efforts to further explore the molecular and cellular mechanisms by which androgens modify sheep follicles and sebaceous glands.
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Affiliation(s)
- Ruijun Shi
- Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Science and Technology, Tarim University, Alar, Xinjiang, China
| | - Shuwei Li
- Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Science and Technology, Tarim University, Alar, Xinjiang, China.
| | - Penggang Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China
| | - Lili Guo
- Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Science and Technology, Tarim University, Alar, Xinjiang, China
| | - Shujuan Gong
- Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Science and Technology, Tarim University, Alar, Xinjiang, China
| | - Yu Wan
- Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Science and Technology, Tarim University, Alar, Xinjiang, China
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17
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Tao K, Bai X, Ji P, Zhang Y, Cao T, Han F, Zhang Z, Guan H, Hu D. A composite of hepatocyte growth factor and 5α-dihydrotestosterone-gelatin microspheres with adipose-derived stem cells enhances wound healing. Skin Pharmacol Physiol 2022; 35:206-214. [PMID: 35439758 DOI: 10.1159/000524188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 12/15/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Reconstructing sebaceous glands is one goal of functionally healing patients who have suffered severe burns, instead of the simple pursuit of wound closure. Effective regeneration of skin appendages remains a challenge in skin wound management and research. OBJECTIVE The aim of this study was to evaluate the differentiation of ADSC into sebaceous glands, and clarified the involvement of HGF and 5α-DHT in this process. METHODS This study used hepatocyte growth factor (HGF)- and 5α-dihydrotestosterone (5α-DHT)-gelatin microspheres to treat human adipose-derived stem cells (ADSCs) and investigated the reconstruction of sebaceous glands. HGF- and 5α-DHT-gelatin microspheres were constructed using microcapsule slow-release technology. Mice full-thickness skin-wound model was established to evaluate wound healing and hematoxylin-eosin staining was utilized to determine the skin structure. RESULTS In vitro analyses found that HGF- and 5α-DHT-gelatin microspheres promoted migration of and tube formation by ADSCs. Furthermore, AKT/ERK signaling, which is related to sebocyte and sweat gland epithelial cell growth, were activated after HGF and 5α-DHT treatment. An in vivo wound healing model demonstrated that ADSCs primed with amnion-loaded HGF- and 5α-DHT-gelatin microspheres promoted wound healing and increased sebaceous gland formation compared to the control group. CONCLUSIONS This study confirms the efficacy of ADSCs treated with amnion and HGF- and 5α-DHT-gelatin microspheres in accelerating wound healing and effectively restoring sebaceous glands. This engineered tissue provides insight into and a novel therapeutic material for burns and full-thickness skin wounds.¬¬.
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Affiliation(s)
- Ke Tao
- Department of Burn Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiaozhi Bai
- Department of Burn Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Peng Ji
- Department of Burn Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yue Zhang
- Department of Burn Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Tao Cao
- Department of Burn Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Fu Han
- Department of Burn Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhi Zhang
- Department of Burn Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Hao Guan
- Department of Burn Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Dahai Hu
- Department of Burn Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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18
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Applications of Stem Cell Therapy and Adipose-Derived Stem Cells for Skin Repair. CURRENT DERMATOLOGY REPORTS 2022. [DOI: 10.1007/s13671-022-00357-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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19
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Ferredoxin reductase regulates proliferation, differentiation, cell cycle and lipogenesis but not apoptosis in SZ95 sebocytes. Exp Cell Res 2021; 405:112680. [PMID: 34090862 DOI: 10.1016/j.yexcr.2021.112680] [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: 10/24/2020] [Revised: 05/07/2021] [Accepted: 05/28/2021] [Indexed: 01/14/2023]
Abstract
Ferredoxin reductase (FDXR), a mitochondrial membrane-associated flavoprotein, is essential for electron transfer and modulates p53-dependent apoptosis in cancer cells.FDXR may be implicated in epidermal and sebocytic differentiation, but its explicit function in sebocytes remains to be elucidated. In the present study, immunohistochemistry revealed that FDXR expression was increased in sebaceous cells of acne lesions. FDXR, PPARγ, LXRα/β, SREBP1 and Sox9 expression was incremental during sebocyte differentiation. FDXR overexpression induced by Ad-GFP-FDXR infection enhanced differentiation, reactive oxygen species (ROS), lipogenesis and PPARγ expression, and consequnently inhibited proliferation in SZ95 sebocytes. Flow cytometry showed that FDXR overexpression induced significant blockade of G2/M phase but had no effect on sub-G1 (apoptotic) sebocytes. Insulin-like growth factor-1 (IGF-1)-induced FDXR and PPARγ expression and lipogenesis were abolished by pretreatment with PI3K inhibitor LY294002. These results suggest that FDXR overexpression might promote differentiation and lipogenesis via ROS production and suppress proliferation via G2/S blockade in SZ95 sebocytes. IGF-1 could facilitate differentiation and lipogenesis through PI3K/Akt/FDXR pathway. FDXR could serve as a potential marker of advanced sebaceous differentiation, and its overexpression may be involved in the development of acne lesions.
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20
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Geueke A, Niemann C. Stem and progenitor cells in sebaceous gland development, homeostasis and pathologies. Exp Dermatol 2021; 30:588-597. [PMID: 33599012 DOI: 10.1111/exd.14303] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/04/2021] [Accepted: 02/14/2021] [Indexed: 12/11/2022]
Abstract
Sebaceous glands (SGs), typically associated with hair follicles, are critical for the homeostasis and function of mammalian skin. The main physiological function of SGs is the production and holocrine secretion of sebum to lubricate and protect the skin. Defective SGs have been linked to a variety of skin disorders, including acne, seborrheic dermatitis and formation of sebaceous tumors. Thus, a better understanding how SGs are formed and maintained is important to unravel the underlying molecular and cellular mechanisms of SG pathologies and to find better and effective therapies. Over the last two decades, research has come a long way from the initial identification of skin epithelial stem cells to the isolation and functional characterization of multiple stem cell pools as well as a better understanding of their unique and complex activities that drive skin homeostasis and operate in skin pathologies. Here, we discuss recent progress in unravelling cellular mechanisms underlying SG development, homeostasis and sebaceous tumor formation and assess the role of stem and progenitor cells in controlling SG physiology and disease processes. The development of elegant in vivo imaging as well as various in vitro and ex vivo stem cell and SG tissue models will advance mechanistic studies on SG function and allow drug screening and testing for efficient and successful targeting SG pathologies.
