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White MJV, Ozkan M, Medellin JEG, Solanki A, Hubbell JA. Inhibition of Talin2 dedifferentiates myofibroblasts and reverses lung and kidney fibrosis. Sci Rep 2025; 15:18010. [PMID: 40410300 PMCID: PMC12102334 DOI: 10.1038/s41598-025-00939-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 05/02/2025] [Indexed: 05/25/2025] Open
Abstract
Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse progression of the disease. To find novel targets for fibrosis therapeutics, we developed a model for the differentiation of monocytes to myofibroblasts that allowed us to screen for proteins involved in myofibroblast differentiation. Inhibition of a novel protein target generated by our model, talin2, reduces myofibroblast-specific morphology, α-smooth muscle actin content, and collagen I content and lowers the pro-fibrotic secretome of myofibroblasts. We find that knockdown of talin2 de-differentiates myofibroblasts and reverses bleomycin-induced lung fibrosis in mice, and further that Tln2-/- mice are resistant to bleomycin-induced lung fibrosis and resistant to unilateral ureteral obstruction-induced kidney fibrosis. Talin2 inhibition is thus a potential treatment for reversing lung and kidney fibroses.
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Affiliation(s)
- Michael J V White
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA
| | - Melis Ozkan
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA
| | | | - Ani Solanki
- Animal Resources Center, University of Chicago, Chicago, IL, 60637, USA
| | - Jeffrey A Hubbell
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA.
- Committee on Immunology, University of Chicago, Chicago, IL, 60637, USA.
- Committee on Cancer Biology, University of Chicago, Chicago, IL, 60637, USA.
- Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, New York, 11201, New York, United States.
- Departments of Biology and Chemistry, Faculty of Arts and Sciences, New York University, New York, 10012, New York, United States.
- Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, 10016, New York, United States.
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Cui JY, Ma J, Gao XX, Sheng ZM, Pan ZX, Shi LH, Zhang BG. Unraveling the role of cancer-associated fibroblasts in colorectal cancer. World J Gastrointest Oncol 2024; 16:4565-4578. [PMID: 39678792 PMCID: PMC11577382 DOI: 10.4251/wjgo.v16.i12.4565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/30/2024] [Accepted: 09/19/2024] [Indexed: 11/12/2024] Open
Abstract
Within the intricate milieu of colorectal cancer (CRC) tissues, cancer-associated fibroblasts (CAFs) act as pivotal orchestrators, wielding considerable influence over tumor progression. This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC, thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions. Through a comprehensive synthesis of current knowledge, this review delineates insights into CAFs-mediated modulation of cancer cell proliferation, invasiveness, immune evasion, and neovascularization, elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors. Additionally, recognizing the high level of heterogeneity within CAFs is crucial, as they encompass a range of subtypes, including myofibroblastic CAFs, inflammatory CAFs, antigen-presenting CAFs, and vessel-associated CAFs. Innovatively, the symbiotic relationship between CAFs and the intestinal microbiota is explored, shedding light on a novel dimension of CRC pathogenesis. Despite remarkable progress, the orchestrated dynamic functions of CAFs remain incompletely deciphered, underscoring the need for continued research endeavors for therapeutic advancements in CRC management.
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Affiliation(s)
- Jia-Yu Cui
- Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Jing Ma
- Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Xin-Xin Gao
- Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Zhi-Mei Sheng
- Affiliated Hospital of Shandong Second Medical University, Department of Pathology, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Zi-Xin Pan
- Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Li-Hong Shi
- School of Rehabilitation Medicine, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Bao-Gang Zhang
- Department of Pathology, Shandong Second Medical University, Weifang 261053, Shandong Province, China
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3
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Rhodes JD, Goldenring JR, Lee SH. Regulation of metaplasia and dysplasia in the stomach by the stromal microenvironment. Exp Mol Med 2024; 56:1322-1330. [PMID: 38825636 PMCID: PMC11263556 DOI: 10.1038/s12276-024-01240-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 03/03/2024] [Accepted: 03/03/2024] [Indexed: 06/04/2024] Open
Abstract
Research on the microenvironment associated with gastric carcinogenesis has focused on cancers of the stomach and often underestimates premalignant stages such as metaplasia and dysplasia. Since epithelial interactions with T cells, macrophages, and type 2 innate lymphoid cells (ILC2s) are indispensable for the formation of precancerous lesions in the stomach, understanding the cellular interactions that promote gastric precancer warrants further investigation. Although various types of immune cells have been shown to play important roles in gastric carcinogenesis, it remains unclear how stromal cells such as fibroblasts influence epithelial transformation in the stomach, especially during precancerous stages. Fibroblasts exist as distinct populations across tissues and perform different functions depending on the expression patterns of cell surface markers and secreted factors. In this review, we provide an overview of known microenvironmental components in the stroma with an emphasis on fibroblast subpopulations and their roles during carcinogenesis in tissues including breast, pancreas, and stomach. Additionally, we offer insights into potential targets of tumor-promoting fibroblasts and identify open areas of research related to fibroblast plasticity and the modulation of gastric carcinogenesis.
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Affiliation(s)
- Jared D Rhodes
- Program in Cancer Biology, Nashville, TN, USA
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - James R Goldenring
- Program in Cancer Biology, Nashville, TN, USA.
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Section of Surgical Sciences, Nashville, TN, USA.
- Department of Cell and Developmental Biology, Nashville, TN, USA.
- Nashville VA Medical Center, Nashville, TN, USA.
| | - Su-Hyung Lee
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Section of Surgical Sciences, Nashville, TN, USA.
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Xu Y, Li W, Lin S, Liu B, Wu P, Li L. Fibroblast diversity and plasticity in the tumor microenvironment: roles in immunity and relevant therapies. Cell Commun Signal 2023; 21:234. [PMID: 37723510 PMCID: PMC10506315 DOI: 10.1186/s12964-023-01204-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 06/22/2023] [Indexed: 09/20/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs), enriched in the tumor stroma, have received increasing attention because of their multifaceted effects on tumorigenesis, development, metastasis, and treatment resistance in malignancies. CAFs contributed to suppressive microenvironment via different mechanisms, while CAFs also exerted some antitumor effects. Therefore, CAFs have been considered promising therapeutic targets for their remarkable roles in malignant tumors. However, patients with malignancies failed to benefit from current CAFs-targeted drugs in many clinical trials, which suggests that further in-depth investigation into CAFs is necessary. Here, we summarize and outline the heterogeneity and plasticity of CAFs mainly by exploring their origin and activation, highlighting the regulation of CAFs in the tumor microenvironment during tumor evolution, as well as the critical roles performed by CAFs in tumor immunity. In addition, we summarize the current immunotherapies targeting CAFs, and conclude with a brief overview of some prospects for the future of CAFs research in the end. Video Abstract.
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Affiliation(s)
- Yashi Xu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Li
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shitong Lin
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binghan Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Wu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- National Clinical Research Center for Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Li Li
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- National Clinical Research Center for Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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5
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Wang M, Fan R, Jiang J, Sun F, Sun Y, Wang Q, Jiang A, Yu Z, Yang T. PIM2 Promotes the Development of Ovarian Endometriosis by Enhancing Glycolysis and Fibrosis. Reprod Sci 2023; 30:2692-2702. [PMID: 37059967 DOI: 10.1007/s43032-023-01208-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 02/28/2023] [Indexed: 04/16/2023]
Abstract
Endometriosis is a common gynecological disorder characterized by the presence of the endometrial glands and the stroma outside the uterine cavity. The disease affects reproductive function and quality of life in women of reproductive age. Endometriosis is similar to tumors in some characteristics, such as glycolysis. PIM2 can promote the development of tumors, but the mechanism of PIM2 in endometriosis is still unclear. Therefore, our goal is to study the mechanism of PIM2 in endometriosis. Through immunohistochemistry, we found PIM2, HK2, PKM2, SMH (smooth muscle myosin heavy chain), Desmin, and α-SMA (α-smooth muscle actin) were strongly expressed in the ovarian endometriosis. In endometriotic cells, PIM2 enhanced glycolysis and fibrosis via upregulating the expression of PKM2. Moreover, the PIM2 inhibitor SMI-4a inhibited the development of endometriosis. And we established a PIM2 knockout mouse model of endometriosis to demonstrate the role of PIM2 in vivo. In summary, our study indicates that PIM2 promotes the development of endometriosis. PIM2 may serve as a promising therapeutic target for endometriosis.
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Affiliation(s)
- Mengxue Wang
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong Province, People's Republic of China
| | - Ruiqi Fan
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong Province, People's Republic of China
| | - Junyi Jiang
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China
| | - Fangyuan Sun
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong Province, People's Republic of China
| | - Yujun Sun
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong Province, People's Republic of China
| | - Qian Wang
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong Province, People's Republic of China
| | - Aifang Jiang
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China
| | - Zhenhai Yu
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China.
| | - Tingting Yang
- Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People's Republic of China.
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Chhabra Y, Weeraratna AT. Fibroblasts in cancer: Unity in heterogeneity. Cell 2023; 186:1580-1609. [PMID: 37059066 PMCID: PMC11422789 DOI: 10.1016/j.cell.2023.03.016] [Citation(s) in RCA: 176] [Impact Index Per Article: 88.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/13/2023] [Accepted: 03/15/2023] [Indexed: 04/16/2023]
Abstract
Tumor cells do not exist in isolation in vivo, and carcinogenesis depends on the surrounding tumor microenvironment (TME), composed of a myriad of cell types and biophysical and biochemical components. Fibroblasts are integral in maintaining tissue homeostasis. However, even before a tumor develops, pro-tumorigenic fibroblasts in close proximity can provide the fertile 'soil' to the cancer 'seed' and are known as cancer-associated fibroblasts (CAFs). In response to intrinsic and extrinsic stressors, CAFs reorganize the TME enabling metastasis, therapeutic resistance, dormancy and reactivation by secreting cellular and acellular factors. In this review, we summarize the recent discoveries on CAF-mediated cancer progression with a particular focus on fibroblast heterogeneity and plasticity.
