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Torregrossa M, Davies L, Hans-Günther M, Simon JC, Franz S, Rinkevich Y. Effects of embryonic origin, tissue cues and pathological signals on fibroblast diversity in humans. Nat Cell Biol 2025; 27:720-735. [PMID: 40263573 DOI: 10.1038/s41556-025-01638-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 02/18/2025] [Indexed: 04/24/2025]
Abstract
Fibroblasts, once perceived as a uniform cell type, are now recognized as a mosaic of distinct populations with specialized roles in tissue homeostasis and pathology. Here we provide a global overview of the expanding compendium of fibroblast cell types and states, their diverse lineage origins and multifaceted functions across various human organs. By integrating insights from developmental biology, lineage tracing and single-cell technologies, we highlight the complex nature of fibroblasts. We delve into their origination from embryonic mesenchyme and tissue-resident populations, elucidating lineage-specific behaviours in response to physiological cues. Furthermore, we highlight the pivotal role of fibroblasts in orchestrating tissue repair, connective tissue remodelling and immune modulation across diverse pathologies. This knowledge is essential to develop novel fibroblast-targeted therapies to restore steady-state fibroblast function and advance regenerative medicine strategies across multiple diseases.
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Affiliation(s)
- Marta Torregrossa
- Department of Dermatology, Venereology and Allergology, Leipzig University Medical Faculty, Leipzig, Germany
| | - Lindsay Davies
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
| | - Machens Hans-Günther
- Department for Plastic Surgery and Hand Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Jan C Simon
- Department of Dermatology, Venereology and Allergology, Leipzig University Medical Faculty, Leipzig, Germany
| | - Sandra Franz
- Department of Dermatology, Venereology and Allergology, Leipzig University Medical Faculty, Leipzig, Germany.
| | - Yuval Rinkevich
- Chinese Institutes for Medical Research, Beijing, China.
- Capital Medical University, Beijing, China.
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2
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Kohlhauser M, Mayrhofer M, Kamolz LP, Smolle C. An Update on Molecular Mechanisms of Scarring-A Narrative Review. Int J Mol Sci 2024; 25:11579. [PMID: 39519131 PMCID: PMC11546163 DOI: 10.3390/ijms252111579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/01/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024] Open
Abstract
Fibroblasts, the principal cellular mediators of connective tissue remodeling, play a crucial role in the formation of physiological and pathological scars. Understanding the intricate interplay between fibroblasts and other cellular and molecular components is essential for elucidating the underlying mechanisms driving scar formation. Hypertrophic scars, keloids and atrophic scars arise from dysregulated wound healing processes characterized by persistent inflammation, aberrant collagen deposition, and impaired extracellular matrix remodeling. Fibroblasts play a central role in the pathogenesis of such pathological scars, driving aberrant extracellular matrix remodeling, subsequently contributing to the formation of raised or depressed fibrotic lesions. The investigation of complex interactions between fibroblasts and the microenvironment is crucial for developing targeted therapeutic interventions aimed at modulating fibroblast activity and improving clinical outcomes in patients with pathological scars. Further research into the molecular pathways governing fibroblast behavior and their heterogeneity holds promise for advancing scar management strategies. This narrative review was performed to shed light on the mechanisms behind scar formation, with a special focus on the role of fibroblasts in the formation of different types of scars, providing insights into the pathophysiology of these conditions. Through the analysis of current knowledge, this review seeks to identify the key cellular and molecular mechanisms involved in fibroblast activation, collagen synthesis, and extracellular matrix remodeling in hypertrophic scar, keloid, or atrophic scar formation.
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Affiliation(s)
- Michael Kohlhauser
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria
| | - Marcel Mayrhofer
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria
| | - Lars-Peter Kamolz
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria
- COREMED—Centre for Regenerative Medicine and Precision Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, 8010 Graz, Austria
| | - Christian Smolle
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria
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3
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Zhang HL, Qiu XX, Liao XH. Dermal Papilla Cells: From Basic Research to Translational Applications. BIOLOGY 2024; 13:842. [PMID: 39452150 PMCID: PMC11504027 DOI: 10.3390/biology13100842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/13/2024] [Accepted: 10/18/2024] [Indexed: 10/26/2024]
Abstract
As an appendage of the skin, hair protects against ultraviolet radiation and mechanical damage and regulates body temperature. It also reflects an individual's health status and serves as an important method of expressing personality. Hair loss and graying are significant psychosocial burdens for many people. Hair is produced from hair follicles, which are exclusively controlled by the dermal papilla (DP) at their base. The dermal papilla cells (DPCs) comprise a cluster of specialized mesenchymal cells that induce the formation of hair follicles during early embryonic development through interaction with epithelial precursor cells. They continue to regulate the growth cycle, color, size, and type of hair after the hair follicle matures by secreting various factors. DPCs possess stem cell characteristics and can be cultured and expanded in vitro. DPCs express numerous stemness-related factors, enabling them to be reprogrammed into induced pluripotent stem cells (iPSCs) using only two, or even one, Yamanaka factor. DPCs are an important source of skin-derived precursors (SKPs). When combined with epithelial stem cells, they can reconstitute skin and hair follicles, participating in the regeneration of the dermis, including the DP and dermal sheath. When implanted between the epidermis and dermis, DPCs can induce the formation of new hair follicles on hairless skin. Subcutaneous injection of DPCs and their exosomes can promote hair growth. This review summarizes the in vivo functions of the DP; highlights the potential of DPCs in cell therapy, particularly for the treatment of hair loss; and discusses the challenges and recent advances in the field, from basic research to translational applications.
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Affiliation(s)
- He-Li Zhang
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China;
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
| | - Xi-Xi Qiu
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
| | - Xin-Hua Liao
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
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4
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Zou Q, Yuan R, Zhang Y, Wang Y, Zheng T, Shi R, Zhang M, Li Y, Fei K, Feng R, Pan B, Zhang X, Gong Z, Zhu L, Tang G, Li M, Li X, Jiang Y. A single-cell transcriptome atlas of pig skin characterizes anatomical positional heterogeneity. eLife 2023; 12:86504. [PMID: 37276016 DOI: 10.7554/elife.86504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 05/22/2023] [Indexed: 06/07/2023] Open
Abstract
Different anatomical locations of the body skin show differences in their gene expression patterns depending on different origins, and the inherent heterogeneous information can be maintained in adults. However, highly resolvable cellular specialization is less well characterized in different anatomical regions of the skin. Pig is regarded as an excellent model animal for human skin research in view of its similar physiology to human. In this study, single-cell RNA sequencing was performed on pig skin tissues from six different anatomical regions of Chenghua (CH) pigs, with a superior skin thickness trait, and the back site of large white (LW) pigs. We obtained 233,715 cells, representing seven cell types, among which we primarily characterized the heterogeneity of the top three cell types, including smooth muscle cells (SMCs), endothelial cells (ECs), and fibroblasts (FBs). Then, we further identified several subtypes of SMCs, ECs, and FBs, and discovered the expression patterns of site-specific genes involved in some important pathways such as the immune response and extracellular matrix (ECM) synthesis in different anatomical regions. By comparing differentially expressed genes of skin FBs among different anatomical regions, we considered TNN, COL11A1, and INHBA as candidate genes for facilitating ECM accumulation. These findings of heterogeneity in the main skin cell types from different anatomical sites will contribute to a better understanding of inherent skin information and place the potential focus on skin generation, transmission, and transplantation, paving the foundation for human skin priming.
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Affiliation(s)
- Qin Zou
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Rong Yuan
- Chengdu Livestock and Poultry Genetic Resources Protection Center, Chengdu, China
| | - Yu Zhang
- BGI Beijing Genome Institute, Beijing, China
| | - Yifei Wang
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Ting Zheng
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Rui Shi
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Mei Zhang
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Yujing Li
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Kaixin Fei
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Ran Feng
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Binyun Pan
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Xinyue Zhang
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Zhengyin Gong
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
| | - Li Zhu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Guoqing Tang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Mingzhou Li
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Xuewei Li
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Yanzhi Jiang
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Ya'an, China
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Ge W, Sun YC, Qiao T, Liu HX, He TR, Wang JJ, Chen CL, Cheng SF, Dyce PW, De Felici M, Shen W. Murine skin-derived multipotent papillary dermal fibroblast progenitors show germline potential in vitro. Stem Cell Res Ther 2023; 14:17. [PMID: 36737797 PMCID: PMC9898921 DOI: 10.1186/s13287-023-03243-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Many laboratories have described the in vitro isolation of multipotent cells with stem cell properties from the skin of various species termed skin-derived stem cells (SDSCs). However, the cellular origin of these cells and their capability to give rise, among various cell types, to male germ cells, remain largely unexplored. METHODS SDSCs were isolated from newborn mice skin, and then differentiated into primordial germ cell-like cells (PGCLCs) in vitro. Single-cell RNA sequencing (scRNA-seq) was then applied to dissect the cellular origin of SDSCs using cells isolated from newborn mouse skin and SDSC colonies. Based on an optimized culture strategy, we successfully generated spermatogonial stem cell-like cells (SSCLCs) in vitro. RESULTS Here, using scRNA-seq and analyzing the profile of 7543 single-cell transcriptomes from newborn mouse skin and SDSCs, we discovered that they mainly consist of multipotent papillary dermal fibroblast progenitors (pDFPs) residing in the dermal layer. Moreover, we found that epidermal growth factor (EGF) signaling is pivotal for the capability of these progenitors to proliferate and form large colonies in vitro. Finally, we optimized the protocol to efficiently generate PGCLCs from SDSCs. Furthermore, PGCLCs were induced into SSCLCs and these SSCLCs showed meiotic potential when cultured with testicular organoids. CONCLUSIONS Our findings here identify pDFPs as SDSCs derived from newborn skin and show for the first time that such precursors can be induced to generate cells of the male germline.
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Affiliation(s)
- Wei Ge
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Yuan-Chao Sun
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Tian Qiao
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Hai-Xia Liu
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Tao-Ran He
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Jun-Jie Wang
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Chun-Lei Chen
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Shun-Feng Cheng
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Paul W Dyce
- Department of Animal Sciences, Auburn University, Auburn, AL, 36849, USA
| | - Massimo De Felici
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Wei Shen
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China.