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Affiliation(s)
- Anna Geueke
- Center for Molecular Medicine Cologne, CMMC Research Institute, University of Cologne, Cologne, Germany
| | - Catherin Niemann
- Center for Molecular Medicine Cologne, CMMC Research Institute, University of Cologne, Cologne, Germany.,Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
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21
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Boecker W, Reusch M, Mielke V, Reusch U, Hallermann C, Loening T, Tiemann M, Buchwalow I. Twenty-Eight Cases of Extraocular Sebaceous Carcinoma: A Correlative Clinicopathological and Immunohistochemical Analysis of Extraocular Sebaceous Carcinomas and Benign Sebaceous Gland Tumors. Am J Dermatopathol 2021; 43:93-102. [PMID: 32568835 DOI: 10.1097/dad.0000000000001667] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
ABSTRACT Extraocular sebaceous carcinoma (ESC) is a rare appendiceal skin tumor. In contrast to ocular sebaceous carcinoma, information about the exact cellular architecture of these lesions is scarce and the histogenesis of ESC is unknown. Here, we extend our previous study and investigate 28 extraocular carcinomas in comparison to 54 benign sebaceous tumors and 8 cases of normal sebaceous glands using a broad spectrum of antibodies against p63, several keratins, adipophilin, EMA, Ki67, androgen receptor, and mismatch repair proteins. This observational study demonstrates that p63- and K5/14-positive basaloid cells are key cells in normal sebaceous gland and in all sebaceous tumors and that these basaloid cells give rise to EMA+, adipophilin+ sebocytes, and K5/14+, K7±, K10± ductal structures. Finally, about half of ESC is associated with superficial in situ neoplasia, which provides evidence that at least part of these carcinomas arises from flat superficial in situ carcinoma. In contrast to the normal sebaceous gland, about half of all sebaceous tumors lack keratin K7. MMR protein IHC-profiles role will be discussed.
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Affiliation(s)
- Werner Boecker
- Gerhard-Domagk-Institute of Pathology, University of Muenster, Münster, Germany
- Dermatopathology Laboratory, Hamburg, Germany
- Gerhard-Seifert Referenzzentrum, Hamburg, Germany; and
| | | | | | | | | | | | | | - Igor Buchwalow
- Gerhard-Domagk-Institute of Pathology, University of Muenster, Münster, Germany
- Institute for Hematopathology, Hamburg, Germany
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22
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Development and Maintenance of Epidermal Stem Cells in Skin Adnexa. Int J Mol Sci 2020; 21:ijms21249736. [PMID: 33419358 PMCID: PMC7766199 DOI: 10.3390/ijms21249736] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/18/2020] [Accepted: 12/18/2020] [Indexed: 01/10/2023] Open
Abstract
The skin surface is modified by numerous appendages. These structures arise from epithelial stem cells (SCs) through the induction of epidermal placodes as a result of local signalling interplay with mesenchymal cells based on the Wnt–(Dkk4)–Eda–Shh cascade. Slight modifications of the cascade, with the participation of antagonistic signalling, decide whether multipotent epidermal SCs develop in interfollicular epidermis, scales, hair/feather follicles, nails or skin glands. This review describes the roles of epidermal SCs in the development of skin adnexa and interfollicular epidermis, as well as their maintenance. Each skin structure arises from distinct pools of epidermal SCs that are harboured in specific but different niches that control SC behaviour. Such relationships explain differences in marker and gene expression patterns between particular SC subsets. The activity of well-compartmentalized epidermal SCs is orchestrated with that of other skin cells not only along the hair cycle but also in the course of skin regeneration following injury. This review highlights several membrane markers, cytoplasmic proteins and transcription factors associated with epidermal SCs.
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23
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Zouboulis CC, Yoshida GJ, Wu Y, Xia L, Schneider MR. Sebaceous gland: Milestones of 30‐year modelling research dedicated to the “brain of the skin”. Exp Dermatol 2020; 29:1069-1079. [DOI: 10.1111/exd.14184] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/13/2020] [Accepted: 08/21/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Christos C. Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology Dessau Medical Center Brandenburg Medical School Theodore Fontane and Faculty of Health Sciences Brandenburg Dessau Germany
| | - Go J. Yoshida
- Department of Immunological Diagnosis Juntendo University School of Medicine Bunkyo‐ku, Tokyo Japan
| | - Yaojiong Wu
- Shenzhen Key Laboratory of Health Sciences and Technology Tsinghua Shenzhen International Graduate School and Tsinghua‐Berkeley Shenzhen Institute Tsinghua University Beijing China
| | - Longqing Xia
- Department of Dermatology Renji Hospital School of Medicine Shanghai Jiaotong University Shanghai China
| | - Marlon R. Schneider
- German Federal Institute for Risk Assessment (BfR) German Centre for the Protection of Laboratory Animals (Bf3R) Berlin Germany
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24
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Saxena N, Mok KW, Rendl M. An updated classification of hair follicle morphogenesis. Exp Dermatol 2020; 28:332-344. [PMID: 30887615 DOI: 10.1111/exd.13913] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/13/2019] [Indexed: 12/12/2022]
Abstract
Hair follicle (HF) formation in developing embryonic skin requires stepwise signalling between the epithelial epidermis and mesenchymal dermis, and their specialized derivatives, the placode/germ/peg and dermal condensate/papilla, respectively. Classically, distinct stages of HF morphogenesis have been defined, in the mouse model, based on (a) changes in cell morphology and aggregation; (b) expression of few known molecular markers; (c) the extent of follicle downgrowth; and (d) the presence of differentiating cell types. Refined genetic strategies and recent emerging technologies, such as live imaging and transcriptome analyses of isolated cell populations or single cells, have enabled a closer dissection of the signalling requirements at different stages of HF formation, particularly early on. They have also led to the discovery of precursor cells for placode, dermal condensate and future bulge stem cells that, combined with molecular insights into their fate specification and subsequent formation, serve as novel landmarks for early HF morphogenetic events and studies of the signalling networks mediating these processes. In this review, we integrate the emergence of HF precursor cell states and novel molecular markers of fate and formation to update the widely used 20-year-old seminal classification guide of HF morphogenetic stages by Paus et al. We then temporally describe the latest insights into the early cellular and molecular events and signalling requirements for HF morphogenesis in relation to one another in a holistic manner.
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Affiliation(s)
- Nivedita Saxena
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York.,Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York.,Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ka-Wai Mok
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York.,Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Michael Rendl
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York.,Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York.,Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.,Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York
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25
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Horsley V. Lifting Each Other Up: Epidermal Stem Cells in Tissue Homeostasis. Dev Cell 2020; 51:296-298. [PMID: 31689385 DOI: 10.1016/j.devcel.2019.10.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Multiple stem cells maintain and repair tissues, yet how they communicate is not well understood. In this issue of Developmental Cell, Veniaminova et al. (2019) report that each sebaceous gland is maintained by local stem cells and that Notch signaling regulates multiple aspects of their function, revealing tissue homeostasis mechanisms.