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Affiliation(s)
- Yash Chhabra
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
| | - Ashani T Weeraratna
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
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7
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Arenas-Luna VM, Montesinos JJ, Cortés-Morales VA, Navarro-Betancourt JR, Peralta-Ildefonso J, Cisneros B, Hernández-Gutiérrez S. In Vitro Evidence of Differential Immunoregulatory Response between MDA-MB-231 and BT-474 Breast Cancer Cells Induced by Bone Marrow-Derived Mesenchymal Stromal Cells Conditioned Medium. Curr Issues Mol Biol 2022; 45:268-285. [PMID: 36661506 PMCID: PMC9857683 DOI: 10.3390/cimb45010020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 01/04/2023] Open
Abstract
Inside tumors, cancer cells display several mechanisms to create an immunosuppressive environment. On the other hand, by migration processes, mesenchymal stromal cells (MSCs) can be recruited by different cancer tumor types from tissues as distant as bone marrow and contribute to tumor pathogenesis. However, the impact of the immunoregulatory role of MSCs associated with the aggressiveness of breast cancer cells by soluble molecules has not been fully elucidated. Therefore, this in vitro work aimed to study the effect of the conditioned medium of human bone marrow-derived-MSCs (hBM-MSC-cm) on the immunoregulatory capability of MDA-MB-231 and BT-474 breast cancer cells. The hBM-MSC-cm on MDA-MB-231 cells induced the overexpression of TGF-β, IDO, and IL-10 genes. Additionally, immunoregulation assays of mononuclear cells (MNCs) in co-culture with MDA-MB-231 and hBM-MSC-cm decreased lymphocyte proliferation, and increased proteins IL-10, TGF-β, and IDO while also reducing TNF levels, shooting the proportion of regulatory T cells. Conversely, the hBM-MSC-cm did not affect the immunomodulatory capacity of BT-474 cells. Thus, a differential immunoregulatory effect was observed between both representative breast cancer cell lines from different origins. Thus, understanding the immune response in a broader tumor context could help to design therapeutic strategies based on the aggressive behavior of tumor cells.
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Affiliation(s)
- Víctor M. Arenas-Luna
- Molecular Biology Laboratory, School of Medicine, Panamerican University, Mexico City 03920, Mexico
- Department of Genetics and Molecular Biology, Center of Research and Advanced Studies (CINVESTAV-IPN), Mexico City 04740, Mexico
| | - Juan J. Montesinos
- Mesenchymal Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico City 06720, Mexico
| | - Víctor A. Cortés-Morales
- Mesenchymal Stem Cells Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center, IMSS, Mexico City 06720, Mexico
| | | | | | - Bulmaro Cisneros
- Department of Genetics and Molecular Biology, Center of Research and Advanced Studies (CINVESTAV-IPN), Mexico City 04740, Mexico
| | - Salomón Hernández-Gutiérrez
- Molecular Biology Laboratory, School of Medicine, Panamerican University, Mexico City 03920, Mexico
- Correspondence:
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Mesenchymal/stromal stem cells: necessary factors in tumour progression. Cell Death Discov 2022; 8:333. [PMID: 35869057 PMCID: PMC9307857 DOI: 10.1038/s41420-022-01107-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 06/21/2022] [Accepted: 06/28/2022] [Indexed: 11/08/2022] Open
Abstract
Mesenchymal/stromal stem cells (MSCs) are a crucial component of the tumour microenvironment (TME). They can be recruited from normal tissues into the TME and educated by tumour cells to transform into tumour-associated MSCs, which are oncogenic cells that promote tumour development and progression by impacting or transforming into various kinds of cells, such as immune cells and endothelial cells. Targeting MSCs in the TME is a novel strategy to prevent malignant processes. Exosomes, as communicators, carry various RNAs and proteins and thus link MSCs and the TME, which provides options for improving outcomes and developing targeted treatment.
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Smilde BJ, Botman E, de Vries TJ, de Vries R, Micha D, Schoenmaker T, Janssen JJWM, Eekhoff EMW. A Systematic Review of the Evidence of Hematopoietic Stem Cell Differentiation to Fibroblasts. Biomedicines 2022; 10:biomedicines10123063. [PMID: 36551819 PMCID: PMC9775738 DOI: 10.3390/biomedicines10123063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/16/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022] Open
Abstract
Fibroblasts have an important role in the maintenance of the extracellular matrix of connective tissues by producing and remodelling extracellular matrix proteins. They are indispensable for physiological processes, and as such also associate with many pathological conditions. In recent years, a number of studies have identified donor-derived fibroblasts in various tissues of bone marrow transplant recipients, while others could not replicate these findings. In this systematic review, we provide an overview of the current literature regarding the differentiation of hematopoietic stem cells into fibroblasts in various tissues. PubMed, Embase, and Web of Science (Core Collection) were systematically searched for original articles concerning fibroblast origin after hematopoietic stem cell transplantation in collaboration with a medical information specialist. Our search found 5421 studies, of which 151 were analysed for full-text analysis by two authors independently, resulting in the inclusion of 104 studies. Only studies in animals and humans, in which at least one marker was used for fibroblast identification, were included. The results were described per organ of fibroblast engraftment. We show that nearly all mouse and human organs show evidence of fibroblasts of hematopoietic stem cell transfer origin. Despite significant heterogeneity in the included studies, most demonstrate a significant presence of fibroblasts of hematopoietic lineage in non-hematopoietic tissues. This presence appears to increase after the occurrence of tissue damage.
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Affiliation(s)
- Bernard J. Smilde
- Department of Internal Medicine Section Endocrinology, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
- Amsterdam Movement Sciences, 1081 HV Amsterdam, The Netherlands
| | - Esmée Botman
- Department of Internal Medicine Section Endocrinology, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
- Amsterdam Movement Sciences, 1081 HV Amsterdam, The Netherlands
| | - Teun J. de Vries
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, 1081 LA Amsterdam, The Netherlands
| | - Ralph de Vries
- Medical Library, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Dimitra Micha
- Department of Human Genetics, Amsterdam University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Ton Schoenmaker
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, 1081 LA Amsterdam, The Netherlands
| | | | - Elisabeth M. W. Eekhoff
- Department of Internal Medicine Section Endocrinology, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
- Amsterdam Movement Sciences, 1081 HV Amsterdam, The Netherlands
- Correspondence: ; Tel.: +31-72-548-4444
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TNS1: Emerging Insights into Its Domain Function, Biological Roles, and Tumors. BIOLOGY 2022; 11:biology11111571. [PMID: 36358270 PMCID: PMC9687257 DOI: 10.3390/biology11111571] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 01/25/2023]
Abstract
Tensins are a family of cellular-adhesion constituents that have been extensively studied. They have instrumental roles in the pathogenesis of numerous diseases. The mammalian tensin family comprises four members: tensin1 (TNS1), tensin2, tensin3, and tensin4. Among them, TNS1 has recently received attention from researchers because of its structural properties. TNS1 engages in various biological processes, such as cell adhesion, polarization, migration, invasion, proliferation, apoptosis, and mechano-transduction, by interacting with various partner proteins. Moreover, the abnormal expression of TNS1 in vivo is associated with the development of various diseases, especially tumors. Interestingly, the role of TNS1 in different tumors is still controversial. Here, we systematically summarize three aspects of TNS1: the gene structure, the biological processes underlying its action, and the dual regulatory role of TNS1 in different tumors through different mechanisms, of which we provide the first overview.
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11
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The Impact of Corticosteroid Administration at Different Time Points on Mucosal Wound Healing in Rats: An Experimental Pilot In Vivo Study. BIOLOGY 2022; 11:biology11091309. [PMID: 36138788 PMCID: PMC9495556 DOI: 10.3390/biology11091309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/28/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022]
Abstract
Simple Summary The objective of this pilot study was to evaluate the impact of corticosteroid (CS) administration at different time points on palatal wound healing in rats. Thirty-six young male rats were divided into three groups. The test groups were treated by CS in the early (1–4 days) and late (5–9 days) stages after palatal wounding, while the control group was left for spontaneous healing. Our findings do not support the positive impact of CS administration on palatal wound healing. While microscopically, we found no difference between the CS and control groups, CS exposure was associated with a macroscopically larger final wound area, reflecting a possible harmful effect of CS. Abstract Background: Conflicting results were found regarding the effect of corticosteroid (CS) administration upon wound healing. The objective of this pilot study was to evaluate the impact of CS administration at different time points on palatal wound healing in rats. Methods: A 4.2 mm diameter punch created a secondary healing excisional palatal defect in thirty-six (36) Wistar-derived, two-month-old male rats weighing 250–270 g. We evaluated the effect of CS by comparing wound healing between three equal groups: 12 rats who were not exposed to CS and two additional groups in which 1 mg/kg dexamethasone (1 mg/kg) was administered daily, early (1–4 days) and late (5–9 days) after injury. The dynamics of the healing process were evaluated weekly in 4 sacrificed rats from each group for three weeks. The wound area was assessed both macroscopically and microscopically; the inflammation score was assessed microscopically. Results: The initial wound area in all the rats was 13.85 mm2. At the end of the study, it decreased to 4.11 ± 0.88 mm2, 7.32 ± 2.11 mm2, and 8.87 ± 3.01 mm2 in control, early, and late CS administration groups, respectively (p = 0.075). Inflammation scores showed a tendency to decrease in the third week in all groups, with no statistical differences. Conclusions: Our findings do not support the positive impact of CS administration on palatal wound healing. While microscopically, we found no difference between the CS and control groups, CS exposure was associated with a macroscopically larger final wound area, reflecting a possible harmful effect of CS.