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Song H, Zhao XB, Chu QS, Zhang J, Gao L, Liao XH. Expression dynamics of lymphoid enhancer-binding factor 1 in terminal Schwann cells, dermal papilla, and interfollicular epidermis. Dev Dyn 2022; 252:527-535. [PMID: 36576725 DOI: 10.1002/dvdy.562] [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: 09/19/2022] [Revised: 12/24/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Transcription factor lymphoid enhancer-binding factor 1 (LEF1) is a downstream mediator of the Wnt/β-catenin signaling pathway. It is expressed in dermal papilla and surrounding cells in the hair follicle, promoting cell proliferation, and differentiation. RESULTS Here, we report that LEF1 is also expressed all through the hair cycle in the terminal Schwann cells (TSCs), a component of the lanceolate complex located at the isthmus. The timing of LEF1 appearance at the isthmus coincides with that of hair follicle innervation. LEF1 is not found at the isthmus in the aberrant hair follicles in nude mice. Instead, LEF1 in TSCs is found in the de novo hair follicles reconstituted on nude mice by stem cells chamber graft assay. Cutaneous denervation experiment demonstrates that the LEF1 expression in TSCs is independent of nerve endings. At last, LEF1 expression in the interfollicular epidermis during the early stage of skin development is significantly suppressed in transgenic mice with T-cell factor 3 (TCF3) overexpression. CONCLUSION We reveal the expression dynamics of LEF1 in skin during development and hair cycle. LEF1 expression in TSCs indicates that the LEF1/Wnt signal might help to establish a niche at the isthmus region for the lanceolate complex, the bulge stem cells and other neighboring cells.
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Affiliation(s)
- Hongzhi Song
- School of Medicine, Shanghai University, Shanghai, China.,School of Life Sciences, Shanghai University, Shanghai, China.,School of Environmental and Chemical Engineering, Shanghai University, Shanghai, China
| | - Xu-Bo Zhao
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Qing-Song Chu
- School of Life Sciences, Shanghai University, Shanghai, China.,Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China
| | - Jianyu Zhang
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Lipeng Gao
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Xin-Hua Liao
- School of Life Sciences, Shanghai University, Shanghai, China
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7
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Hörner SJ, Couturier N, Gueiber DC, Hafner M, Rudolf R. Development and In Vitro Differentiation of Schwann Cells. Cells 2022; 11:3753. [PMID: 36497014 PMCID: PMC9739763 DOI: 10.3390/cells11233753] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/16/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
Schwann cells are glial cells of the peripheral nervous system. They exist in several subtypes and perform a variety of functions in nerves. Their derivation and culture in vitro are interesting for applications ranging from disease modeling to tissue engineering. Since primary human Schwann cells are challenging to obtain in large quantities, in vitro differentiation from other cell types presents an alternative. Here, we first review the current knowledge on the developmental signaling mechanisms that determine neural crest and Schwann cell differentiation in vivo. Next, an overview of studies on the in vitro differentiation of Schwann cells from multipotent stem cell sources is provided. The molecules frequently used in those protocols and their involvement in the relevant signaling pathways are put into context and discussed. Focusing on hiPSC- and hESC-based studies, different protocols are described and compared, regarding cell sources, differentiation methods, characterization of cells, and protocol efficiency. A brief insight into developments regarding the culture and differentiation of Schwann cells in 3D is given. In summary, this contribution provides an overview of the current resources and methods for the differentiation of Schwann cells, it supports the comparison and refinement of protocols and aids the choice of suitable methods for specific applications.
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Affiliation(s)
- Sarah Janice Hörner
- Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, 68163 Mannheim, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany
- Center for Mass Spectrometry and Optical Spectroscopy, Mannheim University of Applied Sciences, 68163 Mannheim, Germany
| | - Nathalie Couturier
- Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, 68163 Mannheim, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany
- Center for Mass Spectrometry and Optical Spectroscopy, Mannheim University of Applied Sciences, 68163 Mannheim, Germany
| | - Daniele Caroline Gueiber
- Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, 68163 Mannheim, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany
- Center for Mass Spectrometry and Optical Spectroscopy, Mannheim University of Applied Sciences, 68163 Mannheim, Germany
- Department of Electronics Engineering, Federal University of Technology Paraná, Ponta Grossa 84017-220, Brazil
| | - Mathias Hafner
- Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, 68163 Mannheim, Germany
- Institute of Medical Technology, Heidelberg University and Mannheim University of Applied Sciences, 69117 Heidelberg, Germany
| | - Rüdiger Rudolf
- Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, 68163 Mannheim, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany
- Center for Mass Spectrometry and Optical Spectroscopy, Mannheim University of Applied Sciences, 68163 Mannheim, Germany
- Institute of Medical Technology, Heidelberg University and Mannheim University of Applied Sciences, 69117 Heidelberg, Germany
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8
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Regan JL, Schumacher D, Staudte S, Steffen A, Lesche R, Toedling J, Jourdan T, Haybaeck J, Golob-Schwarzl N, Mumberg D, Henderson D, Győrffy B, Regenbrecht CR, Keilholz U, Schäfer R, Lange M. Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for EGR2 in tumorigenesis. iScience 2022; 25:104498. [PMID: 35720265 PMCID: PMC9204726 DOI: 10.1016/j.isci.2022.104498] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/28/2022] [Accepted: 05/26/2022] [Indexed: 11/12/2022] Open
Abstract
Recent evidence demonstrates that colon cancer stem cells (CSCs) can generate neurons that synapse with tumor innervating fibers required for tumorigenesis and disease progression. Greater understanding of the mechanisms that regulate CSC driven tumor neurogenesis may therefore lead to more effective treatments. RNA-sequencing analyses of ALDHPositive CSCs from colon cancer patient-derived organoids (PDOs) and xenografts (PDXs) showed CSCs to be enriched for neural development genes. Functional analyses of genes differentially expressed in CSCs from PDO and PDX models demonstrated the neural crest stem cell (NCSC) regulator EGR2 to be required for tumor growth and to control expression of homebox superfamily embryonic master transcriptional regulator HOX genes and the neural stem cell and master cell fate regulator SOX2. These data support CSCs as the source of tumor neurogenesis and suggest that targeting EGR2 may provide a therapeutic differentiation strategy to eliminate CSCs and block nervous system driven disease progression.
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Affiliation(s)
- Joseph L. Regan
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Dirk Schumacher
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
| | - Stephanie Staudte
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
- Department of Radiation Oncology and Radiotherapy, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Andreas Steffen
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
| | - Ralf Lesche
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Nuvisan ICB GmbH, 13353 Berlin, Germany
| | - Joern Toedling
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Nuvisan ICB GmbH, 13353 Berlin, Germany
| | - Thibaud Jourdan
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
| | - Johannes Haybaeck
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Diagnostic and Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8036 Graz, Austria
| | - Nicole Golob-Schwarzl
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Department of Dermatology and Venereology, Medical University of Graz, 8036 Graz, Austria
| | - Dominik Mumberg
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
| | - David Henderson
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Bayer AG, Business Development and Licensing and Open Innovation, Pharmaceuticals, 13342 Berlin, Germany
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary
- TTK Cancer Biomarker Research Group, Institute of Enzymology, 1117 Budapest, Hungary
| | - Christian R.A. Regenbrecht
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
- CELLphenomics GmbH, 13125 Berlin, Germany
- Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Ulrich Keilholz
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Reinhold Schäfer
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
| | - Martin Lange
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Nuvisan ICB GmbH, 13353 Berlin, Germany
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9
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Guo R, You X, Meng K, Sha R, Wang Z, Yuan N, Peng Q, Li Z, Xie Z, Chen R, Feng Y. Single-Cell RNA Sequencing Reveals Heterogeneity of Myf5-Derived Cells and Altered Myogenic Fate in the Absence of SRSF2. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2105775. [PMID: 35460187 PMCID: PMC9218650 DOI: 10.1002/advs.202105775] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/05/2022] [Indexed: 06/14/2023]
Abstract
Splicing factor SRSF2 acts as a critical regulator for cell survival, however, it remains unknown whether SRSF2 is involved in myoblast proliferation and myogenesis. Here, knockdown of SRSF2 in myoblasts causes high rates of apoptosis and defective differentiation. Combined conditional knockout and lineage tracing approaches show that Myf5-cre mice lacking SRSF2 die immediately at birth and exhibit a complete absence of mature myofibers. Mutant Myf5-derived cells (tdtomato-positive cells) are randomly scattered in the myogenic and non-myogenic regions, indicating loss of the community effect required for skeletal muscle differentiation. Single-cell RNA-sequencing reveals high heterogeneity of myf5-derived cells and non-myogenic cells are significantly increased at the expense of skeletal muscle cells in the absence of SRSF2, reflecting altered cell fate. SRSF2 is demonstrated to regulate the entry of Myf5 cells into the myogenic program and ensures their survival by preventing precocious differentiation and apoptosis. In summary, SRSF2 functions as an essential regulator for Myf5-derived cells to respond correctly to positional cues and to adopt their myogenic fate.
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Affiliation(s)
- Ruochen Guo
- CAS Key Laboratory of NutritionMetabolism and Food SafetyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031P. R. China
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong ProvinceJining Medical UniversityJining272067P. R. China
| | - Xue You
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong ProvinceJining Medical UniversityJining272067P. R. China
| | - Kai Meng
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong ProvinceJining Medical UniversityJining272067P. R. China
| | - Rula Sha
- CAS Key Laboratory of NutritionMetabolism and Food SafetyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031P. R. China
| | - Zhenzhen Wang
- CAS Key Laboratory of NutritionMetabolism and Food SafetyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031P. R. China
| | - Ningyang Yuan
- CAS Key Laboratory of NutritionMetabolism and Food SafetyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031P. R. China
| | - Qian Peng
- CAS Key Laboratory of NutritionMetabolism and Food SafetyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031P. R. China
| | - Zhigang Li
- CAS Key Laboratory of NutritionMetabolism and Food SafetyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031P. R. China
| | - Zhiqin Xie
- CAS Key Laboratory of NutritionMetabolism and Food SafetyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031P. R. China
| | - Ruijiao Chen
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong ProvinceJining Medical UniversityJining272067P. R. China
| | - Ying Feng
- CAS Key Laboratory of NutritionMetabolism and Food SafetyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031P. R. China
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong ProvinceJining Medical UniversityJining272067P. R. China
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10
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Teng Y, Fan Y, Ma J, Lu W, Liu N, Chen Y, Pan W, Tao X. The PI3K/Akt Pathway: Emerging Roles in Skin Homeostasis and a Group of Non-Malignant Skin Disorders. Cells 2021; 10:cells10051219. [PMID: 34067630 PMCID: PMC8156939 DOI: 10.3390/cells10051219] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 12/20/2022] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway regulates cell proliferation, differentiation, and migration, along with angiogenesis and metabolism. Additionally, it could mediate skin development and homeostasis. There is much evidence to suggest that dysregulation of PI3K/Akt pathway is frequently associated with several human cutaneous malignancies like malignant melanoma (MM), basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (SCC), as well as their poor outcomes. Nevertheless, emerging roles of PI3K/Akt pathway cascade in a group of common non-malignant skin disorders including acne and psoriasis, among others, have been recognized. The enhanced understanding of dysfunction of PI3K/Akt pathway in patients with these non-malignant disorders has offered a solid foundation for the progress of updated therapeutic targets. This article reviews the latest advances in the roles of PI3K/Akt pathway and their targets in the skin homeostasis and progression of a wide range of non-malignant skin disorders and describes the current progress in preclinical and clinical researches on the involvement of PI3K/Akt pathway targeted therapies.