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Affiliation(s)
- Valerie Horsley
- Department of Molecular, Cellular, and Developmental Biology and Department of Dermatology, Yale University, 219 Prospect Street, New Haven, CT 06520, USA.
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26
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Weng T, Wu P, Zhang W, Zheng Y, Li Q, Jin R, Chen H, You C, Guo S, Han C, Wang X. Regeneration of skin appendages and nerves: current status and further challenges. J Transl Med 2020; 18:53. [PMID: 32014004 PMCID: PMC6996190 DOI: 10.1186/s12967-020-02248-5] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 01/28/2020] [Indexed: 12/14/2022] Open
Abstract
Tissue-engineered skin (TES), as an analogue of native skin, is promising for wound repair and regeneration. However, a major drawback of TES products is a lack of skin appendages and nerves to enhance skin healing, structural integrity and skin vitality. Skin appendages and nerves are important constituents for fully functional skin. To date, many studies have yielded remarkable results in the field of skin appendages reconstruction and nerve regeneration. However, patients often complain about a loss of skin sensation and even cutaneous chronic pain. Restoration of pain, temperature, and touch perceptions should now be a major challenge to solve in order to improve patients’ quality of life. Current strategies to create skin appendages and sensory nerve regeneration are mainly based on different types of seeding cells, scaffold materials, bioactive factors and involved signaling pathways. This article provides a comprehensive overview of different strategies for, and advances in, skin appendages and sensory nerve regeneration, which is an important issue in the field of tissue engineering and regenerative medicine.
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Affiliation(s)
- Tingting Weng
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Pan Wu
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Wei Zhang
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Yurong Zheng
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China
| | - Qiong Li
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Ronghua Jin
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Haojiao Chen
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Chuangang You
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Songxue Guo
- Department of Plastic Surgery, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310009, China
| | - Chunmao Han
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China
| | - Xingang Wang
- Department of Burns & Wound Care Center, Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, 310009, China.
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27
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Clayton RW, Langan EA, Ansell DM, de Vos IJHM, Göbel K, Schneider MR, Picardo M, Lim X, van Steensel MAM, Paus R. Neuroendocrinology and neurobiology of sebaceous glands. Biol Rev Camb Philos Soc 2020; 95:592-624. [PMID: 31970855 DOI: 10.1111/brv.12579] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 12/17/2019] [Accepted: 12/19/2019] [Indexed: 12/11/2022]
Abstract
The nervous system communicates with peripheral tissues through nerve fibres and the systemic release of hypothalamic and pituitary neurohormones. Communication between the nervous system and the largest human organ, skin, has traditionally received little attention. In particular, the neuro-regulation of sebaceous glands (SGs), a major skin appendage, is rarely considered. Yet, it is clear that the SG is under stringent pituitary control, and forms a fascinating, clinically relevant peripheral target organ in which to study the neuroendocrine and neural regulation of epithelia. Sebum, the major secretory product of the SG, is composed of a complex mixture of lipids resulting from the holocrine secretion of specialised epithelial cells (sebocytes). It is indicative of a role of the neuroendocrine system in SG function that excess circulating levels of growth hormone, thyroxine or prolactin result in increased sebum production (seborrhoea). Conversely, growth hormone deficiency, hypothyroidism, and adrenal insufficiency result in reduced sebum production and dry skin. Furthermore, the androgen sensitivity of SGs appears to be under neuroendocrine control, as hypophysectomy (removal of the pituitary) renders SGs largely insensitive to stimulation by testosterone, which is crucial for maintaining SG homeostasis. However, several neurohormones, such as adrenocorticotropic hormone and α-melanocyte-stimulating hormone, can stimulate sebum production independently of either the testes or the adrenal glands, further underscoring the importance of neuroendocrine control in SG biology. Moreover, sebocytes synthesise several neurohormones and express their receptors, suggestive of the presence of neuro-autocrine mechanisms of sebocyte modulation. Aside from the neuroendocrine system, it is conceivable that secretion of neuropeptides and neurotransmitters from cutaneous nerve endings may also act on sebocytes or their progenitors, given that the skin is richly innervated. However, to date, the neural controls of SG development and function remain poorly investigated and incompletely understood. Botulinum toxin-mediated or facial paresis-associated reduction of human sebum secretion suggests that cutaneous nerve-derived substances modulate lipid and inflammatory cytokine synthesis by sebocytes, possibly implicating the nervous system in acne pathogenesis. Additionally, evidence suggests that cutaneous denervation in mice alters the expression of key regulators of SG homeostasis. In this review, we examine the current evidence regarding neuroendocrine and neurobiological regulation of human SG function in physiology and pathology. We further call attention to this line of research as an instructive model for probing and therapeutically manipulating the mechanistic links between the nervous system and mammalian skin.
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Affiliation(s)
- Richard W Clayton
- Centre for Dermatology, School of Biological Sciences, University of Manchester, and NIHR Manchester Biomedical Research Centre, Stopford Building, Oxford Road, Manchester, M13 9PT, U.K.,Skin Research Institute of Singapore, Agency for Science, Technology and Research, 11 Mandalay Road, #17-01 Clinical Sciences Building, 308232, Singapore
| | - Ewan A Langan
- Centre for Dermatology, School of Biological Sciences, University of Manchester, and NIHR Manchester Biomedical Research Centre, Stopford Building, Oxford Road, Manchester, M13 9PT, U.K.,Department of Dermatology, Allergology und Venereology, University of Lübeck, Ratzeburger Allee 160, Lübeck, 23538, Germany
| | - David M Ansell
- Centre for Dermatology, School of Biological Sciences, University of Manchester, and NIHR Manchester Biomedical Research Centre, Stopford Building, Oxford Road, Manchester, M13 9PT, U.K.,Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, U.K
| | - Ivo J H M de Vos
- Skin Research Institute of Singapore, Agency for Science, Technology and Research, 11 Mandalay Road, #17-01 Clinical Sciences Building, 308232, Singapore
| | - Klaus Göbel
- Skin Research Institute of Singapore, Agency for Science, Technology and Research, 11 Mandalay Road, #17-01 Clinical Sciences Building, 308232, Singapore.,Department of Dermatology, Cologne Excellence Cluster on Stress Responses in Aging Associated Diseases (CECAD), and Centre for Molecular Medicine Cologne, The University of Cologne, Joseph-Stelzmann-Straße 26, Cologne, 50931, Germany
| | - Marlon R Schneider
- German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Straße 8-10, Berlin, 10589, Germany
| | - Mauro Picardo
- Cutaneous Physiopathology and Integrated Centre of Metabolomics Research, San Gallicano Dermatological Institute IRCCS, Via Elio Chianesi 53, Rome, 00144, Italy
| | - Xinhong Lim
- Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore