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12
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Menezes S, Okail MH, Jalil SMA, Kocher HM, Cameron AJM. Cancer-associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets. J Pathol 2022; 257:526-544. [PMID: 35533046 PMCID: PMC9327514 DOI: 10.1002/path.5926] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/03/2022] [Accepted: 05/05/2022] [Indexed: 11/29/2022]
Abstract
Cancer-associated fibroblasts (CAFs) have conflicting roles in the suppression and promotion of cancer. Current research focuses on targeting the undesirable properties of CAFs, while attempting to maintain tumour-suppressive roles. CAFs have been widely associated with primary or secondary therapeutic resistance, and strategies to modify CAF function have therefore largely focussed on their combination with existing therapies. Despite significant progress in preclinical studies, clinical translation of CAF targeted therapies has achieved limited success. Here we will review our emerging understanding of heterogeneous CAF populations in tumour biology and use examples from pancreatic ductal adenocarcinoma to explore why successful clinical targeting of protumourigenic CAF functions remains elusive. Single-cell technologies have allowed the identification of CAF subtypes with a differential impact on prognosis and response to therapy, but currently without clear consensus. Identification and pharmacological targeting of CAF subtypes associated with immunotherapy response offers new hope to expand clinical options for pancreatic cancer. Various CAF subtype markers may represent biomarkers for patient stratification, to obtain enhanced response with existing and emerging combinatorial therapeutic strategies. Thus, CAF subtyping is the next frontier in understanding and exploiting the tumour microenvironment for therapeutic benefit. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Shinelle Menezes
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
| | - Mohamed Hazem Okail
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
| | - Siti Munira Abd Jalil
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
| | - Hemant M Kocher
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
- Barts and the London HPB Centre, The Royal London HospitalBarts Health NHS TrustLondonUK
| | - Angus J M Cameron
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science CentreLondonUK
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13
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Wilson SE. Fibrosis Is a Basement Membrane-Related Disease in the Cornea: Injury and Defective Regeneration of Basement Membranes May Underlie Fibrosis in Other Organs. Cells 2022; 11:309. [PMID: 35053425 PMCID: PMC8774201 DOI: 10.3390/cells11020309] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/07/2022] [Accepted: 01/12/2022] [Indexed: 02/06/2023] Open
Abstract
Every organ develops fibrosis that compromises functions in response to infections, injuries, or diseases. The cornea is a relatively simple, avascular organ that offers an exceptional model to better understand the pathophysiology of the fibrosis response. Injury and defective regeneration of the epithelial basement membrane (EBM) or the endothelial Descemet's basement membrane (DBM) triggers the development of myofibroblasts from resident corneal fibroblasts and bone marrow-derived blood borne fibrocytes due to the increased entry of TGF beta-1/-2 into the stroma from the epithelium and tears or residual corneal endothelium and aqueous humor. The myofibroblasts, and disordered extracellular matrix these cells produce, persist until the source of injury is removed, the EBM and/or DBM are regenerated, or replaced surgically, resulting in decreased stromal TGF beta requisite for myofibroblast survival. A similar BM injury-related pathophysiology can underly the development of fibrosis in other organs such as skin and lung. The normal liver does not contain traditional BMs but develops sinusoidal endothelial BMs in many fibrotic diseases and models. However, normal hepatic stellate cells produce collagen type IV and perlecan that can modulate TGF beta localization and cognate receptor binding in the space of Dissé. BM-related fibrosis is deserving of more investigation in all organs.
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Affiliation(s)
- Steven E Wilson
- Cole Eye Institute, I-32, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
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14
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Vaish U, Jain T, Are AC, Dudeja V. Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting. Int J Mol Sci 2021; 22:13408. [PMID: 34948209 PMCID: PMC8706283 DOI: 10.3390/ijms222413408] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/20/2021] [Accepted: 12/09/2021] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.
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Affiliation(s)
| | | | | | - Vikas Dudeja
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (U.V.); (T.J.); (A.C.A.)
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15
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Arif S, Attiogbe E, Moulin VJ. Granulation tissue myofibroblasts during normal and pathological skin healing: The interaction between their secretome and the microenvironment. Wound Repair Regen 2021; 29:563-572. [PMID: 33887793 DOI: 10.1111/wrr.12919] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 01/02/2023]
Abstract
The first role that was proposed for the myofibroblasts located in skin granulation tissue was to contract the edges of the wound in order to reduce the surface to be repaired. This role, linked to the presence of alpha smooth muscle actin, was very quickly confirmed and is part of the definition of granulation tissue myofibroblasts. However, myofibroblasts are cells that also play a much more central role in wound healing. Indeed, it has been shown that these cells produce large quantities of matrix components, and that they stimulate angiogenesis and can recruit immune cells. These actions take place via the secretion of molecules into their environment or indirectly via the production of microvesicles containing pro-fibrotic and pro-angiogenic molecules. Pathologically, granulation tissue can develop into a hypertrophic scar that histologically looks like granulation tissue, but which can remain for months or even years. It has been hypothesized that the myofibroblasts in these tissues remained present instead of disappearing by apoptosis, causing the maintenance of granulation tissue rather than allowing its change into a mature scar. Understanding the roles of both pathological and healthy myofibroblasts in wound tissue is crucial in order to better intervene in the healing mechanism.
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Affiliation(s)
- Syrine Arif
- Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Centre de recherche du CHU de Québec-Université Laval, Quebec City, Quebec, Canada
| | - Emilie Attiogbe
- Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Centre de recherche du CHU de Québec-Université Laval, Quebec City, Quebec, Canada
| | - Véronique J Moulin
- Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Centre de recherche du CHU de Québec-Université Laval, Quebec City, Quebec, Canada.,Department of Surgery, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada
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16
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Biffi G, Tuveson DA. Diversity and Biology of Cancer-Associated Fibroblasts. Physiol Rev 2021; 101:147-176. [PMID: 32466724 PMCID: PMC7864232 DOI: 10.1152/physrev.00048.2019] [Citation(s) in RCA: 731] [Impact Index Per Article: 182.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 05/19/2020] [Accepted: 05/20/2020] [Indexed: 02/08/2023] Open
Abstract
Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.
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Affiliation(s)
- Giulia Biffi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York; and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
| | - David A Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York; and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
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17
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Papait A, Stefani FR, Cargnoni A, Magatti M, Parolini O, Silini AR. The Multifaceted Roles of MSCs in the Tumor Microenvironment: Interactions With Immune Cells and Exploitation for Therapy. Front Cell Dev Biol 2020; 8:447. [PMID: 32637408 PMCID: PMC7317293 DOI: 10.3389/fcell.2020.00447] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/13/2020] [Indexed: 12/18/2022] Open
Abstract
The tumor microenvironment (TME) plays a critical role in tumorigenesis and is composed of different cellular components, including immune cells and mesenchymal stromal cells (MSCs). In this review, we will discuss MSCs in the TME setting and more specifically their interactions with immune cells and how they can both inhibit (immunosurveillance) and favor (immunoediting) tumor growth. We will also discuss how MSCs are used as a therapeutic strategy in cancer. Due to their unique immunomodulatory properties, MSCs isolated from perinatal tissues are intensely explored as therapeutic interventions in various inflammatory-based disorders with promising results. However, their therapeutic applications in cancer remain for the most part controversial and, importantly, the interactions between administered perinatal MSC and immune cells in the TME remain to be clearly defined.
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Affiliation(s)
- Andrea Papait
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | | | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Marta Magatti
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo A. Gemelli, Rome, Italy
| | - Antonietta Rosa Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
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18
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Anqi C, Takabatake K, Kawai H, Oo MW, Yoshida S, Fujii M, Omori H, Sukegawa S, Nakano K, Tsujigiwa H, Jinhua Z, Nagatsuka H. Differentiation and roles of bone marrow-derived cells on the tumor microenvironment of oral squamous cell carcinoma. Oncol Lett 2019; 18:6628-6638. [PMID: 31807176 PMCID: PMC6876317 DOI: 10.3892/ol.2019.11045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 09/06/2019] [Indexed: 12/29/2022] Open
Abstract
The stroma affects the properties and dynamics of the tumor. Previous studies have demonstrated that bone marrow-derived cells (BMDCs) possess the capability of differentiating into stromal cells. However, the characteristics and roles of BMDCs in oral squamous cell carcinoma remain unclear. The current study therefore investigated their locations and features by tracing green fluorescent protein (GFP)-labeled BMDCs in a transplantation mouse model. After irradiation, BALB-c nu-nu mice were injected with bone marrow cells from C57BL/6-BALB-C-nu/nu-GFP transgenic mice. These recipient mice were then injected subcutaneously in the head with human squamous cell carcinoma-2 cells. Immunohistochemistry for GFP, Vimentin, CD11b, CD31 and α-smooth muscle actin (SMA), and double-fluorescent immunohistochemistry for GFP-Vimentin, GFP-CD11b, GFP-CD31 and GFP-α-SMA was subsequently performed. Many round-shaped GFP-positive cells were observed in the cancer stroma, which indicated that BMDCs served a predominant role in tumorigenesis. Vimentin(+) GFP(+) cells may also be a member of the cancer-associated stroma, originating from bone marrow. Round or spindle-shaped CD11b(+) GFP(+) cells identified in the present study may be macrophages derived from bone marrow. CD31(+)GFP(+) cells exhibited a high tendency towards bone marrow-derived angioblasts. The results also indicated that spindle-shaped α-SMA(+) GFP(+) cells were not likely to represent bone marrow-derived cancer-associated fibroblasts. BMDCs gathering within the tumor microenvironment exhibited multilineage potency and participated in several important processes, such as tumorigenesis, tumor invasion and angiogenesis.
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Affiliation(s)
- Chang Anqi
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.,Department of Anatomy, Basic Medical Science College, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Kiyofumi Takabatake
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
| | - Hotaka Kawai
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
| | - May Wathone Oo
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
| | - Saori Yoshida
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
| | - Masae Fujii
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
| | - Haruka Omori
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
| | - Shintaro Sukegawa
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.,Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan
| | - Keisuke Nakano
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
| | - Hidetsugu Tsujigiwa
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.,Department of Life Science, Faculty of Science, Okayama University of Science, Okayama 700-0005, Japan
| | - Zheng Jinhua
- Department of Anatomy, Basic Medical Science College, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
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19
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Thankam FG, Palanikumar G, Fitzgibbons RJ, Agrawal DK. Molecular Mechanisms and Potential Therapeutic Targets in Incisional Hernia. J Surg Res 2018; 236:134-143. [PMID: 30694748 DOI: 10.1016/j.jss.2018.11.037] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 09/27/2018] [Accepted: 11/20/2018] [Indexed: 12/21/2022]
Abstract
The pathophysiology underlying the formation, progression, and surgical healing of incisional hernia (IH) that develops as a major complication associated with abdominal laparotomy is poorly understood. The proposed mechanisms include the switch of collagen phenotype and the proliferation of abnormal fibroblasts after surgery. The focus of this article was to critically review the cellular, biochemical, and potential molecular events associated with the development of IH. The disturbance in collagen homeostasis with alterations in the expression of collagen subtypes, including type 1, type 3, type 4, and type 5, and impairment in the transdifferentiation of fibroblasts to myofibroblasts are discussed. The phenotype switch of wound-repair fibroblasts results in mechanically compromised extracellular matrix that triggers the proliferation of abnormal fibroblasts. High-mobility group box 1 could be involved in wound progression, whereas signaling events mediated by tumor necrosis factor β1, connective tissue growth factor, lysyl oxidase, and hypoxia-inducible factor 1 play significant role in the wound healing response. Thus, the ratio of tumor necrosis factorβ1: high-mobility group box 1 could be a critical determinant of the underlying pathology. Potential target sites for therapeutic intervention in the management of IH are recognized.
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Affiliation(s)
- Finosh G Thankam
- Departments of Clinical and Translational Science and Surgery, Creighton University School of Medicine, Omaha, Nebraska
| | - Gunasekar Palanikumar
- Departments of Clinical and Translational Science and Surgery, Creighton University School of Medicine, Omaha, Nebraska
| | - Robert J Fitzgibbons
- Departments of Clinical and Translational Science and Surgery, Creighton University School of Medicine, Omaha, Nebraska
| | - Devendra K Agrawal
- Departments of Clinical and Translational Science and Surgery, Creighton University School of Medicine, Omaha, Nebraska.