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Affiliation(s)
- Yan Teng
- Department of Dermatology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China; (Y.T.); (Y.F.); (J.M.); (W.L.)
| | - Yibin Fan
- Department of Dermatology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China; (Y.T.); (Y.F.); (J.M.); (W.L.)
| | - Jingwen Ma
- Department of Dermatology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China; (Y.T.); (Y.F.); (J.M.); (W.L.)
| | - Wei Lu
- Department of Dermatology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China; (Y.T.); (Y.F.); (J.M.); (W.L.)
| | - Na Liu
- Graduate School of Bengbu Medical College, Bengbu 233000, China; (N.L.); (Y.C.)
| | - Yingfang Chen
- Graduate School of Bengbu Medical College, Bengbu 233000, China; (N.L.); (Y.C.)
| | - Weili Pan
- Department of Dermatology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China; (Y.T.); (Y.F.); (J.M.); (W.L.)
- Correspondence: (W.P.); (X.T.)
| | - Xiaohua Tao
- Department of Dermatology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China; (Y.T.); (Y.F.); (J.M.); (W.L.)
- Correspondence: (W.P.); (X.T.)
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11
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Williams AL, Bohnsack BL. The Ocular Neural Crest: Specification, Migration, and Then What? Front Cell Dev Biol 2021; 8:595896. [PMID: 33425902 PMCID: PMC7785809 DOI: 10.3389/fcell.2020.595896] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 12/04/2020] [Indexed: 12/11/2022] Open
Abstract
During vertebrate embryonic development, a population of dorsal neural tube-derived stem cells, termed the neural crest (NC), undergo a series of morphogenetic changes and extensive migration to become a diverse array of cell types. Around the developing eye, this multipotent ocular NC cell population, called the periocular mesenchyme (POM), comprises migratory mesenchymal cells that eventually give rise to many of the elements in the anterior of the eye, such as the cornea, sclera, trabecular meshwork, and iris. Molecular cell biology and genetic analyses of congenital eye diseases have provided important information on the regulation of NC contributions to this area of the eye. Nevertheless, a complete understanding of the NC as a contributor to ocular development remains elusive. In addition, positional information during ocular NC migration and the molecular pathways that regulate end tissue differentiation have yet to be fully elucidated. Further, the clinical challenges of ocular diseases, such as Axenfeld-Rieger syndrome (ARS), Peters anomaly (PA) and primary congenital glaucoma (PCG), strongly suggest the need for better treatments. While several aspects of NC evolution have recently been reviewed, this discussion will consolidate the most recent current knowledge on the specification, migration, and contributions of the NC to ocular development, highlighting the anterior segment and the knowledge obtained from the clinical manifestations of its associated diseases. Ultimately, this knowledge can inform translational discoveries with potential for sorely needed regenerative therapies.
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Affiliation(s)
- Antionette L Williams
- Division of Ophthalmology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States
| | - Brenda L Bohnsack
- Division of Ophthalmology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States.,Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
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12
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Deng Z, Liu F, Chen M, Huang C, Xiao W, Gao S, Jian D, Ouyang Y, Xu S, Li J, Shi Q, Xie H, Zhang G, Li J. Keratinocyte-Immune Cell Crosstalk in a STAT1-Mediated Pathway: Novel Insights Into Rosacea Pathogenesis. Front Immunol 2021; 12:674871. [PMID: 34290700 PMCID: PMC8287635 DOI: 10.3389/fimmu.2021.674871] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 06/21/2021] [Indexed: 02/05/2023] Open
Abstract
Rosacea is a common chronic inflammatory condition that mainly affects the central face. However, the molecular background of the normal central face and the transcriptional profiling and immune cell composition of rosacea lesions remain largely unknown. Here, we performed whole-skin and epidermal RNA-seq of central facial skin from healthy individuals, lesions and matched normal skin from rosacea patients. From whole-skin RNA-seq, the site-specific gene signatures for central facial skin were mainly enriched in epithelial cell differentiation, with upregulation of the activator protein-1 (AP1) transcription factor (TF). We identified the common upregulated inflammatory signatures and diminished keratinization signature for rosacea lesions. Gene ontology, pathway, TF enrichment and immunohistochemistry results suggested that STAT1 was the potential core of the critical TF networks connecting the epithelial-immune crosstalk in rosacea lesions. Epidermal RNA-seq and immunohistochemistry analysis further validated the epithelial-derived STAT1 signature in rosacea lesions. The epidermal STAT1/IRF1 signature was observed across ETR, PPR, and PhR subtypes. Immune cell composition revealed that macrophages were common in all 3 subtypes. Finally, we described subtype-specific gene signatures and immune cell composition correlated with phenotypes. These findings reveal the specific epithelial differentiation in normal central facial skin, and epithelial-immune crosstalk in lesions providing insight into an initial keratinocyte pattern in the pathogenesis of rosacea.
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Affiliation(s)
- Zhili Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China
| | - Fangfen Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Mengting Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China
| | - Chuchu Huang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China
| | - Wenqin Xiao
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China
| | - Sini Gao
- Department of Pathology, Shantou University Medical College, Shantou, China
| | - Dan Jian
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Yuyan Ouyang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - San Xu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China
| | - Jinmao Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Qian Shi
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Hongfu Xie
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Guohong Zhang
- Department of Pathology, Shantou University Medical College, Shantou, China
- *Correspondence: Ji Li, ; Guohong Zhang,
| | - Ji Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China
- Department of Dermatology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- *Correspondence: Ji Li, ; Guohong Zhang,
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13
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Wang B, Liu XM, Liu ZN, Wang Y, Han X, Lian AB, Mu Y, Jin MH, Liu JY. Human hair follicle-derived mesenchymal stem cells: Isolation, expansion, and differentiation. World J Stem Cells 2020; 12:462-470. [PMID: 32742563 PMCID: PMC7360986 DOI: 10.4252/wjsc.v12.i6.462] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/18/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
Hair follicles are easily accessible skin appendages that protect against cold and potential injuries. Hair follicles contain various pools of stem cells, such as epithelial, melanocyte, and mesenchymal stem cells (MSCs) that continuously self-renew, differentiate, regulate hair growth, and maintain skin homeostasis. Recently, MSCs derived from the dermal papilla or dermal sheath of the human hair follicle have received attention because of their accessibility and broad differentiation potential. In this review, we describe the applications of human hair follicle-derived MSCs (hHF-MSCs) in tissue engineering and regenerative medicine. We have described protocols for isolating hHF-MSCs from human hair follicles and their culture condition in detail. We also summarize strategies for maintaining hHF-MSCs in a highly proliferative but undifferentiated state after repeated in vitro passages, including supplementation of growth factors, 3D suspension culture technology, and 3D aggregates of MSCs. In addition, we report the potential of hHF-MSCs in obtaining induced smooth muscle cells and tissue-engineered blood vessels, regenerated hair follicles, induced red blood cells, and induced pluripotent stem cells. In summary, the abundance, convenient accessibility, and broad differentiation potential make hHF-MSCs an ideal seed cell source of regenerative medical and cell therapy.
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Affiliation(s)
- Bo Wang
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Xiao-Mei Liu
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Zi-Nan Liu
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Yuan Wang
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Xing Han
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Ao-Bo Lian
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Ying Mu
- Research Center for Analytical Instrumentation, Institute of Cyber-Systems and Control, State Key Laboratory of Industrial Control Technology, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Ming-Hua Jin
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Jin-Yu Liu
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
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14
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Abstract
Wild sheep and many primitive domesticated breeds have two coats: coarse hairs covering shorter, finer fibres. Both are shed annually. Exploitation of wool for apparel in the Bronze Age encouraged breeding for denser fleeces and continuously growing white fibres. The Merino is regarded as the culmination of this process. Archaeological discoveries, ancient images and parchment records portray this as an evolutionary progression, spanning millennia. However, examination of the fleeces from feral, two-coated and woolled sheep has revealed a ready facility of the follicle population to change from shedding to continuous growth and to revert from domesticated to primitive states. Modifications to coat structure, colour and composition have occurred in timeframes and to sheep population sizes that exclude the likelihood of variations arising from mutations and natural selection. The features are characteristic of the domestication phenotype: an assemblage of developmental, physiological, skeletal and hormonal modifications common to a wide variety of species under human control. The phenotypic similarities appeared to result from an accumulation of cryptic genetic changes early during vertebrate evolution. Because they did not affect fitness in the wild, the mutations were protected from adverse selection, becoming apparent only after exposure to a domestic environment. The neural crest, a transient embryonic cell population unique to vertebrates, has been implicated in the manifestations of the domesticated phenotype. This hypothesis is discussed with reference to the development of the wool follicle population and the particular roles of Notch pathway genes, culminating in the specific cell interactions that typify follicle initiation.
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15
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Inflammation Alters the Secretome and Immunomodulatory Properties of Human Skin-Derived Precursor Cells. Cells 2020; 9:cells9040914. [PMID: 32276503 PMCID: PMC7226778 DOI: 10.3390/cells9040914] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/25/2020] [Accepted: 04/04/2020] [Indexed: 12/11/2022] Open
Abstract
Human skin-derived precursors (SKP) represent a group of somatic stem/precursor cells that reside in dermal skin throughout life that harbor clinical potential. SKP have a high self-renewal capacity, the ability to differentiate into multiple cell types and low immunogenicity, rendering them key candidates for allogeneic cell-based, off-the-shelf therapy. However, potential clinical application of allogeneic SKP requires that these cells retain their therapeutic properties under all circumstances and, in particular, in the presence of an inflammation state. Therefore, in this study, we investigated the impact of pro-inflammatory stimulation on the secretome and immunosuppressive properties of SKP. We demonstrated that pro-inflammatory stimulation of SKP significantly changes their expression and the secretion profile of chemo/cytokines and growth factors. Most importantly, we observed that pro-inflammatory stimulated SKP were still able to suppress the graft-versus-host response when cotransplanted with human PBMC in severe-combined immune deficient (SCID) mice, albeit to a much lesser extent than unstimulated SKP. Altogether, this study demonstrates that an inflammatory microenvironment has a significant impact on the immunological properties of SKP. These alterations need to be taken into account when developing allogeneic SKP-based therapies.