| | - Maurice A M van Steensel
- Skin Research Institute of Singapore, Agency for Science, Technology and Research, 11 Mandalay Road, #17-01 Clinical Sciences Building, 308232, Singapore.,Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore
| | - Ralf Paus
- Centre for Dermatology, School of Biological Sciences, University of Manchester, and NIHR Manchester Biomedical Research Centre, Stopford Building, Oxford Road, Manchester, M13 9PT, U.K.,Dr. Phllip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB 2023A, Miami, FL, 33136, U.S.A.,Monasterium Laboratory, Mendelstraße 17, Münster, 48149, Germany
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28
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27 TH Fondation René Touraine Annual SCIENTIFIC MEETING 2019: Skin Appendages - Developmental and Pathophysiological Aspects. Exp Dermatol 2019; 28:1353-1367. [PMID: 31854035 DOI: 10.1111/exd.14039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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29
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Holocrine Secretion Occurs outside the Tight Junction Barrier in Multicellular Glands: Lessons from Claudin-1-Deficient Mice. J Invest Dermatol 2019; 140:298-308.e5. [PMID: 31445004 DOI: 10.1016/j.jid.2019.06.150] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 05/28/2019] [Accepted: 06/10/2019] [Indexed: 10/26/2022]
Abstract
Holocrine secretion is a specific mode of secretion involving secretion of entire cytoplasmic materials with remnants of dead cells, as observed in multicellular exocrine glands of reptiles, birds, and mammals. Here, we found that sebaceous glands in mice, representative of multicellular exocrine glands of mammals, exhibit a form of polarized stratified epithelium equipped with tight junctions (TJs), and found that holocrine secretion occurred outside the TJ barriers. Sebaceous glands share characteristics of stratified epithelia with interfollicular epidermis, including basal-layer-restricted cell proliferation, TJ barrier formation at a specific single layer of cells with apico-basolateral plasma membrane polarity, and cell death outside the TJ barrier. Knockout of claudin-1, a transmembrane adhesive protein in TJs, in mice caused leakage of the TJ barrier in sebaceous glands and incomplete degradation of the plasma membrane and nuclei during holocrine secretion. Claudin-1 knockout resulted in the accumulation of incompletely degenerated sebocytes in sebaceous ducts, suggesting that the TJ barrier was necessary for differentiation of holocrine secretion. The redefinition of sebaceous glands as TJ-forming stratified epithelia provides an important framework to understand the molecular mechanism of holocrine secretion.
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30
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Fan NW, Ho TC, Lin EH, Wu CW, Chien HY, Tsao YP. Pigment epithelium-derived factor peptide reverses mouse age-related meibomian gland atrophy. Exp Eye Res 2019; 185:107678. [DOI: 10.1016/j.exer.2019.05.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 04/23/2019] [Accepted: 05/22/2019] [Indexed: 01/29/2023]
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31
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Andersen MS, Hannezo E, Ulyanchenko S, Estrach S, Antoku Y, Pisano S, Boonekamp KE, Sendrup S, Maimets M, Pedersen MT, Johansen JV, Clement DL, Feral CC, Simons BD, Jensen KB. Tracing the cellular dynamics of sebaceous gland development in normal and perturbed states. Nat Cell Biol 2019; 21:924-932. [PMID: 31358966 PMCID: PMC6978139 DOI: 10.1038/s41556-019-0362-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 06/18/2019] [Indexed: 12/12/2022]
Abstract
The sebaceous gland (SG) is an essential component of the skin, and SG dysfunction is debilitating1,2. Yet, the cellular bases for its origin, development and subsequent maintenance remain poorly understood. Here, we apply large-scale quantitative fate mapping to define the patterns of cell fate behaviour during SG development and maintenance. We show that the SG develops from a defined number of lineage-restricted progenitors that undergo a programme of independent and stochastic cell fate decisions. Following an expansion phase, equipotent progenitors transition into a phase of homeostatic turnover, which is correlated with changes in the mechanical properties of the stroma and spatial restrictions on gland size. Expression of the oncogene KrasG12D results in a release from these constraints and unbridled gland expansion. Quantitative clonal fate analysis reveals that, during this phase, the primary effect of the Kras oncogene is to drive a constant fate bias with little effect on cell division rates. These findings provide insight into the developmental programme of the SG, as well as the mechanisms that drive tumour progression and gland dysfunction.
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Affiliation(s)
- Marianne Stemann Andersen
- BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Edouard Hannezo
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
- The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK
- The Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Svetlana Ulyanchenko
- BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Soline Estrach
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Centre National de la Recherche Scientifique UMR 7284, Université Cote d'Azur, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Yasuko Antoku
- BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Sabrina Pisano
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Centre National de la Recherche Scientifique UMR 7284, Université Cote d'Azur, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Kim E Boonekamp
- BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Sarah Sendrup
- BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Martti Maimets
- BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marianne Terndrup Pedersen
- BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens V Johansen
- BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Ditte L Clement
- BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Chloe C Feral
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Centre National de la Recherche Scientifique UMR 7284, Université Cote d'Azur, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Benjamin D Simons
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK.
- The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
- The Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
| | - Kim B Jensen
- BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
- Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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32
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Yang R, Liu F, Wang J, Chen X, Xie J, Xiong K. Epidermal stem cells in wound healing and their clinical applications. Stem Cell Res Ther 2019; 10:229. [PMID: 31358069 PMCID: PMC6664527 DOI: 10.1186/s13287-019-1312-z] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The skin has important barrier, sensory, and immune functions, contributing to the health and integrity of the organism. Extensive skin injuries that threaten the entire organism require immediate and effective treatment. Wound healing is a natural response, but in severe conditions, such as burns and diabetes, this process is insufficient to achieve effective treatment. Epidermal stem cells (EPSCs) are a multipotent cell type and are committed to the formation and differentiation of the functional epidermis. As the contributions of EPSCs in wound healing and tissue regeneration have been increasingly attracting the attention of researchers, a rising number of therapies based on EPSCs are currently under development. In this paper, we review the characteristics of EPSCs and the mechanisms underlying their functions during wound healing. Applications of EPSCs are also discussed to determine the potential and feasibility of using EPSCs clinically in wound healing.