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20
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Raz Y, Cohen N, Shani O, Bell RE, Novitskiy SV, Abramovitz L, Levy C, Milyavsky M, Leider-Trejo L, Moses HL, Grisaru D, Erez N. Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. J Exp Med 2018; 215:3075-3093. [PMID: 30470719 PMCID: PMC6279405 DOI: 10.1084/jem.20180818] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 09/05/2018] [Accepted: 10/23/2018] [Indexed: 12/21/2022] Open
Abstract
Raz et al. demonstrate that the expression of PDGFRα distinguishes two functional CAF populations in breast tumors and lung metastases and identify a subpopulation of CAFs that are specifically recruited to the tumor microenvironment from mesenchymal stromal cells in the BM. Cancer-associated fibroblasts (CAFs) are highly prominent in breast tumors, but their functional heterogeneity and origin are still largely unresolved. We report that bone marrow (BM)–derived mesenchymal stromal cells (MSCs) are recruited to primary breast tumors and to lung metastases and differentiate to a distinct subpopulation of CAFs. We show that BM-derived CAFs are functionally important for tumor growth and enhance angiogenesis via up-regulation of Clusterin. Using newly generated transgenic mice and adoptive BM transplantations, we demonstrate that BM-derived fibroblasts are a substantial source of CAFs in the tumor microenvironment. Unlike resident CAFs, BM-derived CAFs do not express PDGFRα, and their recruitment resulted in a decrease in the percentage of PDGFRα-expressing CAFs. Strikingly, decrease in PDGFRα in breast cancer patients was associated with worse prognosis, suggesting that BM-derived CAFs may have deleterious effects on survival. Therefore, PDGFRα expression distinguishes two functionally unique CAF populations in breast tumors and metastases and may have important implications for patient stratification and precision therapeutics.
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Affiliation(s)
- Yael Raz
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Obstetrics and Gynecology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Noam Cohen
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ophir Shani
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Rachel E Bell
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sergey V Novitskiy
- Department of Cancer Biology, Vanderbilt University School of Medicine and Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, TN
| | - Lilach Abramovitz
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Carmit Levy
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michael Milyavsky
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Leonor Leider-Trejo
- Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Harold L Moses
- Department of Cancer Biology, Vanderbilt University School of Medicine and Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, TN
| | - Dan Grisaru
- Department of Obstetrics and Gynecology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Neta Erez
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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21
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Pilling D, Gomer RH. The Development of Serum Amyloid P as a Possible Therapeutic. Front Immunol 2018; 9:2328. [PMID: 30459752 PMCID: PMC6232687 DOI: 10.3389/fimmu.2018.02328] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 09/19/2018] [Indexed: 02/06/2023] Open
Abstract
Pentraxins such as serum amyloid P (SAP; also known as PTX2) regulate several aspects of the innate immune system. SAP inhibits the differentiation of monocyte-derived fibroblast-like cells called fibrocytes, promotes the formation of immuno-regulatory macrophages, and inhibits neutrophil adhesion to extracellular matrix proteins. In this minireview, we describe how these effects of SAP have led to its possible use as a therapeutic, and how modulating SAP effects might be used for other therapeutics. Fibrosing diseases such as pulmonary fibrosis, cardiac fibrosis, liver fibrosis, and renal fibrosis are associated with 30-45% of deaths in the US. Fibrosis involves both fibrocyte differentiation and profibrotic macrophage differentiation, and possibly because SAP inhibits both of these processes, in 9 different animal models, SAP inhibited fibrosis. In Phase 1B and Phase 2 clinical trials, SAP injections reduced the decline in lung function in pulmonary fibrosis patients, and in a small Phase 2 trial SAP injections reduced fibrosis in myelofibrosis patients. Acute respiratory distress syndrome/ acute lung injury (ARDS/ALI) involves the accumulation of neutrophils in the lungs, and possibly because SAP inhibits neutrophil adhesion, SAP injections reduced the severity of ARDS in an animal model. Conversely, depleting SAP is a potential therapeutic for amyloidosis, topically removing SAP from wound fluid speeds wound healing in animal models, and blocking SAP binding to one of its receptors makes cultured macrophages more aggressive toward tuberculosis bacteria. These results suggest that modulating pentraxin signaling might be useful for a variety of diseases.
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Affiliation(s)
- Darrell Pilling
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Richard H Gomer
- Department of Biology, Texas A&M University, College Station, TX, United States
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22
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Lassance L, Marino GK, Medeiros CS, Thangavadivel S, Wilson SE. Fibrocyte migration, differentiation and apoptosis during the corneal wound healing response to injury. Exp Eye Res 2018; 170:177-187. [PMID: 29481786 DOI: 10.1016/j.exer.2018.02.018] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 01/30/2018] [Accepted: 02/23/2018] [Indexed: 01/03/2023]
Abstract
The aim of this study was to determine whether bone marrow-derived fibrocytes migrate into the cornea after stromal scar-producing injury and differentiate into alpha-smooth muscle actin (αSMA) + myofibroblasts. Chimeric mice expressing green fluorescent protein (GFP) bone marrow cells had fibrosis (haze)-generating irregular phototherapeutic keratectomy (PTK). Multiplex immunohistochemistry (IHC) for GFP and fibrocyte markers (CD34, CD45, and vimentin) was used to detect fibrocyte infiltration into the corneal stroma and the development of GFP+ αSMA+ myofibroblasts. IHC for activated caspase-3, GFP and CD45 was used to detect fibrocyte and other hematopoietic cells undergoing apoptosis. Moderate haze developed in PTK-treated mouse corneas at 14 days after surgery and worsened, and persisted, at 21 days after surgery. GFP+ CD34+ CD45+ fibrocytes, likely in addition to other CD34+ and/or CD45+ hematopoietic and stem/progenitor cells, infiltrated the cornea and were present in the stroma in high numbers by one day after PTK. The fibrocytes and other bone marrow-derived cells progressively decreased at four days and seven days after surgery. At four days after PTK, 5% of the GFP+ cells expressed activated caspase-3. At 14 days after PTK, more than 50% of GFP+ CD45+ cells were also αSMA+ myofibroblasts. At 21 days after PTK, few GFP+ αSMA+ cells persisted in the stroma and more than 95% of those remaining expressed activated caspase-3, indicating they were undergoing apoptosis. GFP+ CD45+ SMA+ cells that developed from 4 to 21 days after irregular PTK were likely developed from fibrocytes. After irregular PTK in the strain of C57BL/6-C57/BL/6-Tg(UBC-GFP)30Scha/J chimeric mice, however, more than 95% of fibrocytes and other hematopoietic cells underwent apoptosis prior to the development of mature αSMA+ myofibroblasts. Most GFP+ CD45+ αSMA+ myofibroblasts that did develop subsequently underwent apoptosis-likely due to epithelial basement membrane regeneration and deprivation of epithelium-derived TGFβ requisite for myofibroblast survival.
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Affiliation(s)
- Luciana Lassance
- Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States
| | | | - Carla S Medeiros
- Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States; University of Sao Paulo, Sao Paulo, Brazil
| | | | - Steven E Wilson
- Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States.
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23
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Affiliation(s)
- H T Hassan
- Institute of Medical Sciences, University of Lincoln, UK.
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24
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André-Lévigne D, Modarressi A, Pepper MS, Pittet-Cuénod B. Reactive Oxygen Species and NOX Enzymes Are Emerging as Key Players in Cutaneous Wound Repair. Int J Mol Sci 2017; 18:ijms18102149. [PMID: 29036938 PMCID: PMC5666831 DOI: 10.3390/ijms18102149] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 10/09/2017] [Accepted: 10/10/2017] [Indexed: 02/07/2023] Open
Abstract
Our understanding of the role of oxygen in cell physiology has evolved from its long-recognized importance as an essential factor in oxidative metabolism to its recognition as an important player in cell signaling. With regard to the latter, oxygen is needed for the generation of reactive oxygen species (ROS), which regulate a number of different cellular functions including differentiation, proliferation, apoptosis, migration, and contraction. Data specifically concerning the role of ROS-dependent signaling in cutaneous wound repair are very limited, especially regarding wound contraction. In this review we provide an overview of the current literature on the role of molecular and reactive oxygen in the physiology of wound repair as well as in the pathophysiology and therapy of chronic wounds, especially under ischemic and hyperglycemic conditions.
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Affiliation(s)
- Dominik André-Lévigne
- Department of Plastic, Reconstructive & Aesthetic Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland.
| | - Ali Modarressi
- Department of Plastic, Reconstructive & Aesthetic Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland.
| | - Michael S Pepper
- Department of Human Genetics and Development, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland.
- SAMRC Extramural Unit for Stem Cell Research and Therapy, and Institute for Cellular and Molecular Medicine, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa.
| | - Brigitte Pittet-Cuénod
- Department of Plastic, Reconstructive & Aesthetic Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland.
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Xavier-Elsas P, Ferreira RN, Gaspar-Elsas MIC. Surgical and immune reconstitution murine models in bone marrow research: Potential for exploring mechanisms in sepsis, trauma and allergy. World J Exp Med 2017; 7:58-77. [PMID: 28890868 PMCID: PMC5571450 DOI: 10.5493/wjem.v7.i3.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 06/11/2017] [Accepted: 06/30/2017] [Indexed: 02/06/2023] Open
Abstract
Bone marrow, the vital organ which maintains lifelong hemopoiesis, currently receives considerable attention, as a source of multiple cell types which may play important roles in repair at distant sites. This emerging function, distinct from, but closely related to, bone marrow roles in innate immunity and inflammation, has been characterized through a number of strategies. However, the use of surgical models in this endeavour has hitherto been limited. Surgical strategies allow the experimenter to predetermine the site, timing, severity and invasiveness of injury; to add or remove aggravating factors (such as infection and defects in immunity) in controlled ways; and to manipulate the context of repair, including reconstitution with selected immune cell subpopulations. This endows surgical models overall with great potential for exploring bone marrow responses to injury, inflammation and infection, and its roles in repair and regeneration. We review three different murine surgical models, which variously combine trauma with infection, antigenic stimulation, or immune reconstitution, thereby illuminating different aspects of the bone marrow response to systemic injury in sepsis, trauma and allergy. They are: (1) cecal ligation and puncture, a versatile model of polymicrobial sepsis; (2) egg white implant, an intriguing model of eosinophilia induced by a combination of trauma and sensitization to insoluble allergen; and (3) ectopic lung tissue transplantation, which allows us to dissect afferent and efferent mechanisms leading to accumulation of hemopoietic cells in the lungs. These models highlight the gain in analytical power provided by the association of surgical and immunological strategies.