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16
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Gleeson BT. Masculinity and the Mechanisms of Human Self-Domestication. ADAPTIVE HUMAN BEHAVIOR AND PHYSIOLOGY 2020. [DOI: 10.1007/s40750-019-00126-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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17
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Bergeron L, Busuttil V, Botto JM. Multipotentiality of skin-derived precursors: application to the regeneration of skin and other tissues. Int J Cosmet Sci 2020; 42:5-15. [PMID: 31612512 DOI: 10.1111/ics.12587] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 10/12/2019] [Indexed: 12/13/2022]
Abstract
Skin-derived precursors (SKPs) have been described as multipotent dermal precursors. Here, we provide a review of the breadth and depth of scientific literature and studies regarding SKPs, accounting for a large number of scientific publications. Interestingly, these progenitors can be isolated from embryonic and adult skin, as well as from a population of dermal cells cultured in vitro in monolayer. Gathering information from different authors, this review explores different aspects of the SKP theme, such as the potential distinct origins of SKPs in rodents and in humans, and also their ability to differentiate in vitro and in vivo into multiple lineages of different progeny. This remarkable capacity makes SKPs an interesting endogenous source of precursors to explore in the framework of experimental and therapeutic applications in different domains. SKPs are not only involved in the skin's dermal maintenance and support as well as wound healing, but also in hair follicle morphogenesis. This review points out the interests of future researches on SKPs for innovative perspectives that may be helpful in many different types of scientific and medical domains.
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Affiliation(s)
- L Bergeron
- Ashland Specialties France, Global Skin Research Center, 655, route du Pin Montard, 06904, Sophia Antipolis, France
| | - V Busuttil
- Ashland Specialties France, Global Skin Research Center, 655, route du Pin Montard, 06904, Sophia Antipolis, France
| | - J-M Botto
- Ashland Specialties France, Global Skin Research Center, 655, route du Pin Montard, 06904, Sophia Antipolis, France
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18
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Yang Z, Ma S, Cao R, Liu L, Cao C, Shen Z, Fu X, Yan L, Wang Q, Liu X, Xiao R. CD49f high Defines a Distinct Skin Mesenchymal Stem Cell Population Capable of Hair Follicle Epithelial Cell Maintenance. J Invest Dermatol 2019; 140:544-555.e9. [PMID: 31494092 DOI: 10.1016/j.jid.2019.08.442] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/21/2019] [Accepted: 08/25/2019] [Indexed: 12/15/2022]
Abstract
The dermis harbors distinct mesenchymal stem cell (MSC) populations, which play equally important roles as epidermal stem cells in skin homeostasis and regeneration. However, to reliably identify and directly isolate the in vivo counterpart of these cells is still challenging. Using the epidermal stem cell marker CD49f, we defined a CD49fhigh distinct mesenchymal subpopulation in the dermis. In vitro and in vivo differentiation assays, and transcriptome analysis demonstrated that CD49fhigh cells possess neural crest-like cell characteristics. Our results showed that the formation of hair follicle-like budding structure and the expressions of key genes regulating hair follicle development were induced when hair follicle epithelial cells were co-cultured with CD49fhigh cells. We also found that CD49fhigh cells activated Notch signaling in co-cultured hair follicle epithelial cells, whereas the inhibition of Notch signaling resulted in epidermal cyst-like spheres and loss of maintenance of hair follicle epithelial cell characteristics. Furthermore, we identified Itga7 and CD49f as an efficient biomarker panel for direct selection of CD49fhigh skin MSCs. Our results lead to a deeper understanding of heterogeneity and the function of MSCs in the skin and may facilitate potential translational applications of these cells.
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Affiliation(s)
- Zhigang Yang
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shize Ma
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rui Cao
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ling Liu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunyan Cao
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhihui Shen
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Fu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Yan
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qian Wang
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xia Liu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ran Xiao
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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19
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Novak D, Hüser L, Elton JJ, Umansky V, Altevogt P, Utikal J. SOX2 in development and cancer biology. Semin Cancer Biol 2019; 67:74-82. [PMID: 31412296 DOI: 10.1016/j.semcancer.2019.08.007] [Citation(s) in RCA: 214] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 08/05/2019] [Accepted: 08/08/2019] [Indexed: 01/06/2023]
Abstract
The transcription factor SOX2 is essential for embryonic development and plays a crucial role in maintaining the stemness of embryonic cells and various adult stem cell populations. On the other hand, dysregulation of SOX2 expression is associated with a multitude of cancer types and it has been shown that SOX2 positively affects cancer cell traits such as the capacity to proliferate, migrate, invade and metastasize. Moreover, there is growing evidence that SOX2 mediates resistance towards established cancer therapies and that it is expressed in cancer stem cells. These findings indicate that studying the role of SOX2 in the context of cancer progression could lead to the development of new therapeutic options. In this review, the current knowledge about the role of SOX2 in development, maintenance of stemness, cancer progression and the resistance towards cancer therapies is summarized.
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Affiliation(s)
- Daniel Novak
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Laura Hüser
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Jonathan J Elton
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Viktor Umansky
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Peter Altevogt
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Jochen Utikal
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
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20
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Zatkova M, Reichova A, Bacova Z, Bakos J. Activation of the Oxytocin Receptor Modulates the Expression of Synaptic Adhesion Molecules in a Cell-Specific Manner. J Mol Neurosci 2019; 68:171-180. [DOI: 10.1007/s12031-019-01296-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 03/11/2019] [Indexed: 11/29/2022]
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21
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22
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Regulatory effects of dermal papillary pluripotent stem cells on polarization of macrophages from M1 to M2 phenotype in vitro. Transpl Immunol 2019; 52:57-67. [DOI: 10.1016/j.trim.2018.11.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 11/14/2018] [Accepted: 11/16/2018] [Indexed: 12/15/2022]
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23
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Brokhman I, Xu J, Coles BL, Razavi R, Engert S, Lickert H, Babona-Pilipos R, Morshead CM, Sibley E, Chen C, van der Kooy D. Dual embryonic origin of the mammalian enteric nervous system. Dev Biol 2019; 445:256-270. [DOI: 10.1016/j.ydbio.2018.11.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 11/21/2018] [Accepted: 11/21/2018] [Indexed: 02/05/2023]
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24
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Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound Healing: A Cellular Perspective. Physiol Rev 2019; 99:665-706. [PMID: 30475656 PMCID: PMC6442927 DOI: 10.1152/physrev.00067.2017] [Citation(s) in RCA: 1564] [Impact Index Per Article: 260.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 06/25/2018] [Accepted: 06/28/2018] [Indexed: 02/08/2023] Open
Abstract
Wound healing is one of the most complex processes in the human body. It involves the spatial and temporal synchronization of a variety of cell types with distinct roles in the phases of hemostasis, inflammation, growth, re-epithelialization, and remodeling. With the evolution of single cell technologies, it has been possible to uncover phenotypic and functional heterogeneity within several of these cell types. There have also been discoveries of rare, stem cell subsets within the skin, which are unipotent in the uninjured state, but become multipotent following skin injury. Unraveling the roles of each of these cell types and their interactions with each other is important in understanding the mechanisms of normal wound closure. Changes in the microenvironment including alterations in mechanical forces, oxygen levels, chemokines, extracellular matrix and growth factor synthesis directly impact cellular recruitment and activation, leading to impaired states of wound healing. Single cell technologies can be used to decipher these cellular alterations in diseased states such as in chronic wounds and hypertrophic scarring so that effective therapeutic solutions for healing wounds can be developed.
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Affiliation(s)
- Melanie Rodrigues
- Department of Surgery, Stanford University School of Medicine , Stanford, California
| | - Nina Kosaric
- Department of Surgery, Stanford University School of Medicine , Stanford, California
| | - Clark A Bonham
- Department of Surgery, Stanford University School of Medicine , Stanford, California
| | - Geoffrey C Gurtner
- Department of Surgery, Stanford University School of Medicine , Stanford, California
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The Human Skin-Derived Precursors for Regenerative Medicine: Current State, Challenges, and Perspectives. Stem Cells Int 2018; 2018:8637812. [PMID: 30123295 PMCID: PMC6079335 DOI: 10.1155/2018/8637812] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/29/2018] [Accepted: 06/13/2018] [Indexed: 02/05/2023] Open
Abstract
Skin-derived precursors (SKPs) are an adult stem cell source with self-renewal and multipotent differentiation. Although rodent SKPs have been discussed in detail in substantial studies, human SKPs (hSKPs) are rarely reported. Understanding the biological properties and possible mechanisms underlying hSKPs has important implications for regenerative medicine particularly clinical applications, as human-derived sources are more suitable for clinical transplantation. The finding that hSKPs derivatives, such as neural and mesodermal progeny, have both in vitro and in vivo function without any genetical modification makes hSKPs a trustable, secure, and accessible resource for cell-based therapy. Here, we provide an overview of hSKPs, describing their characteristics, originations and niches, and potential applications. A comparison between traditional and innovative culture methods used for hSKPs is also introduced. Furthermore, we discuss the challenges and the future perspectives towards the field of hSKPs. With this review, we hope to point out the current stage of hSKPs and highlight the problems that remain in this field.
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Steinbach SK, Wang T, Carruthers MH, Li A, Besla R, Johnston AP, Robbins CS, Husain M. Aortic Sca-1 + Progenitor Cells Arise from the Somitic Mesoderm Lineage in Mice. Stem Cells Dev 2018; 27:888-897. [PMID: 29717623 DOI: 10.1089/scd.2018.0038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Sca-1+ progenitor cells in the adult mouse aorta are known to generate vascular smooth muscle cells (VSMCs), but their embryological origins and temporal abundance are not known. Using tamoxifen-inducible Myf5-CreER mice, we demonstrate that Sca-1+ adult aortic cells arise from the somitic mesoderm beginning at E8.5 and continue throughout somitogenesis. Myf5 lineage-derived Sca-1+ cells greatly expand in situ, starting at 4 weeks of age, and become a major source of aortic Sca-1+ cells by 6 weeks of age. Myf5-derived adult aortic cells are capable of forming multicellular sphere-like structures in vitro and express the pluripotency marker Sox2. Exposure to transforming growth factor-β3 induces these spheres to differentiate into calponin-expressing VSMCs. Pulse-chase experiments using tamoxifen-inducible Sox2-CreERT2 mice at 8 weeks of age demonstrate that ∼35% of all adult aortic Sca-1+ cells are derived from Sox2+ cells. The present study demonstrates that aortic Sca-1+ progenitor cells are derived from the somitic mesoderm formed at the earliest stages of somitogenesis and from Sox2-expressing progenitors in adult mice.