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Affiliation(s)
- Ronghua Yang
- Department of Burn Surgery, The First People’s Hospital of Foshan, Foshan, 528000 China
| | - Fengxia Liu
- Department of Human Anatomy, School of Basic Medical Science, Xinjiang Medical University, Urumqi, 830001 China
| | - Jingru Wang
- Department of Burn Surgery, The First People’s Hospital of Foshan, Foshan, 528000 China
| | - Xiaodong Chen
- Department of Burn Surgery, The First People’s Hospital of Foshan, Foshan, 528000 China
| | - Julin Xie
- Department of Burn Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 512100 China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Morphological Sciences Building, Central South University, 172 Tongzi Po Road, Changsha, 410013 Hunan China
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33
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Cao L, Chen L, Li H, Wei Z, Xie S, Zhang M, Lin Y, Huang H. Differential antigen expression between human eccrine sweat glands and hair follicles/pilosebaceous units. J Mol Histol 2019; 50:335-342. [PMID: 31062203 DOI: 10.1007/s10735-019-09830-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 04/29/2019] [Indexed: 02/07/2023]
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34
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Oulès B, Rognoni E, Hoste E, Goss G, Fiehler R, Natsuga K, Quist S, Mentink R, Donati G, Watt FM. Mutant Lef1 controls Gata6 in sebaceous gland development and cancer. EMBO J 2019; 38:embj.2018100526. [PMID: 30886049 PMCID: PMC6484415 DOI: 10.15252/embj.2018100526] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 02/17/2019] [Accepted: 02/19/2019] [Indexed: 12/21/2022] Open
Abstract
Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a β‐catenin‐independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9‐positive Lef1‐negative hair follicle progenitors that give rise to the upper SG. Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.
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Affiliation(s)
- Bénédicte Oulès
- Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK
| | - Emanuel Rognoni
- Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.,Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Esther Hoste
- Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.,Unit for Cellular and Molecular Pathophysiology, VIB Center for Inflammation Research, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Georgina Goss
- Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK
| | | | - Ken Natsuga
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Sven Quist
- Clinic for Dermatology and Venereology, Otto-von-Guericke-University, Magdeburg, Germany
| | | | - Giacomo Donati
- Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.,Department of Life Sciences and Systems Biology, Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Fiona M Watt
- Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK
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35
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Common J, Barker J, Steensel M. What does acne genetics teach us about disease pathogenesis? Br J Dermatol 2019; 181:665-676. [DOI: 10.1111/bjd.17721] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2019] [Indexed: 12/18/2022]
Affiliation(s)
- J.E.A. Common
- Skin Research Institute of Singapore, Agency for Science, Technology and Research (A*STAR) Singapore
| | - J.N. Barker
- St John's Institute of Dermatology Faculty of Life Sciences and Medicine King's College London London U.K
| | - M.A.M. Steensel
- Skin Research Institute of Singapore, Agency for Science, Technology and Research (A*STAR) Singapore
- Lee Kong Chian School of Medicine Nanyang Technological University Clinical Sciences Building Novena Singapore
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36
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Boecker W, Reusch M, Mielke V, Reusch U, Loening T, Tiemann M, Buchwalow I. Spatial analysis of p63, K5 and K7 defines two groups of progenitor cells that differentially contribute to the maintenance of normal sebaceous glands, extraocular sebaceous carcinoma and benign sebaceous tumors. J Dermatol 2019; 46:249-258. [PMID: 30663115 DOI: 10.1111/1346-8138.14765] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 11/29/2018] [Indexed: 01/18/2023]
Abstract
The histogenesis of extraocular sebaceous carcinomas is - in contrast to ocular sebaceous carcinomas - unclear, and information about the exact cellular architecture of these lesions and even of the normal sebaceous gland is still scarce. This study attempts to elucidate the histogenesis of sebaceous tumors, using multicolor immunofluorescence stainings to analyze 21 cases of sebaceous tumors (six each of extraocular sebaceous carcinoma, sebaceous adenoma and sebaceoma, and three cases of steatocystomas) and eight cases of normal sebaceous glands for p63, several keratins, androgen receptor, adipophilin, epithelial membrane antigen (EMA) and Ki-67. The data of this observational study provide evidence for the existence of two subpopulations of progenitors in normal sebaceous glands: (i) p63+ K5+ progenitors which generate the K10+ luminal cells of sebaceous ducts; and (ii) p63+ K5+ K7+ progenitors which finally generate K7+ adipophilin+ EMA+ sebocytes. Without exception, all types of sebaceous tumors contained p63+ K5+ cells. Furthermore, these tumors showed a cellular hierarchy and differentiation to adipophilin+ and/or EMA+ mature sebocytes and to K10+ ductal cells through intermediary cells. Notably, a considerable number of sebaceous tumors lack the K7 pathway of cell maintenance in the normal sebaceous lobule. Based on our data, we propose a cellular algorithmic model of the hierarchy of normal sebaceous glands and of sebocytic tumors in which p63+ K5+ cells play a major role.
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Affiliation(s)
- Werner Boecker
- Gerhard-Domagk-Institute of Pathology, University of Muenster, Muenster, Germany.,Dermatopathology Laboratory, Hamburg, Germany.,Gerhard-Seifert Reference Center for Gyneco-, Oral- and Breast Pathology, Hamburg, Germany
| | | | | | | | - Thomas Loening
- Dermatopathology Laboratory, Hamburg, Germany.,Gerhard-Seifert Reference Center for Gyneco-, Oral- and Breast Pathology, Hamburg, Germany
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37
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Abstract
A multilayered epithelium to fulfil its function must be replaced throughout the lifespan. This is possible due to the presence of multipotent, self-renewing epidermal stem cells that give rise to differentiated cell lineages: keratinocytes, hairs, as well as sebocytes. Till now the molecular mechanisms responsible for stem cell quiescent, proliferation, and differentiation have not been fully established. It is suggested that epidermal stem cells might change their fate, both due to intrinsic events and as a result of niche-dependent extrinsic signals; however other yet unknown factors may also be involved in this process. Given the increasing excitement evoked by self-renewing epidermal stem cells, as one of the sources of adult stem cells, it seems important to reveal the mechanisms that govern their fate. In this chapter, we describe recent advances in the characterisation of the epidermal stem cells and their compartments. Furthermore, we focus on the interplay between epidermal stem cells and extrinsic signals and their role in quiescence, proliferation, and differentiation of appropriate epidermal stem cell lineages.