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26
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Borriello L, Nakata R, Sheard MA, Fernandez GE, Sposto R, Malvar J, Blavier L, Shimada H, Asgharzadeh S, Seeger RC, DeClerck YA. Cancer-Associated Fibroblasts Share Characteristics and Protumorigenic Activity with Mesenchymal Stromal Cells. Cancer Res 2017; 77:5142-5157. [PMID: 28687621 DOI: 10.1158/0008-5472.can-16-2586] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 04/30/2017] [Accepted: 06/29/2017] [Indexed: 11/16/2022]
Abstract
Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship with MSCs is not clear. Here, we have isolated from primary human neuroblastoma tumors a population of αFAP- and FSP-1-expressing CAFs that share phenotypic and functional characteristics with bone marrow-derived MSCs (BM-MSC). Analysis of human neuroblastoma tumors also confirmed the presence of αFAP- and FSP-1-positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSCs) enhanced in vitro neuroblastoma cell proliferation, survival, and resistance to chemotherapy and stimulated neuroblastoma tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The protumorigenic activity of MSCs in vitro and in xenografted mice was dependent on the coactivation of JAK2/STAT3 and MEK/ERK1/2 in neuroblastoma cells. In a mouse model of orthotopically implanted neuroblastoma cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type of protumorigenic CAF in the tumor microenvironment of neuroblastoma and to STAT3 and ERK1/2 as mediators of their activity. Cancer Res; 77(18); 5142-57. ©2017 AACR.
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Affiliation(s)
- Lucia Borriello
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Keck School of Medicine of the University of Southern California, Los Angeles, California.,Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - Rie Nakata
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Keck School of Medicine of the University of Southern California, Los Angeles, California.,Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - Michael A Sheard
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Keck School of Medicine of the University of Southern California, Los Angeles, California.,Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - G Esteban Fernandez
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - Richard Sposto
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Keck School of Medicine of the University of Southern California, Los Angeles, California.,Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.,Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Jemily Malvar
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Keck School of Medicine of the University of Southern California, Los Angeles, California.,Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - Laurence Blavier
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Keck School of Medicine of the University of Southern California, Los Angeles, California.,Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - Hiroyuki Shimada
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.,Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Shahab Asgharzadeh
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Keck School of Medicine of the University of Southern California, Los Angeles, California.,Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.,Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Robert C Seeger
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Keck School of Medicine of the University of Southern California, Los Angeles, California.,Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - Yves A DeClerck
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Keck School of Medicine of the University of Southern California, Los Angeles, California. .,Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California.,The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.,Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
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27
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Wound-Healing Studies in Cornea and Skin: Parallels, Differences and Opportunities. Int J Mol Sci 2017; 18:ijms18061257. [PMID: 28604651 PMCID: PMC5486079 DOI: 10.3390/ijms18061257] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 05/24/2017] [Accepted: 05/31/2017] [Indexed: 02/06/2023] Open
Abstract
The cornea and the skin are both organs that provide the outer barrier of the body. Both tissues have developed intrinsic mechanisms that protect the organism from a wide range of external threats, but at the same time also enable rapid restoration of tissue integrity and organ-specific function. The easy accessibility makes the skin an attractive model system to study tissue damage and repair. Findings from skin research have contributed to unravelling novel fundamental principles in regenerative biology and the repair of other epithelial-mesenchymal tissues, such as the cornea. Following barrier disruption, the influx of inflammatory cells, myofibroblast differentiation, extracellular matrix synthesis and scar formation present parallel repair mechanisms in cornea and skin wound healing. Yet, capillary sprouting, while pivotal in proper skin wound healing, is a process that is rather associated with pathological repair of the cornea. Understanding the parallels and differences of the cellular and molecular networks that coordinate the wound healing response in skin and cornea are likely of mutual importance for both organs with regard to the development of regenerative therapies and understanding of the disease pathologies that affect epithelial-mesenchymal interactions. Here, we review the principal events in corneal wound healing and the mechanisms to restore corneal transparency and barrier function. We also refer to skin repair mechanisms and their potential implications for regenerative processes in the cornea.
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Girard D, Laverdet B, Buhé V, Trouillas M, Ghazi K, Alexaline MM, Egles C, Misery L, Coulomb B, Lataillade JJ, Berthod F, Desmoulière A. Biotechnological Management of Skin Burn Injuries: Challenges and Perspectives in Wound Healing and Sensory Recovery. TISSUE ENGINEERING PART B-REVIEWS 2017; 23:59-82. [DOI: 10.1089/ten.teb.2016.0195] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Dorothée Girard
- University of Limoges, Myelin Maintenance and Peripheral Neuropathies (EA 6309), Faculties of Medicine and Pharmacy, Limoges, France
| | - Betty Laverdet
- University of Limoges, Myelin Maintenance and Peripheral Neuropathies (EA 6309), Faculties of Medicine and Pharmacy, Limoges, France
| | - Virginie Buhé
- University of Western Brittany, Laboratory of Neurosciences of Brest (EA 4685), Brest, France
| | - Marina Trouillas
- Paris Sud University, Unité mixte Inserm/SSA 1197, IRBA/CTSA/HIA Percy, École du Val de Grâce, Clamart, France
| | - Kamélia Ghazi
- Sorbonne University, Université de Technologie de Compiègne, CNRS UMR 7338 Biomechanics and Bioengineering, Centre de Recherche Royallieu, Compiègne, France
| | - Maïa M. Alexaline
- Paris Sud University, Unité mixte Inserm/SSA 1197, IRBA/CTSA/HIA Percy, École du Val de Grâce, Clamart, France
| | - Christophe Egles
- Sorbonne University, Université de Technologie de Compiègne, CNRS UMR 7338 Biomechanics and Bioengineering, Centre de Recherche Royallieu, Compiègne, France
| | - Laurent Misery
- University of Western Brittany, Laboratory of Neurosciences of Brest (EA 4685), Brest, France
| | - Bernard Coulomb
- Paris Sud University, Unité mixte Inserm/SSA 1197, IRBA/CTSA/HIA Percy, École du Val de Grâce, Clamart, France
| | - Jean-Jacques Lataillade
- Paris Sud University, Unité mixte Inserm/SSA 1197, IRBA/CTSA/HIA Percy, École du Val de Grâce, Clamart, France
| | - François Berthod
- Centre LOEX de l'Université Laval, Centre de recherche du CHU de Québec and Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, Canada
| | - Alexis Desmoulière
- University of Limoges, Myelin Maintenance and Peripheral Neuropathies (EA 6309), Faculties of Medicine and Pharmacy, Limoges, France
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29
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Stone RC, Pastar I, Ojeh N, Chen V, Liu S, Garzon KI, Tomic-Canic M. Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res 2016; 365:495-506. [PMID: 27461257 DOI: 10.1007/s00441-016-2464-0] [Citation(s) in RCA: 423] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 06/24/2016] [Indexed: 12/28/2022]
Abstract
The epithelial-mesenchymal transition (EMT) describes the global process by which stationary epithelial cells undergo phenotypic changes, including the loss of cell-cell adhesion and apical-basal polarity, and acquire mesenchymal characteristics that confer migratory capacity. EMT and its converse, MET (mesenchymal-epithelial transition), are integral stages of many physiologic processes and, as such, are tightly coordinated by a host of molecular regulators. Converging lines of evidence have identified EMT as a component of cutaneous wound healing, during which otherwise stationary keratinocytes (the resident skin epithelial cells) migrate across the wound bed to restore the epidermal barrier. Moreover, EMT plays a role in the development of scarring and fibrosis, as the matrix-producing myofibroblasts arise from cells of the epithelial lineage in response to injury but are pathologically sustained instead of undergoing MET or apoptosis. In this review, we summarize the role of EMT in physiologic repair and pathologic fibrosis of tissues and organs. We conclude that further investigation into the contribution of EMT to the faulty repair of fibrotic wounds might identify components of EMT signaling as common therapeutic targets for impaired healing in many tissues. Graphical Abstract Model for injury-triggered EMT activation in physiologic wound repair (left) and fibrotic wound healing (right).
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Affiliation(s)
- Rivka C Stone
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB, Room 2023A, Miami, FL 33136, USA
- The Research Residency Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Fla., USA
| | - Irena Pastar
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB, Room 2023A, Miami, FL 33136, USA
| | - Nkemcho Ojeh
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB, Room 2023A, Miami, FL 33136, USA
- Faculty of Medical Sciences, The University of the West Indies, Bridgetown, Barbados
| | - Vivien Chen
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB, Room 2023A, Miami, FL 33136, USA
| | - Sophia Liu
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB, Room 2023A, Miami, FL 33136, USA
| | - Karen I Garzon
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB, Room 2023A, Miami, FL 33136, USA
| | - Marjana Tomic-Canic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB, Room 2023A, Miami, FL 33136, USA.
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30
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Barcellos-de-Souza P, Comito G, Pons-Segura C, Taddei ML, Gori V, Becherucci V, Bambi F, Margheri F, Laurenzana A, Del Rosso M, Chiarugi P. Mesenchymal Stem Cells are Recruited and Activated into Carcinoma-Associated Fibroblasts by Prostate Cancer Microenvironment-Derived TGF-β1. Stem Cells 2016; 34:2536-2547. [PMID: 27300750 DOI: 10.1002/stem.2412] [Citation(s) in RCA: 179] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 04/29/2016] [Indexed: 12/26/2022]
Abstract
Tumor stromal cells can supply appropriate signals that may develop aggressive phenotypes of carcinoma cells and establish a complex scenario which culminates in metastasis. Recent works proposed that bone marrow-derived mesenchymal stem cells (MSC) are recruited to primary tumors. However, the exact functions of these cells in the tumor microenvironment are not well characterized, as it is reported that MSC can either promote or inhibit tumor progression. In the present study, we aim at investigating the signaling molecules which regulate the interplay between MSC, prostate carcinoma (PCa) cells and two important cellular types constituting the tumor-associated stroma, macrophages and fibroblasts, during their progression toward malignancy. We identified TGF-β1 as a crucial molecule able to attract MSC recruitment both to PCa cells as well as to tumor stroma components. Moreover, PCa- and tumor stroma-secreted TGF-β1 is important to induce MSC transdifferentiation into carcinoma-associated fibroblast (CAF)-like cells. Consequently, the CAF-like phenotype acquired by MSC is central to promote tumor progression related effects. Thus, tumor-educated MSC enhance PCa invasiveness compared to nonactivated MSC. Additionally, differing from normal MSC, CAF-like MSC perform vascular mimicry and recruit monocytes, which can be further polarized to M2 macrophages within the PCa environment. Our findings indicate a prominent role for TGF-β1 in MSC mobilization and activation strengthened by the fact that the blockade of TGF-β1 signaling impairs MSC promotion of PCa progression. Stem Cells 2016;34:2536-2547.