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Affiliation(s)
- Sarah K Steinbach
- 1 Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network , Toronto, Canada .,2 McEwen Centre for Regenerative Medicine, University Health Network , Toronto, Canada
| | - Tao Wang
- 1 Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network , Toronto, Canada .,3 Department of Physiology, University of Toronto , Toronto, Canada .,4 Cardiovascular Sciences Collaborative Program, University of Toronto , Toronto, Canada
| | - Martha H Carruthers
- 1 Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network , Toronto, Canada
| | - Angela Li
- 5 Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network , Toronto, Canada .,6 Ted Rogers Centre for Heart Research, University Health Network , Toronto, Canada .,7 Peter Munk Cardiac Centre, University Health Network , Toronto, Canada .,8 Department of Immunology, University of Toronto , Toronto, Canada
| | - Rickvinder Besla
- 5 Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network , Toronto, Canada .,6 Ted Rogers Centre for Heart Research, University Health Network , Toronto, Canada .,7 Peter Munk Cardiac Centre, University Health Network , Toronto, Canada .,9 Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Canada
| | | | - Clinton S Robbins
- 5 Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network , Toronto, Canada .,6 Ted Rogers Centre for Heart Research, University Health Network , Toronto, Canada .,7 Peter Munk Cardiac Centre, University Health Network , Toronto, Canada .,8 Department of Immunology, University of Toronto , Toronto, Canada .,9 Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Canada
| | - Mansoor Husain
- 1 Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network , Toronto, Canada .,2 McEwen Centre for Regenerative Medicine, University Health Network , Toronto, Canada .,3 Department of Physiology, University of Toronto , Toronto, Canada .,4 Cardiovascular Sciences Collaborative Program, University of Toronto , Toronto, Canada .,6 Ted Rogers Centre for Heart Research, University Health Network , Toronto, Canada .,7 Peter Munk Cardiac Centre, University Health Network , Toronto, Canada .,9 Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Canada .,11 Department of Medicine, University of Toronto , Toronto, Canada
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Duncan T, Lowe A, Sidhu K, Sachdev P, Lewis T, Lin RCY, Sytnyk V, Valenzuela M. Replicable Expansion and Differentiation of Neural Precursors from Adult Canine Skin. Stem Cell Reports 2018; 9:557-570. [PMID: 28793248 PMCID: PMC5550271 DOI: 10.1016/j.stemcr.2017.07.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 07/07/2017] [Accepted: 07/10/2017] [Indexed: 11/28/2022] Open
Abstract
Repopulation of brain circuits by neural precursors is a potential therapeutic strategy for neurodegenerative disorders; however, choice of cell is critical. Previously, we introduced a two-step culture system that generates a high yield of neural precursors from small samples of adult canine skin. Here, we probe their gene and protein expression profiles in comparison with dermal fibroblasts and brain-derived neural stem cells and characterize their neuronal potential. To date, we have produced >50 skin-derived neural precursor (SKN) lines. SKNs can be cultured in a highly replicable fashion and uniformly express a panel of identifying markers. Upon differentiation, they self-upregulate neural specification genes, generating neurons with basic electrophysiological functionality. This unique population of neural precursors, derived from mature skin, overcomes many of the practical issues that have limited clinical translation of alternative cell types. Easily accessible, neuronally committed, and patient specific, SKNs may have potential for the treatment of brain disorders.
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Affiliation(s)
- Thomas Duncan
- Regenerative Neuroscience Group, Brain and Mind Centre, University of Sydney, Sydney, NSW 2050, Australia
| | - Aileen Lowe
- Regenerative Neuroscience Group, Brain and Mind Centre, University of Sydney, Sydney, NSW 2050, Australia; Stem Cell Laboratory, University of New South Wales, Sydney, NSW 2031, Australia
| | - Kuldip Sidhu
- Stem Cell Laboratory, University of New South Wales, Sydney, NSW 2031, Australia
| | - Perminder Sachdev
- Centre for Healthy Brain Ageing, University of New South Wales, Sydney, NSW 2031, Australia; School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia
| | - Trevor Lewis
- School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Ruby C Y Lin
- School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Vladimir Sytnyk
- School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Michael Valenzuela
- Regenerative Neuroscience Group, Brain and Mind Centre, University of Sydney, Sydney, NSW 2050, Australia.
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28
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Yang SH, Choi MH, Shin HJ. UV Protection Effect of Lignin Extracted by Steam Explosion Technique from Domestic Bamboo Stems. ACTA ACUST UNITED AC 2017. [DOI: 10.7841/ksbbj.2017.32.4.342] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abstract
The sensation of touch is mediated by mechanosensory neurons that are embedded in skin and relay signals from the periphery to the central nervous system. During embryogenesis, axons elongate from these neurons to make contact with the developing skin. Concurrently, the epithelium of skin transforms from a homogeneous tissue into a heterogeneous organ that is made up of distinct layers and microdomains. Throughout this process, each neuronal terminal must form connections with an appropriate skin region to serve its function. This Review presents current knowledge of the development of the sensory microdomains in mammalian skin and the mechanosensory neurons that innervate them.
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Affiliation(s)
- Blair A Jenkins
- Department of Physiology & Cellular Biophysics and Department of Dermatology, Columbia University in the City of New York, New York, NY 10032, USA
| | - Ellen A Lumpkin
- Department of Physiology & Cellular Biophysics and Department of Dermatology, Columbia University in the City of New York, New York, NY 10032, USA
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30
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Iribar H, Pérez-López V, Etxaniz U, Gutiérrez-Rivera A, Izeta A. Schwann Cells in the Ventral Dermis Do Not Derive from Myf5-Expressing Precursors. Stem Cell Reports 2017; 9:1477-1487. [PMID: 29033303 PMCID: PMC5830985 DOI: 10.1016/j.stemcr.2017.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 09/12/2017] [Accepted: 09/13/2017] [Indexed: 12/19/2022] Open
Abstract
The embryonic origin of lineage precursors of the trunk dermis is somewhat controversial. Precursor cells traced by Myf5 and Twist2 (Dermo1) promoter activation (i.e., cells of presumed dermomyotomal lineage) have been reported to generate Schwann cells. On the other hand, abundant data demonstrate that dermal Schwann cells derive from the neural crest. This is relevant because dermal precursors give rise to neural lineages, and multilineage differentiation potential qualifies them as adult stem cells. However, it is currently unclear whether neural lineages arise from dedifferentiated Schwann cells instead of mesodermally derived dermal precursor cells. To clarify these discrepancies, we traced SOX2+ adult dermal precursor cells by two independent Myf5 lineage tracing strains. We demonstrate that dermal Schwann cells do not belong to the Myf5+ cell lineage, indicating that previous tracing data reflected aberrant cre recombinase expression and that bona fide Myf5+ dermal precursors cannot transdifferentiate to neural lineages in physiological conditions.
Adult Myf5-creSor mice aberrantly trace dermal Schwann cells (dSCs) Dedifferentiated, SOX2+ dSCs are the neural-competent precursors in the dermis These findings cast doubt on the multipotency of adult skin-derived precursors
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Affiliation(s)
- Haizea Iribar
- Tissue Engineering Laboratory, Bioengineering Area, Instituto Biodonostia, San Sebastian 20014, Spain
| | - Virginia Pérez-López
- Tissue Engineering Laboratory, Bioengineering Area, Instituto Biodonostia, San Sebastian 20014, Spain
| | - Usue Etxaniz
- Tissue Engineering Laboratory, Bioengineering Area, Instituto Biodonostia, San Sebastian 20014, Spain
| | - Araika Gutiérrez-Rivera
- Tissue Engineering Laboratory, Bioengineering Area, Instituto Biodonostia, San Sebastian 20014, Spain.
| | - Ander Izeta
- Tissue Engineering Laboratory, Bioengineering Area, Instituto Biodonostia, San Sebastian 20014, Spain; Department of Biomedical Engineering, School of Engineering, Tecnun-University of Navarra, San Sebastian 20009, Spain.
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31
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Fan Z, Miao Y, Qu Q, Xiao S, Wang J, Du L, Liu B, Hu Z. Unlocking the vital role of host cells in hair follicle reconstruction by semi-permeable capsules. PLoS One 2017; 12:e0179279. [PMID: 28614369 PMCID: PMC5470686 DOI: 10.1371/journal.pone.0179279] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 05/27/2017] [Indexed: 12/21/2022] Open
Abstract
Organ regeneration is becoming a promising choice for many patients; however, many details about the mechanisms underlying organ regeneration remain unknown. As regenerative organs, hair follicles offer a good model to study the mechanisms associated with regenerative medicine. The relevant studies have mainly focused on donor cells, and there are no systematic studies involving the effect of host factors on hair follicle reconstruction. Thus, we intend to explore the effect of host cells on hair follicle reconstruction. Epidermal and dermal cells from red fluorescent protein (RFP) transgenic newborn mice were injected into green fluorescent protein (GFP) transgenic mice. In addition, we wrapped the mixed dermal and epidermal cells from GFP transgenic and RFP transgenic mice by the Cell-in-a-Box kit to form "capsules," so that the cells within would be isolated from host cells. These capsules were cultured in vitro and transplanted in vivo. Fully developed reconstructed hair follicles were observed after the injection of mixed cells. These reconstructed follicles mainly consisted of donor cells, as well as a small number of host cells. The encapsulated cells gradually aggregated into cell spheres in vitro without apparent differentiation towards hair follicles. With respect to the transplanted capsules, concentric circle structures were observed, but no hair follicles or hair shafts formed. When the concentric circle structures were transplanted in vivo, mature hair follicles were observed 30 days later. Host cells were found in the reconstructed hair follicles. Thus, we conclude that host cells participate in the process of hair follicle reconstruction, and they play a vital role in the process, especially for the maturation of reconstructed hair follicles. Furthermore, we established a special hair follicle reconstruction system with the help of capsules: transplant cells were isolated from host, but other factors from host could exchange with cells inside.