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38
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Karrich JJ, Romera-Hernández M, Papazian N, Veenbergen S, Cornelissen F, Aparicio-Domingo P, Stenhouse FH, Peddie CD, Hoogenboezem RM, den Hollander CWJ, Gaskell T, Medley T, Boon L, Blackburn CC, Withers DR, Samsom JN, Cupedo T. Expression of Plet1 controls interstitial migration of murine small intestinal dendritic cells. Eur J Immunol 2018; 49:290-301. [PMID: 30537036 PMCID: PMC6492104 DOI: 10.1002/eji.201847671] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 10/30/2018] [Accepted: 12/05/2018] [Indexed: 12/25/2022]
Abstract
Under homeostatic conditions, dendritic cells (DCs) continuously patrol the intestinal lamina propria. Upon antigen encounter, DCs initiate C‐C motif chemokine receptor 7 (CCR7) expression and migrate into lymph nodes to direct T cell activation and differentiation. The mechanistic underpinnings of DC migration from the tissues to lymph nodes have been largely elucidated, contributing greatly to our understanding of DC functionality and intestinal immunity. In contrast, the molecular mechanisms allowing DCs to efficiently migrate through the complex extracellular matrix of the intestinal lamina propria prior to antigen encounter are still incompletely understood. Here we show that small intestinal murine CD11b+CD103+ DCs express Placenta‐expressed transcript 1 (Plet1), a glycophoshatidylinositol (GPI)‐anchored surface protein involved in migration of keratinocytes during wound healing. In the absence of Plet1, CD11b+CD103+ DCs display aberrant migratory behavior, and accumulate in the small intestine, independent of CCR7 responsiveness. RNA‐sequencing indicated involvement of Plet1 in extracellular matrix‐interactiveness, and subsequent in‐vitro migration assays revealed that Plet1 augments the ability of DCs to migrate through extracellular matrix containing environments. In conclusion, our findings reveal that expression of Plet1 facilitates homeostatic interstitial migration of small intestinal DCs.
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Affiliation(s)
- Julien J Karrich
- Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | - Natalie Papazian
- Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Sharon Veenbergen
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Ferry Cornelissen
- Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | - Frances H Stenhouse
- MRC, Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - C Diana Peddie
- MRC, Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Remco M Hoogenboezem
- Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | - Terri Gaskell
- MRC, Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Tanya Medley
- MRC, Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | | | - C Clare Blackburn
- MRC, Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - David R Withers
- MRC, Centre for Immune Regulation, University of Birmingham, Birmingham, UK
| | - Janneke N Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Tom Cupedo
- Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Xie HT, Sullivan DA, Chen D, Hatton MP, Kam WR, Liu Y. Biomarkers for Progenitor and Differentiated Epithelial Cells in the Human Meibomian Gland. Stem Cells Transl Med 2018; 7:887-892. [PMID: 30251359 PMCID: PMC6265637 DOI: 10.1002/sctm.18-0037] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 07/23/2018] [Indexed: 01/21/2023] Open
Abstract
The meibomian gland (MG) is a sebaceous gland that secretes through a holocrine process. Because such secretion requires the destruction of MG acinar epithelial cells, they need constant renewal and differentiation. The processes that promote these regenerative events in the human MG are unknown, nor is it known how to distinguish MG progenitor and differentiated cells. We discovered that Lrig1 and DNase2 serve as biomarkers for human MG progenitor and differentiated cells, respectively. Lrig1 is expressed in MG basal epithelial cells in the acinar periphery, a location where progenitor cells originate in sebaceous glands. DNase2 is expressed in the differentiated epithelial cells of the MG central acinus. Furthermore, proliferation stimulates, and differentiation suppresses, Lrig1 expression in human MG epithelial cells. The opposite is true for DNase2 expression. Our biomarker identification may have significant value in clinical efforts to restore MG function and to regenerate MGs after disease‐induced dropout. Stem Cells Translational Medicine2018;7:887–892
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Affiliation(s)
- Hua-Tao Xie
- Schepens Eye Research Institute, Massachusetts Eye and Ear, and Department of Ophthalmology, Harvard Medical School, Boston Massachusetts, USA.,Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - David A Sullivan
- Schepens Eye Research Institute, Massachusetts Eye and Ear, and Department of Ophthalmology, Harvard Medical School, Boston Massachusetts, USA
| | - Di Chen
- Schepens Eye Research Institute, Massachusetts Eye and Ear, and Department of Ophthalmology, Harvard Medical School, Boston Massachusetts, USA.,Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
| | - Mark P Hatton
- Schepens Eye Research Institute, Massachusetts Eye and Ear, and Department of Ophthalmology, Harvard Medical School, Boston Massachusetts, USA.,Ophthalmic Consultants of Boston, Boston, Massachusetts, USA
| | - Wendy R Kam
- Schepens Eye Research Institute, Massachusetts Eye and Ear, and Department of Ophthalmology, Harvard Medical School, Boston Massachusetts, USA
| | - Yang Liu
- Schepens Eye Research Institute, Massachusetts Eye and Ear, and Department of Ophthalmology, Harvard Medical School, Boston Massachusetts, USA
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Schneider MR, Zouboulis CC. Primary sebocytes and sebaceous gland cell lines for studying sebaceous lipogenesis and sebaceous gland diseases. Exp Dermatol 2018; 27:484-488. [DOI: 10.1111/exd.13513] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Marlon R. Schneider
- German Federal Institute for Risk Assessment (BfR); German Centre for the Protection of Laboratory Animals (Bf3R); Berlin Germany
| | - Christos C. Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology; Dessau Medical Center; Brandenburg Medical School Theodore Fontane; Dessau Germany
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Ceria nanocrystals decorated mesoporous silica nanoparticle based ROS-scavenging tissue adhesive for highly efficient regenerative wound healing. Biomaterials 2018; 151:66-77. [DOI: 10.1016/j.biomaterials.2017.10.018] [Citation(s) in RCA: 228] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 09/18/2017] [Accepted: 10/08/2017] [Indexed: 02/07/2023]
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42
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Shi G, Wang TT, Quan JH, Li SJ, Zhang MF, Liao PY, Fan YM. Sox9 facilitates proliferation, differentiation and lipogenesis in primary cultured human sebocytes. J Dermatol Sci 2017; 85:44-50. [DOI: 10.1016/j.jdermsci.2016.10.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 10/09/2016] [Accepted: 10/12/2016] [Indexed: 12/11/2022]
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Ehrmann C, Schneider MR. Genetically modified laboratory mice with sebaceous glands abnormalities. Cell Mol Life Sci 2016; 73:4623-4642. [PMID: 27457558 PMCID: PMC11108334 DOI: 10.1007/s00018-016-2312-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 07/12/2016] [Accepted: 07/19/2016] [Indexed: 12/19/2022]
Abstract
Sebaceous glands (SG) are exocrine glands that release their product by holocrine secretion, meaning that the whole cell becomes a secretion following disruption of the membrane. SG may be found in association with a hair follicle, forming the pilosebaceous unit, or as modified SG at different body sites such as the eyelids (Meibomian glands) or the preputial glands. Depending on their location, SG fulfill a number of functions, including protection of the skin and fur, thermoregulation, formation of the tear lipid film, and pheromone-based communication. Accordingly, SG abnormalities are associated with several diseases such as acne, cicatricial alopecia, and dry eye disease. An increasing number of genetically modified laboratory mouse lines develop SG abnormalities, and their study may provide important clues regarding the molecular pathways regulating SG development, physiology, and pathology. Here, we summarize in tabulated form the available mouse lines with SG abnormalities and, focusing on selected examples, discuss the insights they provide into SG biology and pathology. We hope this survey will become a helpful information source for researchers with a primary interest in SG but also as for researchers from unrelated fields that are unexpectedly confronted with a SG phenotype in newly generated mouse lines.