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Affiliation(s)
- Pedro Barcellos-de-Souza
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy. .,Ministry of Education of Brazil, CAPES Foundation, Brasília, DF, Brazil.
| | - Giuseppina Comito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy
| | - Coral Pons-Segura
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy
| | - Maria Letizia Taddei
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy
| | - Valentina Gori
- Department of Oncohematology, Transfusion Medicine and Cell Therapy, Meyer Children's Hospital, Florence, Italy
| | - Valentina Becherucci
- Department of Oncohematology, Transfusion Medicine and Cell Therapy, Meyer Children's Hospital, Florence, Italy
| | - Franco Bambi
- Department of Oncohematology, Transfusion Medicine and Cell Therapy, Meyer Children's Hospital, Florence, Italy
| | - Francesca Margheri
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy
| | - Anna Laurenzana
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy
| | - Mario Del Rosso
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy
| | - Paola Chiarugi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy
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31
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Seo BR, Bhardwaj P, Choi S, Gonzalez J, Andresen Eguiluz RC, Wang K, Mohanan S, Morris PG, Du B, Zhou XK, Vahdat LT, Verma A, Elemento O, Hudis CA, Williams RM, Gourdon D, Dannenberg AJ, Fischbach C. Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Sci Transl Med 2016; 7:301ra130. [PMID: 26290412 DOI: 10.1126/scitranslmed.3010467] [Citation(s) in RCA: 245] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies.
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Affiliation(s)
- Bo Ri Seo
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Priya Bhardwaj
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Siyoung Choi
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Jacqueline Gonzalez
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | | | - Karin Wang
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Sunish Mohanan
- Department of Biological and Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Patrick G Morris
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Baoheng Du
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Xi K Zhou
- Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, NY 10065, USA
| | - Linda T Vahdat
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Akanksha Verma
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Olivier Elemento
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Clifford A Hudis
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Rebecca M Williams
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Delphine Gourdon
- Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Andrew J Dannenberg
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Claudia Fischbach
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, NY 14853, USA.
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32
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Torricelli AAM, Santhanam A, Wu J, Singh V, Wilson SE. The corneal fibrosis response to epithelial-stromal injury. Exp Eye Res 2016; 142:110-8. [PMID: 26675407 DOI: 10.1016/j.exer.2014.09.012] [Citation(s) in RCA: 213] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Revised: 09/23/2014] [Accepted: 09/30/2014] [Indexed: 12/22/2022]
Abstract
The corneal wound healing response, including the development of stromal opacity in some eyes, is a process that often leads to scarring that occurs after injury, surgery or infection to the cornea. Immediately after epithelial and stromal injury, a complex sequence of processes contributes to wound repair and regeneration of normal corneal structure and function. In some corneas, however, often depending on the type and extent of injury, the response may also lead to the development of mature vimentin+ α-smooth muscle actin+ desmin+ myofibroblasts. Myofibroblasts are specialized fibroblastic cells generated in the cornea from keratocyte-derived or bone marrow-derived precursor cells. The disorganized extracellular matrix components secreted by myofibroblasts, in addition to decreased expression of corneal crystallins in these cells, are central biological processes that result in corneal stromal fibrosis associated with opacity or "haze". Several factors are associated with myofibroblast generation and haze development after PRK surgery in rabbits, a reproducible model of scarring, including the amount of tissue ablated, which may relate to the extent of keratocyte apoptosis in the early response to injury, irregularity of stromal surface after surgery, and changes in corneal stromal proteoglycans, but normal regeneration of the epithelial basement membrane (EBM) appears to be a critical factor determining whether a cornea heals with relative transparency or vision-limiting stromal opacity. Structural and functional abnormalities of the regenerated EBM facilitate prolonged entry of epithelium-derived growth factors such as transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) into the stroma that both drive development of mature myofibroblasts from precursor cells and lead to persistence of the cells in the anterior stroma. A major discovery that has contributed to our understanding of haze development is that keratocytes and corneal fibroblasts produce critical EBM components, such as nidogen-1, nidogen-2 and perlecan, that are essential for complete regeneration of a normal EBM once laminin secreted by epithelial cells self-polymerizes into a nascent EBM. Mature myofibroblasts that become established in the anterior stroma are a barrier to keratocyte/corneal fibroblast contributions to the nascent EBM. These myofibroblasts, and the opacity they produce, often persist for months or years after the injury. Transparency is subsequently restored when the EBM is completely regenerated, myofibroblasts are deprived of TGFβ and undergo apoptosis, and the keratocytes re-occupy the anterior stroma and reabsorb disordered extracellular matrix. The aim of this review is to highlight factors involved in the generation of stromal haze and its subsequent removal.
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Affiliation(s)
- Andre A M Torricelli
- Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA; University of Sao Paulo, Sao Paulo, Brazil
| | | | - Jiahui Wu
- Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Vivek Singh
- Prof. Brien Holden Eye Research Centre, C-TRACER, LV Prasad Eye Institute, Hyderabad, Andhra Pradesh, India
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33
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Sakai D, Nishimura K, Tanaka M, Nakajima D, Grad S, Alini M, Kawada H, Ando K, Mochida J. Migration of bone marrow-derived cells for endogenous repair in a new tail-looping disc degeneration model in the mouse: a pilot study. Spine J 2015; 15:1356-65. [PMID: 25459743 DOI: 10.1016/j.spinee.2013.07.491] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2011] [Revised: 03/13/2013] [Accepted: 07/30/2013] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Mobilization and homing of bone marrow-derived cells (BMCs) play a pivotal role in healing and regeneration of various tissues. However, the cellular response of BMCs in avascular tissue such as the intervertebral disc (IVD) has not been studied in detail. One of the main obstacles to this is a lack of a suitable mouse disc degeneration model. PURPOSE The purpose of this study was to establish a reproducible disc degeneration mouse model suitable for analyzing the cellular response of the disc microenvironment and to determine whether BMCs are recruited into the IVD. STUDY DESIGN An experimental animal study of disc degeneration investigating the potential of BMCs in an endogenous repair of the IVD. METHODS We transplanted whole bone marrow cells from mice ubiquitously expressing enhanced green fluorescent protein into lethally irradiated mice. Intervertebral disc degeneration was induced through uneven loading by creating a loop in the tail of these mice. The vertebral bone-disc-vertebral bone units were harvested, and BMCs were identified by immunohistochemistry. RESULTS A new disc degeneration model was established in the mouse. Applying this model in the bone marrow chimeric mice increased the number of BMCs in the peripheral bone marrow and vascular canals in the endplate, and some were found in the IVD. The migration of BMCs was related to the severity of IVD degeneration. CONCLUSIONS Although providing a new disc degeneration model in mice, the present study provides evidence to suggest that although BMCs are recruited during disc degeneration, only a limited number of BMCs migrate to the IVD, presumably because of its avascular nature. This fact provides important elements for developing new treatments as many growth factors and compounds are being tested, both in investigational levels and clinical trials to nourish resident endogenous cells during the degenerative process.
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Affiliation(s)
- Daisuke Sakai
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan; Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan; AO Spine Research Network.
| | - Kazuhiro Nishimura
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan
| | - Masahiro Tanaka
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan; Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan
| | - Daisuke Nakajima
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan; Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan
| | - Sibylle Grad
- AO Spine Research Network; Musculoskeletal Regeneration Program, AO Research Institute Davos, Clavadelerstrasse 8, 7270 Davos, Switzerland
| | - Mauro Alini
- AO Spine Research Network; Musculoskeletal Regeneration Program, AO Research Institute Davos, Clavadelerstrasse 8, 7270 Davos, Switzerland
| | - Hiroshi Kawada
- Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan
| | - Kiyoshi Ando
- Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan
| | - Joji Mochida
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan; Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan
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Pilling D, Cox N, Vakil V, Verbeek JS, Gomer RH. The long pentraxin PTX3 promotes fibrocyte differentiation. PLoS One 2015; 10:e0119709. [PMID: 25774777 PMCID: PMC4361553 DOI: 10.1371/journal.pone.0119709] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 01/16/2015] [Indexed: 12/31/2022] Open
Abstract
Monocyte-derived, fibroblast-like cells called fibrocytes are associated with fibrotic lesions. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP is a member of the pentraxin family of proteins that includes C-reactive protein (CRP; PTX1) and pentraxin-3 (PTX3). All three pentraxins are associated with fibrosis, but only SAP and CRP have been studied for their effects on fibrocyte differentiation. We find that compared to SAP and CRP, PTX3 promotes human and murine fibrocyte differentiation. The effect of PTX3 is dependent on FcγRI. In competition studies, the fibrocyte-inhibitory activity of SAP is dominant over PTX3. Binding competition studies indicate that SAP and PTX3 bind human FcγRI at different sites. In murine models of lung fibrosis, PTX3 is present in fibrotic areas, and the PTX3 distribution is associated with collagen deposition. In lung tissue from pulmonary fibrosis patients, PTX3 has a widespread distribution, both in unaffected tissue and in fibrotic lesions, whereas SAP is restricted to areas adjacent to vessels, and absent from fibrotic areas. These data suggest that the relative levels of SAP and PTX3 present at sites of fibrosis may have a significant effect on the ability of monocytes to differentiate into fibrocytes.
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Affiliation(s)
- Darrell Pilling
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
- * E-mail: (DP); (RHG)
| | - Nehemiah Cox
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
| | - Varsha Vakil
- Department of Biochemistry and Cell Biology, Rice University, Houston, Texas, United States of America
| | - J. Sjef Verbeek
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Richard H. Gomer
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
- Department of Biochemistry and Cell Biology, Rice University, Houston, Texas, United States of America
- * E-mail: (DP); (RHG)
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Park DS, Park JC, Lee JS, Kim TW, Kim KJ, Jung BJ, Shim EK, Choi EY, Park SY, Cho KS, Kim CS. Effect of FGF-2 on Collagen Tissue Regeneration by Human Vertebral Bone Marrow Stem Cells. Stem Cells Dev 2015; 24:228-43. [DOI: 10.1089/scd.2014.0148] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- Dong-Soo Park
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - Jung-Chul Park
- Department of Periodontology, College of Dentistry, Dankook University, Cheonan, Korea
| | - Jung-Seok Lee
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - Tae-Wan Kim
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - Ki-Joon Kim
- Department of Neurosurgery, Naeun Hospital, Anyang, Korea
| | - Byung-Joo Jung
- Department of Neurosurgery, Naeun Hospital, Anyang, Korea
| | - Eun-Kyung Shim
- Biomedical Research Institute, iBMT Co., Ltd., Anyang, Korea
| | - Eun-Young Choi
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - So-Yon Park
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - Kyoo-Sung Cho
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - Chang-Sung Kim
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
- BK21 PLUS Project, Department of Applied Life Science, College of Dentistry, Yonsei University, Seoul, Korea
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Mitchell RA, Yaddanapudi K. Stromal-dependent tumor promotion by MIF family members. Cell Signal 2014; 26:2969-78. [PMID: 25277536 PMCID: PMC4293307 DOI: 10.1016/j.cellsig.2014.09.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 09/23/2014] [Indexed: 12/25/2022]
Abstract
Solid tumors are composed of a heterogeneous population of cells that interact with each other and with soluble and insoluble factors that, when combined, strongly influence the relative proliferation, differentiation, motility, matrix remodeling, metabolism and microvessel density of malignant lesions. One family of soluble factors that is becoming increasingly associated with pro-tumoral phenotypes within tumor microenvironments is that of the migration inhibitory factor family which includes its namesake, MIF, and its only known family member, D-dopachrome tautomerase (D-DT). This review seeks to highlight our current understanding of the relative contributions of a variety of immune and non-immune tumor stromal cell populations and, within those contexts, will summarize the literature associated with MIF and/or D-DT.