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Affiliation(s)
- Zhexiang Fan
- Department of Plastic and Aesthetic Surgery, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yong Miao
- Department of Plastic and Aesthetic Surgery, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qian Qu
- Department of Plastic and Aesthetic Surgery, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shune Xiao
- Department of Plastic and Aesthetic Surgery, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jin Wang
- Department of Plastic and Aesthetic Surgery, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lijuan Du
- Department of Plastic and Aesthetic Surgery, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Bingcheng Liu
- Department of Plastic and Aesthetic Surgery, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhiqi Hu
- Department of Plastic and Aesthetic Surgery, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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32
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Huang WY, Huang YC, Huang KS, Chan CC, Chiu HY, Tsai RY, Chan JY, Lin SJ. Stress-induced premature senescence of dermal papilla cells compromises hair follicle epithelial-mesenchymal interaction. J Dermatol Sci 2017; 86:114-122. [DOI: 10.1016/j.jdermsci.2017.01.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Revised: 11/24/2016] [Accepted: 01/05/2017] [Indexed: 12/11/2022]
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33
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Chen G, Ishan M, Yang J, Kishigami S, Fukuda T, Scott G, Ray MK, Sun C, Chen SY, Komatsu Y, Mishina Y, Liu HX. Specific and spatial labeling of P0-Cre versus Wnt1-Cre in cranial neural crest in early mouse embryos. Genesis 2017; 55. [PMID: 28371069 DOI: 10.1002/dvg.23034] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 03/22/2017] [Accepted: 03/22/2017] [Indexed: 01/02/2023]
Abstract
P0-Cre and Wnt1-Cre mouse lines have been widely used in combination with loxP-flanked mice to label and genetically modify neural crest (NC) cells and their derivatives. Wnt1-Cre has been regarded as the gold standard and there have been concerns about the specificity of P0-Cre because it is not clear about the timing and spatial distribution of the P0-Cre transgene in labeling NC cells at early embryonic stages. We re-visited P0-Cre and Wnt1-Cre models in the labeling of NC cells in early mouse embryos with a focus on cranial NC. We found that R26-lacZ Cre reporter responded to Cre activity more reliably than CAAG-lacZ Cre reporter during early embryogenesis. Cre immunosignals in P0-Cre and reporter (lacZ and RFP) activity in P0-Cre/R26-lacZ and P0-Cre/R26-RFP embryos was detected in the cranial NC and notochord regions in E8.0-9.5 (4-19 somites) embryos. P0-Cre transgene expression was observed in migrating NC cells and was more extensive in the forebrain and hindbrain but not apparent in the midbrain. Differences in the Cre distribution patterns of P0-Cre and Wnt1-Cre were profound in the midbrain and hindbrain regions, that is, extensive in the midbrain of Wnt1-Cre and in the hindbrain of P0-Cre embryos. The difference between P0-Cre and Wnt1-Cre in labeling cranial NC may provide a better explanation of the differential distributions of their NC derivatives and of the phenotypes caused by Cre-driven genetic modifications.
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Affiliation(s)
- Guiqian Chen
- Regenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, Georgia, 30602
| | - Mohamed Ishan
- Regenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, Georgia, 30602
| | - Jingwen Yang
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan, 48109
| | - Satoshi Kishigami
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709
| | - Tomokazu Fukuda
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709
| | - Greg Scott
- Knockout Core, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709
| | - Manas K Ray
- Knockout Core, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709
| | - Chenming Sun
- Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, 30602
| | - Shi-You Chen
- Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, 30602
| | - Yoshihiro Komatsu
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan, 48109.,Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709.,Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, 77030
| | - Yuji Mishina
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan, 48109.,Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709.,Knockout Core, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709
| | - Hong-Xiang Liu
- Regenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, Georgia, 30602
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34
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35
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36
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Inagaki E, Hatou S, Higa K, Yoshida S, Shibata S, Okano H, Tsubota K, Shimmura S. Skin-Derived Precursors as a Source of Progenitors for Corneal Endothelial Regeneration. Stem Cells Transl Med 2017; 6:788-798. [PMID: 28186681 PMCID: PMC5442762 DOI: 10.1002/sctm.16-0162] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 09/16/2016] [Accepted: 09/30/2016] [Indexed: 12/13/2022] Open
Abstract
Corneal blindness is the fourth leading cause of blindness in the world. Current treatment is allogenic corneal transplantation, which is limited by shortage of donors and immunological rejection. Skin-derived precursors (SKPs) are postnatal stem cells, which are self-renewing, multipotent precursors that can be isolated and expanded from the dermis. Facial skin may therefore be an accessible autologous source of neural crest derived cells. SKPs were isolated from facial skin of Wnt1-Cre/Floxed EGFP mouse. After inducing differentiation with medium containing retinoic acid and GSK 3-β inhibitor, SKPs formed polygonal corneal endothelial-like cells (sTECE). Expression of major corneal endothelial markers were confirmed by Reverse transcription polymerase chain reaction (RT-PCR) and quantitative Real time polymerase chain reaction (qRT-PCR). Western blots confirmed the expression of Na, K-ATPase protein, the major functional marker of corneal endothelial cells. Immunohistochemistry revealed the expression of zonular occludens-1 and Na, K-ATPase in cell-cell junctions. In vitro functional analysis of Na, K-ATPase pump activity revealed that sTECE had significantly high pump function compared to SKPs or control 3T3 cells. Moreover, sTECE transplanted into a rabbit model of bullous keratopathy successfully maintained corneal thickness and transparency. Furthermore, we successfully induced corneal endothelial-like cells from human SKPs, and showed that transplanted corneas also maintained corneal transparency and thickness. Our findings suggest that SKPs may be used as a source of autologous cells for the treatment of corneal endothelial disease. Stem Cells Translational Medicine 2017;6:788-798.
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Affiliation(s)
- Emi Inagaki
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Shin Hatou
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Kazunari Higa
- Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan
| | - Satoru Yoshida
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Shinsuke Shibata
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Kazuo Tsubota
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Shigeto Shimmura
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
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37
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Bayati V, Abbaspour MR, Neisi N, Hashemitabar M. Skin-derived precursors possess the ability of differentiation into the epidermal progeny and accelerate burn wound healing. Cell Biol Int 2016; 41:187-196. [PMID: 27981666 DOI: 10.1002/cbin.10717] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 12/10/2016] [Indexed: 12/31/2022]
Abstract
Skin-derived precursors (SKPs) are remnants of the embryonic neural crest stem cells that reside in the dermis until adulthood. Although they possess a wide range of differentiation potentials, their differentiation into keratinocyte-like cells and their roles in skin wound healing are obscure. The present study aimed to investigate the differentiation of SKPs into keratinocyte-like cells and evaluate their role in healing of third degree burn wounds. To this aim, SKPs were differentiated into keratinocyte-like cells on tissue culture plate and collagen-chitosan scaffold prepared by freeze-drying. Their differentiation capability was detected by real-time RT-PCR and immunofluorescence. Thereafter, they were cultured on scaffold and implanted in a rat model of burn wound. Histopathological and immunohistochemical analyses were employed to examine the reconstituted skin. The research findings revealed that SKPs were able to differentiate along the epidermal lineage and this ability can be enhanced on a suitable scaffold. Additionally, the results indicated that SKPs apparently promoted wound healing process and accelerate its transition from proliferating stage to maturational phase, especially if they were differentiated into keratinocyte-like cells. Regarding the results, it is concluded that SKPs are able to differentiate into keratinocyte-like cells, particularly when they are cultured on collagen-chitosan scaffold. Moreover, they can regenerate epidermal and dermal layers including thick collagen bundles, possibly through differentiation into keratinocyte-like cells.
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Affiliation(s)
- Vahid Bayati
- Cellular and Molecular Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 61357-15794, Iran.,Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 61357-15794, Iran
| | - Mohammad Reza Abbaspour
- Targeted Drug Delivery Research Centre, Mashhad University of Medical Sciences, Mashhad, 91775-1365, Iran
| | - Niloofar Neisi
- Department of Medical Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 61357-15794, Iran
| | - Mahmoud Hashemitabar
- Cellular and Molecular Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 61357-15794, Iran.,Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, 61357-15794, Iran
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38
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Liu JA, Cheung M. Neural crest stem cells and their potential therapeutic applications. Dev Biol 2016; 419:199-216. [PMID: 27640086 DOI: 10.1016/j.ydbio.2016.09.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 09/07/2016] [Accepted: 09/07/2016] [Indexed: 12/13/2022]
Abstract
The neural crest (NC) is a remarkable transient structure generated during early vertebrate development. The neural crest progenitors have extensive migratory capacity and multipotency, harboring stem cell-like characteristics such as self-renewal. They can differentiate into a variety of cell types from craniofacial skeletal tissues to the trunk peripheral nervous system (PNS). Multiple regulators such as signaling factors, transcription factors, and migration machinery components are expressed at different stages of NC development. Gain- and loss-of-function studies in various vertebrate species revealed epistatic relationships of these molecules that could be assembled into a gene regulatory network defining the processes of NC induction, specification, migration, and differentiation. These basic developmental studies led to the subsequent establishment and molecular validation of neural crest stem cells (NCSCs) derived by various strategies. We provide here an overview of the isolation and characterization of NCSCs from embryonic, fetal, and adult tissues; the experimental strategies for the derivation of NCSCs from embryonic stem cells, induced pluripotent stem cells, and skin fibroblasts; and recent developments in the use of patient-derived NCSCs for modeling and treating neurocristopathies. We discuss future research on further refinement of the culture conditions required for the differentiation of pluripotent stem cells into axial-specific NC progenitors and their derivatives, developing non-viral approaches for the generation of induced NC cells (NCCs), and using a genomic editing approach to correct genetic mutations in patient-derived NCSCs for transplantation therapy. These future endeavors should facilitate the therapeutic applications of NCSCs in the clinical setting.
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Affiliation(s)
- Jessica Aijia Liu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Martin Cheung
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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39
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Ge W, Cheng SF, Dyce PW, De Felici M, Shen W. Skin-derived stem cells as a source of primordial germ cell- and oocyte-like cells. Cell Death Dis 2016; 7:e2471. [PMID: 27831564 PMCID: PMC5260893 DOI: 10.1038/cddis.2016.366] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 08/30/2016] [Accepted: 09/01/2016] [Indexed: 12/19/2022]
Abstract
The skin is a unique organ that contains a variety of stem cells for the maintenance of skin homeostasis and the repair of skin tissues following injury and disease. Skin-derived stem cells (SDSCs) constitute a heterogeneous population of stem cells generated in vitro from dermis, which can be cultured as spherical aggregates of cells in suspension culture. Under certain in vitro or in vivo conditions, SDSCs show multipotency and can generate a variety of neural, mesodermal, and endodermal cell types such as neurons, glia, fibroblasts, adipocytes, muscle cells, chondroblasts, osteoblats, and islet β-cell-like cells. SDSCs are likely derived from multipotent stem cells located in the hair follicles that are, in turn, derived from embryonic migratory neural crest or mesoderm cells. During the past decade, a wave of reports have shown that germ cells can be generated from various types of stem cells. It has been shown that SDSCs are able to produce primordial germ cell-like cells in vitro, and even oocyte-like cells (OLCs). Whether these germ cell-like cells (GCLCs) can give rise to viable progeny remains, however, unknown. In this review, we will discuss the origin and characteristics of SDSCs from which the GCLC are derived, the possible mechanisms of this differentiation process, and finally the prospective biomedical applications of the SDSC-derived GCLCs.
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Affiliation(s)
- Wei Ge
- Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Shun-Feng Cheng
- Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Paul W Dyce
- Department of Animal Sciences, Auburn University, Auburn, AL 36849, USA
| | - Massimo De Felici
- Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome 00133, Italy
| | - Wei Shen
- Institute of Reproductive Sciences, Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong, College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
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Abstract
From the initial discovery of the neural crest over 150 years ago to the seminal studies of Le Douarin and colleagues in the latter part of the twentieth century, understanding of the neural crest has moved from the descriptive to the experimental. Now, in the twenty-first century, neural crest research has migrated into the genomic age. Here, we reflect upon the major advances in neural crest biology and the open questions that will continue to make research on this incredible vertebrate cell type an important subject in developmental biology for the century to come.