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Affiliation(s)
- Carmen Ehrmann
- Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany
| | - Marlon R Schneider
- Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany.
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Wang X, Wang X, Liu J, Cai T, Guo L, Wang S, Wang J, Cao Y, Ge J, Jiang Y, Tredget EE, Cao M, Wu Y. Hair Follicle and Sebaceous Gland De Novo Regeneration With Cultured Epidermal Stem Cells and Skin-Derived Precursors. Stem Cells Transl Med 2016; 5:1695-1706. [PMID: 27458264 DOI: 10.5966/sctm.2015-0397] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 05/12/2016] [Indexed: 12/17/2022] Open
Abstract
: Stem cell-based organ regeneration is purported to enable the replacement of impaired organs in the foreseeable future. Here, we demonstrated that a combination of cultured epidermal stem cells (Epi-SCs) derived from the epidermis and skin-derived precursors (SKPs) was capable of reconstituting functional hair follicles and sebaceous glands (SG). When Epi-SCs and SKPs were mixed in a hydrogel and implanted into an excisional wound in nude mice, the Epi-SCs formed de novo epidermis along with hair follicles, and SKPs contributed to dermal papilla in the neogenic hair follicles. Notably, a combination of culture-expanded Epi-SCs and SKPs derived from the adult human scalp were sufficient to generate hair follicles and hair. Bone morphogenetic protein 4, but not Wnts, sustained the expression of alkaline phosphatase in SKPs in vitro and the hair follicle-inductive property in vivo when SKPs were engrafted with neonatal epidermal cells into excisional wounds. In addition, Epi-SCs were capable of differentiating into sebocytes and formed de novo SGs, which excreted lipids as do normal SGs. Thus our results indicate that cultured Epi-SCs and SKPs are sufficient to generate de novo hair follicles and SGs, implying great potential to develop novel bioengineered skin substitutes with appendage genesis capacity. SIGNIFICANCE In postpartum humans, skin appendages lost in injury are not regenerated, despite the considerable achievement made in skin bioengineering. In this study, transplantation of a combination of culture-expanded epidermal stem cells and skin-derived progenitors from mice and adult humans led to de novo regeneration of functional hair follicles and sebaceous glands. The data provide transferable knowledge for the development of novel bioengineered skin substitutes with epidermal appendage regeneration capacity.
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Affiliation(s)
- Xiaoxiao Wang
- School of Life Sciences, Tsinghua University, Beijing, People's Republic of China
- Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Beijing, People's Republic of China
| | - Xusheng Wang
- School of Life Sciences, Tsinghua University, Beijing, People's Republic of China
- Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Beijing, People's Republic of China
| | - Jianjun Liu
- Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, People's Republic of China
| | - Ting Cai
- School of Life Sciences, Tsinghua University, Beijing, People's Republic of China
- Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Beijing, People's Republic of China
| | - Ling Guo
- Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Beijing, People's Republic of China
| | - Shujuan Wang
- State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Beijing, People's Republic of China
| | - Jinmei Wang
- Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Beijing, People's Republic of China
| | - Yanpei Cao
- Clinical Research Center, University College Dublin, Belfield, Dublin, Ireland
| | - Jianfeng Ge
- School of Life Sciences, Tsinghua University, Beijing, People's Republic of China
- Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Beijing, People's Republic of China
| | - Yuyang Jiang
- State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Beijing, People's Republic of China
| | - Edward E Tredget
- Wound Healing Research Group, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Mengjun Cao
- Shenzhen Fuhua Aesthetic Hospital, Shenzhen, People's Republic of China
| | - Yaojiong Wu
- Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Beijing, People's Republic of China
- Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Beijing, People's Republic of China
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Ali NJA, Dias Gomes M, Bauer R, Brodesser S, Niemann C, Iden S. Essential Role of Polarity Protein Par3 for Epidermal Homeostasis through Regulation of Barrier Function, Keratinocyte Differentiation, and Stem Cell Maintenance. J Invest Dermatol 2016; 136:2406-2416. [PMID: 27452221 DOI: 10.1016/j.jid.2016.07.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 06/22/2016] [Accepted: 07/05/2016] [Indexed: 12/17/2022]
Abstract
Partitioning-defective (Par) proteins contribute to multiprotein complexes that drive cell polarity and fate in invertebrates. Of these, the ternary Par3-atypical protein kinase C-Par6 polarity complex mediates asymmetry in various systems, whereas Par3 and aPKC/Par6 can also act independently. aPKC-λ has recently been implicated in epidermal differentiation and stem cell fate; however, whether Par3 contributes to the homeostasis of adult stratified epithelia is currently unknown. Here, we provide functional evidence that epidermal Par3 loss disturbed the inside-out skin barrier, coinciding with altered expression and localization of principle tight junction components, and that epidermal differentiation and thickness were increased. Moreover, Par3 inactivation caused an initial expansion and later decline of hair follicle bulge stem cells, accompanied by an enrichment of committed progenitors, formation of hypertrophic sebaceous glands, and increased epidermal differentiation, suggesting aberrant cell fate decisions. Importantly, and opposite to aPKCλ deletion, Par3 loss did not enhance perpendicular cell divisions. Instead, in Par3-deficient hair follicles, spindles were shifted toward planar orientation, indicating that abnormal differentiation after Par3 inactivation is unlikely to be attributed to increased perpendicular spindle orientation. Collectively, mammalian Par3 controls the epidermal barrier, differentiation, and stem cell maintenance in the pilosebaceous unit, which are all essential for the homeostasis of an important barrier-forming epithelium.
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Affiliation(s)
- Noelle J A Ali
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany
| | - Martim Dias Gomes
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany
| | - Ronja Bauer
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany
| | - Susanne Brodesser
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany
| | - Catherin Niemann
- Center for Biochemistry, Medical Faculty, University of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany
| | - Sandra Iden
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
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Abstract
Background Sebaceous glands contribute significantly to the barrier functions of the skin. However, little is known about their homeostasis and tumorigenesis. Recently, increased expression of stem cell marker Lrig1 has been reported in sebaceous carcinoma-like tumors of K14ΔNLef1 transgenic mice. In this study, we analyzed the Lrig1 expression in human sebaceous tumors. Methods Twenty-eight formalin-fixed paraffin-embedded sebaceous tumor specimens (7 sebaceous hyperplasias, 7 sebaceous adenomas, 10 sebaceomas and 4 sebaceous carcinomas) were stained with anti-Lrig1, anti-CD44v3 and anti-Ki67 antibody. Results Four (100%) sebaceous carcinomas, 8 (80%) sebaceomas, 3 (43%) sebaceous adenomas and no sebaceous hyperplasia showed Lrig1 overexpression. Discussion and Conclusion Lrig1 is a known tumor suppressor gene and is usually considered to be an indicator of poorly aggressive tumors. In human sebaceous tumors, the stronger Lrig1 staining in sebaceous carcinoma compared to other sebaceous tumors might be a feature of an advanced stage in tumorigenesis and a bad prognosis. In our study, 100% of sebaceous carcinomas revealed Lrig1 overexpression. We propose that Lrig1 may be used as a possible new marker of poorly differentiated sebaceous carcinoma.