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Affiliation(s)
- Robert A Mitchell
- JG Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY 40202, United States.
| | - Kavitha Yaddanapudi
- JG Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY 40202, United States
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Darby IA, Laverdet B, Bonté F, Desmoulière A. Fibroblasts and myofibroblasts in wound healing. Clin Cosmet Investig Dermatol 2014; 7:301-11. [PMID: 25395868 PMCID: PMC4226391 DOI: 10.2147/ccid.s50046] [Citation(s) in RCA: 450] [Impact Index Per Article: 40.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
(Myo)fibroblasts are key players for maintaining skin homeostasis and for orchestrating physiological tissue repair. (Myo)fibroblasts are embedded in a sophisticated extracellular matrix (ECM) that they secrete, and a complex and interactive dialogue exists between (myo)fibroblasts and their microenvironment. In addition to the secretion of the ECM, (myo)fibroblasts, by secreting matrix metalloproteinases and tissue inhibitors of metalloproteinases, are able to remodel this ECM. (Myo)fibroblasts and their microenvironment form an evolving network during tissue repair, with reciprocal actions leading to cell differentiation, proliferation, quiescence, or apoptosis, and actions on growth factor bioavailability by binding, sequestration, and activation. In addition, the (myo)fibroblast phenotype is regulated by mechanical stresses to which they are subjected and thus by mechanical signaling. In pathological situations (excessive scarring or fibrosis), or during aging, this dialogue between the (myo)fibroblasts and their microenvironment may be altered or disrupted, leading to repair defects or to injuries with damaged and/or cosmetic skin alterations such as wrinkle development. The intimate dialogue between the (myo)fibroblasts and their microenvironment therefore represents a fascinating domain that must be better understood in order not only to characterize new therapeutic targets and drugs able to prevent or treat pathological developments but also to interfere with skin alterations observed during normal aging or premature aging induced by a deleterious environment.
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Affiliation(s)
- Ian A Darby
- School of Medical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Betty Laverdet
- Department of Physiology and EA 6309, FR 3503, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France
| | | | - Alexis Desmoulière
- Department of Physiology and EA 6309, FR 3503, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France
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Negative regulation of GADD34 on myofibroblasts during cutaneous wound healing. BIOMED RESEARCH INTERNATIONAL 2014; 2014:137049. [PMID: 25210702 PMCID: PMC4156997 DOI: 10.1155/2014/137049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 08/04/2014] [Accepted: 08/05/2014] [Indexed: 01/15/2023]
Abstract
The growth arrest and DNA damage-inducible protein, GADD34, has been proved to be involved in TGF-β signaling pathway and correlates with cell death, which are two important mechanisms in regulating myofibroblast differentiation and apoptosis during tissue repair. But roles of GADD34 in myofibroblasts differentiation and apoptosis remain unknown. To investigate the function of GADD34 in these processes, we subjected WT and GADD34−/− mice to dermal wound healing. Here we show that GADD34−/− mice exhibited accelerated wound closure compared with WT mice. In addition, GADD34−/− mice showed increased number of myofibroblasts, elevated collagen production, and decreased cell apoptosis during wound healing. Moreover, we found that GADD34−/− mice showed increased phosphorylation of Smad3 and lower level of cleaved caspase-3. Thus these results indicate that GADD34 appears to suppress myofibroblast differentiation through inhibiting Smad3-dependent TGFβ signal pathway and promote its apoptosis by activating caspase-3 pathway.
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Laverdet B, Micallef L, Lebreton C, Mollard J, Lataillade JJ, Coulomb B, Desmoulière A. Use of mesenchymal stem cells for cutaneous repair and skin substitute elaboration. ACTA ACUST UNITED AC 2014; 62:108-17. [DOI: 10.1016/j.patbio.2014.01.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 01/31/2014] [Indexed: 12/20/2022]
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Abstract
Progressive lung fibrosis in humans, typified by idiopathic pulmonary fibrosis (IPF), is a serious cause of morbidity and mortality in people. Similar diseases have been described in dogs, cats, and horses. The cause and pathogenesis of such diseases in all species is poorly understood. There is growing evidence in human medicine that IPF is a manifestation of abnormal wound repair in response to epithelial injury. Because viruses can contribute to epithelial injury, there is increasing interest in a possible role of viruses, particularly gammaherpesviruses, in the pathogenesis of pulmonary fibrosis. This review provides background information on progressive fibrosing lung disease in human and veterinary medicine and summarizes the evidence for an association between gammaherpesvirus infection and pulmonary fibrosis, especially Epstein-Barr virus in human pulmonary fibrosis, and equine herpesvirus 5 in equine multinodular pulmonary fibrosis. Data derived from experimental lung infection in mice with the gammaherpesvirus murine herpesvirus are presented, emphasizing the host and viral factors that may contribute to lung fibrosis. The experimental data are considered in the context of the pathogenesis of naturally occurring pulmonary fibrosis in humans and horses.
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Affiliation(s)
- K. J. Williams
- Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
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Abstract
Pericytes are interstitial mesenchymal cells found in many major organs. In the kidney, microvascular pericytes are defined anatomically as extensively branched, collagen-producing cells in close contact with endothelial cells. Although many molecular markers have been proposed, none of them can identify the pericytes with satisfactory specificity or sensitivity. The roles of microvascular pericytes in kidneys were poorly understood in the past. Recently, by using genetic lineage tracing to label collagen-producing cells or mesenchymal cells, the elusive characteristics of the pericytes have been illuminated. The purpose of this article is to review recent advances in the understanding of microvascular pericytes in the kidneys. In healthy kidney, the pericytes are found to take part in the maintenance of microvascular stability. Detachment of the pericytes from the microvasculature and loss of the close contact with endothelial cells have been observed during renal insult. Renal microvascular pericytes have been shown to be the major source of scar-forming myofibroblasts in fibrogenic kidney disease. Targeting the crosstalk between pericytes and neighboring endothelial cells or tubular epithelial cells may inhibit the pericyte-myofibroblast transition, prevent peritubular capillary rarefaction, and attenuate renal fibrosis. In addition, renal pericytes deserve attention for their potential to produce erythropoietin in healthy kidneys as pericytes stand in the front line, sensing the change of oxygenation and hemoglobin concentration. Further delineation of the mechanisms underlying the reduced erythropoietin production occurring during pericyte-myofibroblast transition may be promising for the development of new treatment strategies for anemia in chronic kidney disease.
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Affiliation(s)
- Szu-Yu Pan
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan ; Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan
| | - Yu-Ting Chang
- Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shuei-Liong Lin
- Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan ; Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Abstract
Organ transplantation appears today to be the best alternative to replace the loss of vital organs induced by various diseases. Transplants can, however, also be rejected by the recipient. In this review, we provide an overview of the mechanisms and the cells/molecules involved in acute and chronic rejections. T cells and B cells mainly control the antigen-specific rejection and act either as effector, regulatory, or memory cells. On the other hand, nonspecific cells such as endothelial cells, NK cells, macrophages, or polymorphonuclear cells are also crucial actors of transplant rejection. Last, beyond cells, the high contribution of antibodies, chemokines, and complement molecules in graft rejection is discussed in this article. The understanding of the different components involved in graft rejection is essential as some of them are used in the clinic as biomarkers to detect and quantify the level of rejection.
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Affiliation(s)
- Aurélie Moreau
- INSERM UMR 1064, Center for Research in Transplantation and Immunology-ITUN, CHU de Nantes 44093, France
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43
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Barcellos-de-Souza P, Gori V, Bambi F, Chiarugi P. Tumor microenvironment: bone marrow-mesenchymal stem cells as key players. Biochim Biophys Acta Rev Cancer 2013; 1836:321-35. [PMID: 24183942 DOI: 10.1016/j.bbcan.2013.10.004] [Citation(s) in RCA: 116] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2013] [Revised: 10/15/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023]
Abstract
Tumor progression is a multistep phenomenon in which tumor-associated stromal cells perform an intricate cross-talk with tumor cells, supplying appropriate signals that may promote tumor aggressiveness. Among several cell types that constitute the tumor stroma, the discovery that bone marrow-derived mesenchymal stem cells (BM-MSC) have a strong tropism for tumors has achieved notoriety in recent years. Not only are the BM-MSC recruited, but they can also engraft at tumor sites and transdifferentiate into cells such as activated fibroblasts, perivascular cells and macrophages, which will perform a key role in tumor progression. Whether the BM-MSC and their derived cells promote or suppress the tumor progression is a controversial issue. Recently, it has been proposed that proinflammatory stimuli can be decisive in driving BM-MSC polarization into cells with either tumor-supportive or tumor-repressive phenotypes (MSC1/MSC2). These considerations are extremely important both to an understanding of tumor biology and to the putative use of BM-MSC as "magic bullets" against tumors. In this review, we discuss the role of BM-MSC in many steps in tumor progression, focusing on the factors that attract BM-MSC to tumors, BM-MSC differentiation ability, the role of BM-MSC in tumor support or inhibition, the immunomodulation promoted by BM-MSC and metastatic niche formation by these cells.
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Affiliation(s)
- Pedro Barcellos-de-Souza
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Tuscany Tumor Institute and Center for Research, Transfer and High Education DenoTHE, Florence, Italy; CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, Brazil.