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Affiliation(s)
- Marianne E Bronner
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
| | - Marcos Simões-Costa
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA
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41
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Kameda Y. Cellular and molecular events on the development of mammalian thyroid C cells. Dev Dyn 2016; 245:323-41. [PMID: 26661795 DOI: 10.1002/dvdy.24377] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 08/05/2015] [Indexed: 12/12/2022] Open
Abstract
Thyroid C cells synthesize and secrete calcitonin, a serum calcium-lowering hormone. This review provides our current understanding of mammalian thyroid C cells from the molecular and morphological perspectives. Several transcription factors and signaling molecules involved in the development of C cells have been identified, and genes expressed in the pharyngeal pouch endoderm, neural crest-derived mesenchyme in the pharyngeal arches, and ultimobranchial body play critical roles for the development of C cells. It has been generally accepted, without much-supporting evidence, that mammalian C cells, as well as the avian cells, are derived from the neural crest. However, by fate mapping of neural crest cells in both Wnt1-Cre/R26R and Connexin(Cxn)43-lacZ transgenic mice, we showed that neural crest cells colonize neither the fourth pharyngeal pouch nor the ultimobranchial body. E-cadherin, an epithelial cell marker, is expressed in thyroid C cells and their precursors, the fourth pharyngeal pouch and ultimobranchial body. Furthermore, E-cadherin is colocalized with calcitonin in C cells. Recently, lineage tracing in Sox17-2A-iCre/R26R mice has clarified that the pharyngeal endoderm-derived cells give rise to C cells. Together, these findings indicate that mouse thyroid C cells are endodermal in origin.
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Affiliation(s)
- Yoko Kameda
- Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
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42
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Naska S, Yuzwa SA, Johnston APW, Paul S, Smith KM, Paris M, Sefton MV, Datti A, Miller FD, Kaplan DR. Identification of Drugs that Regulate Dermal Stem Cells and Enhance Skin Repair. Stem Cell Reports 2015; 6:74-84. [PMID: 26724904 PMCID: PMC4719140 DOI: 10.1016/j.stemcr.2015.12.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 12/01/2015] [Accepted: 12/01/2015] [Indexed: 01/24/2023] Open
Abstract
Here, we asked whether we could identify pharmacological agents that enhance endogenous stem cell function to promote skin repair, focusing on skin-derived precursors (SKPs), a dermal precursor cell population. Libraries of compounds already used in humans were screened for their ability to enhance the self-renewal of human and rodent SKPs. We identified and validated five such compounds, and showed that two of them, alprostadil and trimebutine maleate, enhanced the repair of full thickness skin wounds in middle-aged mice. Moreover, SKPs isolated from drug-treated skin displayed long-term increases in self-renewal when cultured in basal growth medium without drugs. Both alprostadil and trimebutine maleate likely mediated increases in SKP self-renewal by moderate hyperactivation of the MEK-ERK pathway. These findings identify candidates for potential clinical use in human skin repair, and provide support for the idea that pharmacological activation of endogenous tissue precursors represents a viable therapeutic strategy.
Small-molecule screens identify compounds that enhance SKP self-renewal Alprostadil and trimebutine maleate both increase SKP self-renewal Both compounds likely act by promoting activation of the MEK-ERK pathway Both compounds activated dermal precursors in vivo to enhance wound healing
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Affiliation(s)
- Sibel Naska
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Scott A Yuzwa
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Adam P W Johnston
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Smitha Paul
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Kristen M Smith
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Maryline Paris
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Michael V Sefton
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5G 1X5, Canada
| | - Alessandro Datti
- S.M.A.R.T. Laboratory for High-Throughput Screening Programs, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Agricultural, Food, and Environmental Sciences, University of Perugia, 06121 Perugia, Italy
| | - Freda D Miller
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1X5, Canada.
| | - David R Kaplan
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada.
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43
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Steinbach SK, Husain M. Vascular smooth muscle cell differentiation from human stem/progenitor cells. Methods 2015; 101:85-92. [PMID: 26678794 DOI: 10.1016/j.ymeth.2015.12.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 12/03/2015] [Accepted: 12/07/2015] [Indexed: 01/16/2023] Open
Abstract
Transplantation of vascular smooth muscle cells (VSMCs) is a promising cellular therapy to promote angiogenesis and wound healing. However, VSMCs are derived from diverse embryonic sources which may influence their role in the development of vascular disease and in its therapeutic modulation. Despite progress in understanding the mechanisms of VSMC differentiation, there remains a shortage of robust methods for generating lineage-specific VSMCs from pluripotent and adult stem/progenitor cells in serum-free conditions. Here we describe a method for differentiating pluripotent stem cells, such as embryonic and induced pluripotent stem cells, as well as skin-derived precursors, into lateral plate-derived VSMCs including 'coronary-like' VSMCs and neural crest-derived VSMC, respectively. We believe this approach will have broad applications in modeling origin-specific disease vulnerability and in developing personalized cell-based vascular grafts for regenerative medicine.
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Affiliation(s)
- Sarah K Steinbach
- McEwen Centre for Regenerative Medicine, Toronto General Research Institute, 101 College St., Toronto, Ontario M5G-1L7, Canada; Division of Experimental Therapeutics, Toronto General Research Institute, 101 College St., Toronto, Ontario M5G-1L7, Canada
| | - Mansoor Husain
- McEwen Centre for Regenerative Medicine, Toronto General Research Institute, 101 College St., Toronto, Ontario M5G-1L7, Canada; Division of Experimental Therapeutics, Toronto General Research Institute, 101 College St., Toronto, Ontario M5G-1L7, Canada; Departments of Medicine, University of Toronto, 1 Kings College Circle, Toronto, Ontario M5S-1A8, Canada; Departments of Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario M5S-1A8, Canada; Departments of Laboratory Medicine & Pathobiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario M5S-1A8, Canada; Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, 1 Kings College Circle, Toronto, Ontario M5S-1A8, Canada; Ted Rogers Centre for Heart Research, University of Toronto, 1 Kings College Circle, Toronto, Ontario M5S-1A8, Canada; Peter Munk Cardiac Centre, University Health Network, 200 Elizabeth St., Toronto, Ontario M5G-2C4, Canada.
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De Kock J, Meuleman P, Raicevic G, Rodrigues RM, Branson S, Meganathan K, De Boe V, Sachinidis A, Leroux-Roels G, Vanhaecke T, Lagneaux L, Rogiers V, Najar M. Human skin-derived precursor cells are poorly immunogenic and modulate the allogeneic immune response. Stem Cells 2015; 32:2215-28. [PMID: 24585677 DOI: 10.1002/stem.1692] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 02/12/2014] [Accepted: 02/20/2014] [Indexed: 12/14/2022]
Abstract
Human skin-derived precursors (hSKPs) are multipotent somatic stem cells that persist within the dermis throughout adulthood and harbor potential clinical applicability. In this study, we investigated their immunogenicity and immunosuppressive features, both in vitro and in vivo. As such, this study provides a solid basis for developing their future clinical applications. We found that hSKPs express HLA-ABC molecules, but not HLA-DR, rendering them poorly immunogenic. Using a coculture set-up, we could further demonstrate that hSKPs inhibit the proliferation of allogeneic activated T cells and alter their cytokine secretion profile, in a dose-dependent manner. Cotransplantation of hSKP and human peripheral blood leukocytes (PBL) into severe combined immune-deficient mice also showed a significant impairment of the graft-versus-host response 1 week post-transplantation and a drastic increase in survival time of 60%. From a mechanistic point of view, we found that hSKPs require cell contact as well as secretion of soluble inhibitory factors in order to modulate the immune response. The expression/secretion levels of these factors further increases upon inflammation or in the presence of activated T cells. As such, we believe that these features could be beneficial in a later allogeneic clinical setting, because rejection of engrafted allogeneic hSKP might be delayed or even avoided due to their own promotion of a tolerogenic microenvironment.
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Affiliation(s)
- Joery De Kock
- Department of In Vitro Toxicology and Dermato-Cosmetology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium
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45
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Johansson E, Andersson L, Örnros J, Carlsson T, Ingeson-Carlsson C, Liang S, Dahlberg J, Jansson S, Parrillo L, Zoppoli P, Barila GO, Altschuler DL, Padula D, Lickert H, Fagman H, Nilsson M. Revising the embryonic origin of thyroid C cells in mice and humans. Development 2015; 142:3519-28. [PMID: 26395490 PMCID: PMC4631767 DOI: 10.1242/dev.126581] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 08/27/2015] [Indexed: 12/13/2022]
Abstract
Current understanding infers a neural crest origin of thyroid C cells, the major source of calcitonin in mammals and ancestors to neuroendocrine thyroid tumors. The concept is primarily based on investigations in quail–chick chimeras involving fate mapping of neural crest cells to the ultimobranchial glands that regulate Ca2+ homeostasis in birds, reptiles, amphibians and fishes, but whether mammalian C cell development involves a homologous ontogenetic trajectory has not been experimentally verified. With lineage tracing, we now provide direct evidence that Sox17+ anterior endoderm is the only source of differentiated C cells and their progenitors in mice. Like many gut endoderm derivatives, embryonic C cells were found to coexpress pioneer factors forkhead box (Fox) a1 and Foxa2 before neuroendocrine differentiation takes place. In the ultimobranchial body epithelium emerging from pharyngeal pouch endoderm in early organogenesis, differential Foxa1/Foxa2 expression distinguished two spatially separated pools of C cell precursors with different growth properties. A similar expression pattern was recapitulated in medullary thyroid carcinoma cells in vivo, consistent with a growth-promoting role of Foxa1. In contrast to embryonic precursor cells, C cell-derived tumor cells invading the stromal compartment downregulated Foxa2, foregoing epithelial-to-mesenchymal transition designated by loss of E-cadherin; both Foxa2 and E-cadherin were re-expressed at metastatic sites. These findings revise mammalian C cell ontogeny, expand the neuroendocrine repertoire of endoderm and redefine the boundaries of neural crest diversification. The data further underpin distinct functions of Foxa1 and Foxa2 in both embryonic and tumor development. Highlighted article: Mouse thyroid C cell precursors arise in foregut endoderm, and not the neural crest, disproving the current concept of a neural crest origin of thyroid neuroendocrine cells.