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Affiliation(s)
- Jöri Pünchera
- Department of Dermatology, University Hospital of Geneva, Geneva, Switzerland
| | - Laurent Barnes
- Department of Dermatology, University Hospital of Geneva, Geneva, Switzerland
| | - Gürkan Kaya
- Department of Dermatology, University Hospital of Geneva, Geneva, Switzerland
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Plet1 is an epigenetically regulated cell surface protein that provides essential cues to direct trophoblast stem cell differentiation. Sci Rep 2016; 6:25112. [PMID: 27121762 PMCID: PMC4848516 DOI: 10.1038/srep25112] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 04/11/2016] [Indexed: 12/28/2022] Open
Abstract
Gene loci that are hypermethylated and repressed in embryonic (ESCs) but hypomethylated and expressed in trophoblast (TSCs) stem cells are very rare and may have particularly important roles in early developmental cell fate decisions, as previously shown for Elf5. Here, we assessed another member of this small group of genes, Placenta Expressed Transcript 1 (Plet1), for its function in establishing trophoblast lineage identity and modulating trophoblast differentiation. We find that Plet1 is tightly repressed by DNA methylation in ESCs but expressed on the cell surface of TSCs and trophoblast giant cells. In hypomethylated ESCs that are prone to acquire some trophoblast characteristics, Plet1 is required to confer a trophoblast-specific gene expression pattern, including up-regulation of Elf5. Plet1 displays an unusual biphasic expression profile during TSC differentiation and thus may be pivotal in balancing trophoblast self-renewal and differentiation. Furthermore, overexpression and CRISPR/Cas9-mediated knockout in TSCs showed that high Plet1 levels favour differentiation towards the trophoblast giant cell lineage, whereas lack of Plet1 preferentially induces syncytiotrophoblast formation. Thus, the endogenous dynamics of Plet1 expression establish important patterning cues within the trophoblast compartment by promoting differentiation towards the syncytiotrophoblast or giant cell pathway in Plet1-low and Plet1-high cells, respectively.
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48
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Falodah FA, Al-Karim S. Immuno- and gene expression analysis of EGFR and Nestin during mice skin development. Tissue Cell 2016; 48:274-81. [PMID: 27105606 DOI: 10.1016/j.tice.2016.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 01/22/2016] [Accepted: 02/06/2016] [Indexed: 11/17/2022]
Abstract
BACKGROUND Skin stem cell populations reside in the adult hair follicle, sebaceous gland, dermis and epidermis. However, the origin of most of the stem cell populations found in the adult epidermis is still unknown. Far more unknown is the embryonic origin of other stem cells that populate the other layers of this tissue. OBJECTIVES The main objectives of the present study were to identify the precise anatomical localization of stem cells in mice during skin developing; and to determine the expression levels by using immuno- and gene expression analysis. SUBJECTS AND METHODS In this comparative cross sectional study, six ages been chosen and divided into: embryonic days (E12.5, E14.5 and E19.5) and litter days (L7, L14 and L19). Skin were removed from the back side and processed to assess both immuno- and gene-expression of EGFR and Nestin surface antigen markers. Data of the different studied age groups was compared using the SPSS software. RESULTS EGFR was mainly expressed in the outer root sheath (ORS), in basal and, to a lesser extent, in suprabasal keratinocytes and tend to lie where the dermis comes closest to the skin surface, while Nestin expressed throughout the dermis in the early embryo, but it is subsequently restricted to the follicular connective tissue sheaths later in development and to hair follicles after birth. Immunoexpression analysis showed a strong EGFR expression in all group ages except E12.5 which recorded as moderate, while Nestin showed strong expression level for all embryonic stages, while in the litters it was moderate. The qRT-PCR results were consistent with those of the immunohistochemical study. The Pearson correlation analyze present a correlation between the cases of study with age (p≤0.01), which indicated to the effect of age to mice development. CONCLUSION EGFR and Nestin showed to have vital role during mice development, and considered to be suitable markers for the study of skin stem cells.
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Affiliation(s)
- Fawaz Adnan Falodah
- Biology Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
| | - Saleh Al-Karim
- Biology Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Embryonic Stem Cell Unit, King Fahad Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
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Ulyanchenko S, O'Neill KE, Medley T, Farley AM, Vaidya HJ, Cook AM, Blair NF, Blackburn CC. Identification of a Bipotent Epithelial Progenitor Population in the Adult Thymus. Cell Rep 2016; 14:2819-32. [PMID: 26997270 PMCID: PMC4819909 DOI: 10.1016/j.celrep.2016.02.080] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 12/28/2015] [Accepted: 02/21/2016] [Indexed: 11/16/2022] Open
Abstract
Thymic epithelial cells (TECs) are critically required for T cell development, but the cellular mechanisms that maintain adult TECs are poorly understood. Here, we show that a previously unidentified subpopulation, EpCam(+)UEA1(-)Ly-51(+)PLET1(+)MHC class II(hi), which comprises <0.5% of adult TECs, contains bipotent TEC progenitors that can efficiently generate both cortical (c) TECs and medullary (m) TECs. No other adult TEC population tested in this study contains this activity. We demonstrate persistence of PLET1(+)Ly-51(+) TEC-derived cells for 9 months in vivo, suggesting the presence of thymic epithelial stem cells. Additionally, we identify cTEC-restricted short-term progenitor activity but fail to detect high efficiency mTEC-restricted progenitors in the adult thymus. Our data provide a phenotypically defined adult thymic epithelial progenitor/stem cell that is able to generate both cTECs and mTECs, opening avenues for improving thymus function in patients.
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Affiliation(s)
- Svetlana Ulyanchenko
- MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK
| | - Kathy E O'Neill
- MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK
| | - Tanya Medley
- MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK
| | - Alison M Farley
- MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK
| | - Harsh J Vaidya
- MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK
| | - Alistair M Cook
- MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK
| | - Natalie F Blair
- MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK
| | - C Clare Blackburn
- MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK.
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50
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Schneider MR. Lipid droplets and associated proteins in sebocytes. Exp Cell Res 2016; 340:205-8. [DOI: 10.1016/j.yexcr.2015.11.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 11/06/2015] [Accepted: 11/08/2015] [Indexed: 12/19/2022]
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