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44
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Singh V, Jaini R, Torricelli AAM, Tuohy VK, Wilson SE. A method to generate enhanced GFP+ chimeric mice to study the role of bone marrow-derived cells in the eye. Exp Eye Res 2013; 116:366-70. [PMID: 24140502 DOI: 10.1016/j.exer.2013.10.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 09/21/2013] [Accepted: 10/07/2013] [Indexed: 10/26/2022]
Abstract
GFP-chimeric mice are important tools to study the role of bone marrow-derived cells in eye physiology. A method is described to generate GFP-chimeric mice using whole-body, sub-lethal radiation (600 rad) of wild-type C57BL/6 recipients followed by tail vein injection of bone marrow cells derived from GFP+ (GFP-transgenic C57/BL/6-Tg(UBC-GFP)30 Scha/J) mice. This method yields stable GFP+ chimeras with greater than 95% chimerism (range 95-99%), achieved within one month of bone marrow transfer confirmed by microscopy and fluorescence-assisted cell sorting (FACS) analysis, with lower mortality after irradiation than prior methods. To demonstrate the efficacy of GFP+ bone marrow chimeric mice, the role of circulating GFP+ bone marrow-derived cells in myofibroblast generation after irregular photo-therapeutic keratectomy (PTK) was analyzed. Many SMA+ myofibroblasts that were generated at one month after PTK were derived from GFP+ bone marrow-derived cells. The GFP+ bone marrow chimeric mouse provides an excellent model for studying the role of bone marrow-derived cells in corneal wound healing, glaucoma surgery, optic nerve head pathology and retinal pathophysiology and wound healing.
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Affiliation(s)
- Vivek Singh
- Cole Eye Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
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Quante M, Varga J, Wang TC, Greten FR. The gastrointestinal tumor microenvironment. Gastroenterology 2013; 145:63-78. [PMID: 23583733 PMCID: PMC4012393 DOI: 10.1053/j.gastro.2013.03.052] [Citation(s) in RCA: 116] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 03/27/2013] [Accepted: 03/28/2013] [Indexed: 12/11/2022]
Abstract
Over the past decade, the microenvironment of gastrointestinal tumors has gained increasing attention because it is required for tumor initiation, progression, and metastasis. The tumor microenvironment has many components and has been recognized as one of the major hallmarks of epithelial cancers. Although therapeutic strategies for gastrointestinal cancer have previously focused on the epithelial cell compartment, there is increasing interest in reagents that alter the microenvironment, based on reported interactions among gastrointestinal epithelial, stromal, and immune cells during gastrointestinal carcinogenesis. We review the different cellular components of the gastrointestinal tumor microenvironment and their functions in carcinogenesis and discuss how improving our understanding of the complex stromal network could lead to new therapeutic strategies.
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Affiliation(s)
- Michael Quante
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München, Germany.
| | - Julia Varga
- Institut für Molekulare Immunologie, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Timothy C Wang
- Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, New York
| | - Florian R Greten
- Institut für Molekulare Immunologie, Klinikum rechts der Isar, Technische Universität München, München, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany.
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Seppanen E, Roy E, Ellis R, Bou-Gharios G, Fisk NM, Khosrotehrani K. Distant mesenchymal progenitors contribute to skin wound healing and produce collagen: evidence from a murine fetal microchimerism model. PLoS One 2013; 8:e62662. [PMID: 23650524 PMCID: PMC3641113 DOI: 10.1371/journal.pone.0062662] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 03/22/2013] [Indexed: 12/13/2022] Open
Abstract
The contribution of distant and/or bone marrow-derived endogenous mesenchymal stem cells (MSC) to skin wounds is controversial. Bone marrow transplantation experiments employed to address this have been largely confounded by radiation-resistant host-derived MSC populations. Gestationally-acquired fetal MSC are known to engraft in maternal bone marrow in all pregnancies and persist for decades. These fetal cells home to damaged maternal tissues, mirroring endogenous stem cell behavior. We used fetal microchimerism as a tool to investigate the natural homing and engraftment of distant MSC to skin wounds. Post-partum wild-type mothers that had delivered transgenic pups expressing luciferase under the collagen type I-promoter were wounded. In vivo bioluminescence imaging (BLI) was then used to track recruitment of fetal cells expressing this mesenchymal marker over 14 days of healing. Fetal cells were detected in 9/43 animals using BLI (Fisher exact p = 0.01 versus 1/43 controls). These collagen type I-expressing fetal cells were specifically recruited to maternal wounds in the initial phases of healing, peaking on day 1 (n = 43, p<0.01). This was confirmed by detection of Y-chromosome+ve fetal cells that displayed fibroblast-like morphology. Histological analyses of day 7 wounds revealed vimentin-expressing fetal cells in dermal tissue. Our results demonstrate the participation of distant mesenchymal cells in skin wounds. These data imply that endogenous MSC populations are likely recruited from bone marrow to wounds to participate in healing.
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Affiliation(s)
- Elke Seppanen
- The University of Queensland, UQ Centre for Clinical Research, Herston Campus, Brisbane, Australia
| | - Edwige Roy
- The University of Queensland, UQ Centre for Clinical Research, Herston Campus, Brisbane, Australia
| | - Rebecca Ellis
- The University of Queensland, UQ Centre for Clinical Research, Herston Campus, Brisbane, Australia
| | - George Bou-Gharios
- The University of Queensland, UQ Centre for Clinical Research, Herston Campus, Brisbane, Australia
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Nicholas M. Fisk
- The University of Queensland, UQ Centre for Clinical Research, Herston Campus, Brisbane, Australia
- Centre for Advanced Prenatal Care, Royal Brisbane and Women’s Hospital, Herston, Australia
| | - Kiarash Khosrotehrani
- The University of Queensland, UQ Centre for Clinical Research, Herston Campus, Brisbane, Australia
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Bone marrow contributions to fibrosis. Biochim Biophys Acta Mol Basis Dis 2013; 1832:955-61. [PMID: 23385196 DOI: 10.1016/j.bbadis.2013.01.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2012] [Revised: 01/21/2013] [Accepted: 01/24/2013] [Indexed: 12/26/2022]
Abstract
Bone marrow transplant experiments in mice using labelled donor bone marrow have indicated that following injury bone marrow derived cells can circulate and home to the injured organs. In particular fibrocytes and myofibroblasts are capable of contributing to the wound healing response, including collagen deposition. In chronic injury this can lead to a pathological degree of fibrosis. Experiments have shown that this can be a relatively insignificant contribution to the scar forming population in certain organs and that the majority of the scar forming cells are intrinsic to the organ. Conversely, in certain circumstances, the circulating cells become major players in the organs fibrotic response. Whilst cell tracking experiments are relatively simple to perform, to actually determine a functional contribution to a fibrotic response more sophisticated approaches are required. This can include the use of bone marrow transplantation from recipients with collagen reporter systems which gives a read out of bone marrow derived cells that are transcriptional active for collagen production in a damaged organ. Another technique is to use bone marrow transplants from donors that have a mutation in the collagen to demonstrate a functional difference in fibrosis when bone marrow transplants performed. Recent reports have identified factors mediating recruitment of circulating fibrocytes to injured organs, such as CXCL12 and CXCL16 and shown that blocking these factors reduced fibrocyte recruitment and subsequent fibrosis. The identification of such factors may enable the development of novel therapies to block further fibrocyte engraftment and fibrosis in situations of pathological scarring. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
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Abstract
Reactive stroma initiates during early prostate cancer development and coevolves with prostate cancer progression. Previous studies have defined the key markers of reactive stroma and have established that reactive stroma biology influences prostate tumorigenesis and progression. The stem/progenitor cells of origin and the mechanisms that regulate their recruitment and activation to myofibroblasts or carcinoma-associated fibroblasts are essentially unknown. Key regulatory factors have been identified, including transforming growth factor β, interleukin-8, fibroblast growth factors, connective tissue growth factor, wingless homologs-Wnts, and stromal cell-derived factor-1, among others. The biology of reactive stroma in cancer is similar to the more predictable biology of the stroma compartment during wound repair at sites where the epithelial barrier function is breached and a stromal response is generated. The coevolution of reactive stroma and the biology of how reactive stroma-carcinoma interactions regulate cancer progression and metastasis are targets for new therapeutic approaches. Such approaches are strategically designed to inhibit cancer progression by uncoupling the reactive stroma niche.
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Affiliation(s)
- David A Barron
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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49
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Abstract
Peripheral blood is a large accessible source of adult stem cells for both basic research and clinical applications. Peripheral blood mononuclear cells (PBMCs) have been reported to contain a multitude of distinct multipotent progenitor cell populations and possess the potential to differentiate into blood cells, endothelial cells, hepatocytes, cardiomyogenic cells, smooth muscle cells, osteoblasts, osteoclasts, epithelial cells, neural cells, or myofibroblasts under appropriate conditions. Furthermore, transplantation of these PBMC-derived cells can regenerate tissues and restore function after injury. This mini-review summarizes the multi-differentiation potential of PBMCs reported in the past years, discusses the possible mechanisms for this multi-differentiation potential, and describes recent techniques for efficient PBMC isolation and purification.
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50
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Chang FC, Chou YH, Chen YT, Lin SL. Novel insights into pericyte-myofibroblast transition and therapeutic targets in renal fibrosis. J Formos Med Assoc 2012; 111:589-98. [PMID: 23217594 DOI: 10.1016/j.jfma.2012.09.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 09/03/2012] [Accepted: 09/10/2012] [Indexed: 12/31/2022] Open
Abstract
Renal fibrosis is a disease affecting millions worldwide and is a harbinger of progressive renal failure. Understanding the mechanisms of renal fibrosis is important for discovering new therapies that are required to prevent loss of renal function. Recently, we identified pericytes that line the kidney microvasculature as the precursor cells of the scar-producing myofibroblasts during kidney injury. Kidney pericytes are extensively branched cells embedded within the capillary basement membrane and stabilize the capillary network through tissue inhibitor of metalloproteinase 3 and angiogenic growth factors. Pericytes detach from endothelial cells and migrate into the interstitial space where they undergo a transition into myofibroblasts after injury. Activation of endothelium, pericyte-myofibroblast transition, and recruitment of inflammatory macrophages lead to capillary rarefaction and fibrosis. Targeting endothelium-pericyte crosstalk by inhibiting vascular endothelial cell growth factor receptors and platelet-derived growth factor receptors in response to injury have been identified as new therapeutic interventions. Furthermore, targeting macrophage activation has also been proven as a novel and safe therapeutic approach for pericyte-myofibroblast transition. However, we are still far from understanding the interaction between pericytes and other cellular elements in normal physiology and during kidney fibrosis. Further studies will be required to translate into more specific therapeutic approaches.
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Affiliation(s)
- Fan-Chi Chang
- Renal Division, Department of Medicine, National Taiwan University Hospital, Taipei, Taiwan
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