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Affiliation(s)
- Ellen Johansson
- Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden
| | - Louise Andersson
- Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden
| | - Jessica Örnros
- Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden
| | - Therese Carlsson
- Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden
| | - Camilla Ingeson-Carlsson
- Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden
| | - Shawn Liang
- Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden
| | - Jakob Dahlberg
- Department of Surgery, Sahlgrenska University Hospital, Göteborg, SE-41345, Sweden
| | - Svante Jansson
- Department of Surgery, Sahlgrenska University Hospital, Göteborg, SE-41345, Sweden
| | | | - Pietro Zoppoli
- Institute for Cancer Genetics, Columbia University, 1130 St Nicholas Avenue, New York, NY 10031, USA
| | - Guillermo O Barila
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Daniel L Altschuler
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Daniela Padula
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, German Research Center for Environmental Health GmgH, Ingolstaedter Landstraße 1, Munich 85764, Germany
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Center Munich, German Research Center for Environmental Health GmgH, Ingolstaedter Landstraße 1, Munich 85764, Germany
| | - Henrik Fagman
- Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Göteborg, SE-41345, Sweden
| | - Mikael Nilsson
- Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg, Göteborg SE-40530, Sweden
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46
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Gresset A, Coulpier F, Gerschenfeld G, Jourdon A, Matesic G, Richard L, Vallat JM, Charnay P, Topilko P. Boundary Caps Give Rise to Neurogenic Stem Cells and Terminal Glia in the Skin. Stem Cell Reports 2015. [PMID: 26212662 PMCID: PMC4618659 DOI: 10.1016/j.stemcr.2015.06.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
While neurogenic stem cells have been identified in rodent and human skin, their manipulation and further characterization are hampered by a lack of specific markers. Here, we perform genetic tracing of the progeny of boundary cap (BC) cells, a neural-crest-derived cell population localized at peripheral nerve entry/exit points. We show that BC derivatives migrate along peripheral nerves to reach the skin, where they give rise to terminal glia associated with dermal nerve endings. Dermal BC derivatives also include cells that self-renew in sphere culture and have broad in vitro differentiation potential. Upon transplantation into adult mouse dorsal root ganglia, skin BC derivatives efficiently differentiate into various types of mature sensory neurons. Together, this work establishes the embryonic origin, pathway of migration, and in vivo neurogenic potential of a major component of skin stem-like cells. It provides genetic tools to study and manipulate this population of high interest for medical applications.
Boundary cap cells give rise to all types of sensory neurons in the developing DRG BC derivatives migrate along peripheral nerves to reach the trunk skin BC cell progeny include glia associated with nerve endings Dermal BC-derived stem cells possess powerful in vivo neurogenic potential
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Affiliation(s)
- Aurélie Gresset
- Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), and INSERM U1024, and Centre National de la Recherche Scientifique (CNRS) UMR 8197, Paris 75005, France
| | - Fanny Coulpier
- Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), and INSERM U1024, and Centre National de la Recherche Scientifique (CNRS) UMR 8197, Paris 75005, France
| | - Gaspard Gerschenfeld
- Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), and INSERM U1024, and Centre National de la Recherche Scientifique (CNRS) UMR 8197, Paris 75005, France; Sorbonne Universités, UPMC Université Paris 06, IFD, 4 Place Jussieu, 75252 Paris Cedex 05, France
| | - Alexandre Jourdon
- Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), and INSERM U1024, and Centre National de la Recherche Scientifique (CNRS) UMR 8197, Paris 75005, France; Sorbonne Universités, UPMC Université Paris 06, IFD, 4 Place Jussieu, 75252 Paris Cedex 05, France
| | - Graziella Matesic
- Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), and INSERM U1024, and Centre National de la Recherche Scientifique (CNRS) UMR 8197, Paris 75005, France
| | - Laurence Richard
- National Reference Centre "Rare Peripheral Neuropathies" Department of Neurology, Centre Hospitalier Universitaire de Limoges, 87042 Limoges, France
| | - Jean-Michel Vallat
- National Reference Centre "Rare Peripheral Neuropathies" Department of Neurology, Centre Hospitalier Universitaire de Limoges, 87042 Limoges, France
| | - Patrick Charnay
- Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), and INSERM U1024, and Centre National de la Recherche Scientifique (CNRS) UMR 8197, Paris 75005, France.
| | - Piotr Topilko
- Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), and INSERM U1024, and Centre National de la Recherche Scientifique (CNRS) UMR 8197, Paris 75005, France
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47
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Evolution of vertebrates as viewed from the crest. Nature 2015; 520:474-482. [PMID: 25903629 DOI: 10.1038/nature14436] [Citation(s) in RCA: 155] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 02/05/2015] [Indexed: 12/21/2022]
Abstract
The origin of vertebrates was accompanied by the advent of a novel cell type: the neural crest. Emerging from the central nervous system, these cells migrate to diverse locations and differentiate into numerous derivatives. By coupling morphological and gene regulatory information from vertebrates and other chordates, we describe how addition of the neural-crest-specification program may have enabled cells at the neural plate border to acquire multipotency and migratory ability. Analysis of the topology of the neural crest gene regulatory network can serve as a useful template for understanding vertebrate evolution, including elaboration of neural crest derivatives.
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48
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Butler SJ, Bronner ME. From classical to current: analyzing peripheral nervous system and spinal cord lineage and fate. Dev Biol 2015; 398:135-46. [PMID: 25446276 PMCID: PMC4845735 DOI: 10.1016/j.ydbio.2014.09.033] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Revised: 09/22/2014] [Accepted: 09/25/2014] [Indexed: 01/13/2023]
Abstract
During vertebrate development, the central (CNS) and peripheral nervous systems (PNS) arise from the neural plate. Cells at the margin of the neural plate give rise to neural crest cells, which migrate extensively throughout the embryo, contributing to the majority of neurons and all of the glia of the PNS. The rest of the neural plate invaginates to form the neural tube, which expands to form the brain and spinal cord. The emergence of molecular cloning techniques and identification of fluorophores like Green Fluorescent Protein (GFP), together with transgenic and electroporation technologies, have made it possible to easily visualize the cellular and molecular events in play during nervous system formation. These lineage-tracing techniques have precisely demonstrated the migratory pathways followed by neural crest cells and increased knowledge about their differentiation into PNS derivatives. Similarly, in the spinal cord, lineage-tracing techniques have led to a greater understanding of the regional organization of multiple classes of neural progenitor and post-mitotic neurons along the different axes of the spinal cord and how these distinct classes of neurons assemble into the specific neural circuits required to realize their various functions. Here, we review how both classical and modern lineage and marker analyses have expanded our knowledge of early peripheral nervous system and spinal cord development.
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Affiliation(s)
- Samantha J Butler
- Department of Neurobiology, TLSB 3129, 610 Charles E Young Drive East, University of California, Los Angeles, Los Angeles, CA 90095-7239, USA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
| | - Marianne E Bronner
- Department of Neurobiology, TLSB 3129, 610 Charles E Young Drive East, University of California, Los Angeles, Los Angeles, CA 90095-7239, USA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
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49
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Delaney SP, Julian LM, Stanford WL. The neural crest lineage as a driver of disease heterogeneity in Tuberous Sclerosis Complex and Lymphangioleiomyomatosis. Front Cell Dev Biol 2014; 2:69. [PMID: 25505789 PMCID: PMC4243694 DOI: 10.3389/fcell.2014.00069] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 11/02/2014] [Indexed: 12/20/2022] Open
Abstract
Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease, best characterized by the formation of proliferative nodules that express smooth muscle and melanocytic antigens within the lung parenchyma, leading to progressive destruction of lung tissue and function. The pathological basis of LAM is associated with Tuberous Sclerosis Complex (TSC), a multi-system disorder marked by low-grade tumors in the brain, kidneys, heart, eyes, lung and skin, arising from inherited or spontaneous germ-line mutations in either of the TSC1 or TSC2 genes. LAM can develop either in a patient with TSC (TSC-LAM) or spontaneously (S-LAM), and it is clear that the majority of LAM lesions of both forms are characterized by an inactivating mutation in either TSC1 or TSC2, as in TSC. Despite this genetic commonality, there is considerable heterogeneity in the tumor spectrum of TSC and LAM patients, the basis for which is currently unknown. There is extensive clinical evidence to suggest that the cell of origin for LAM, as well as many of the TSC-associated tumors, is a neural crest cell, a highly migratory cell type with extensive multi-lineage potential. Here we explore the hypothesis that the types of tumors that develop and the tissues that are affected in TSC and LAM are dictated by the developmental timing of TSC gene mutations, which determines the identities of the affected cell types and the size of downstream populations that acquire a mutation. We further discuss the evidence to support a neural crest origin for LAM and TSC tumors, and propose approaches for generating humanized models of TSC and LAM that will allow cell of origin theories to be experimentally tested. Identifying the cell of origin and developing appropriate humanized models is necessary to truly understand LAM and TSC pathology and to establish effective and long-lasting therapeutic approaches for these patients.
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Affiliation(s)
- Sean P Delaney
- Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute Ottawa, ON, Canada ; Faculty of Graduate and Postdoctoral Studies, University of Ottawa Ottawa, ON, Canada ; Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada
| | - Lisa M Julian
- Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute Ottawa, ON, Canada ; Faculty of Graduate and Postdoctoral Studies, University of Ottawa Ottawa, ON, Canada
| | - William L Stanford
- Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute Ottawa, ON, Canada ; Faculty of Graduate and Postdoctoral Studies, University of Ottawa Ottawa, ON, Canada ; Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada ; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa Ottawa, ON, Canada
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50
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Driskell RR, Watt FM. Understanding fibroblast heterogeneity in the skin. Trends Cell Biol 2014; 25:92-9. [PMID: 25455110 DOI: 10.1016/j.tcb.2014.10.001] [Citation(s) in RCA: 280] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 10/09/2014] [Accepted: 10/13/2014] [Indexed: 01/06/2023]
Abstract
Fibroblasts are found in most tissues, yet they remain poorly characterised. Different fibroblast subpopulations with distinct functions have been identified in the skin. This functional heterogeneity reflects the varied fibroblast lineages that arise from a common embryonic precursor. In addition to autocrine signals, fibroblasts are highly responsive to Wnt-regulated signals from the overlying epidermis, which can act both locally, via extracellular matrix (ECM) deposition, and via secreted factors that impact the behaviour of fibroblasts in different dermal locations. These findings may explain some of the changes that occur in connective tissue during wound healing and cancer progression.
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Affiliation(s)
- Ryan R Driskell
- Centre for Stem Cells and Regenerative Medicine, King's College London, 28th Floor, Tower Wing, Guy's Hospital Campus, London SE1 9RT, UK
| | - Fiona M Watt
- Centre for Stem Cells and Regenerative Medicine, King's College London, 28th Floor, Tower Wing, Guy's Hospital Campus, London SE1 9RT, UK.
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