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Zhang J, Mou D, Zhu L, Zhou J, Yu Q, Yang G, Luo C, Meng J, Mao K, Liu J, Yan B, Yang X. Curcumin Inhibits Lipopolysaccharide-Induced Inflammation Through the HMGB1/NF-κB Signaling Pathway to Promote the Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells. Mol Biotechnol 2025:10.1007/s12033-025-01437-1. [PMID: 40310592 DOI: 10.1007/s12033-025-01437-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 03/20/2025] [Indexed: 05/02/2025]
Abstract
Curcumin has strong anti-inflammatory properties and promotes the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). The aim of this study was to explore the role and potential molecular mechanism of curcumin in ameliorating osteogenic differentiation disorders caused by inflammation. We used LPS to induce an inflammatory response in hBMSCs. The expression of related mRNAs and proteins was detected by RT‒qPCR, Western blotting, immunofluorescence, and ELISA. The osteogenic differentiation of hBMSCs was detected by alkaline phosphatase (ALP) staining and alizarin red S (ARS) staining. The results showed that after LPS treatment, the levels of the inflammatory cytokines TNF-α, IL-6 and IL-1β in hBMSCs increased, and the activity of ALP, the level of calcium salt deposition and the expression levels of the osteogenic proteins Runx2, COL1, OCN and OPN significantly decreased. The curcumin treatment alleviated this effect. These results indicated that curcumin improved the LPS-induced inflammation and osteogenic differentiation disorder in hBMSCs. Further studies revealed that the therapeutic effect of curcumin was caused by the inhibition of HMGB1 expression. From a mechanistic perspective, curcumin inhibits LPS-induced inflammation by inhibiting the expression of HMGB1, thereby inhibiting the NF-κB pathway and activating the NRF2 pathway, thereby improving the disordered osteogenic differentiation of hBMSCs. In conclusion, curcumin can reduce the LPS-induced inflammation of hBMSCs and ameliorate their osteogenic differentiation disorders.
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Affiliation(s)
- Jimei Zhang
- Gastroenterology Department, Chenggong Hospital, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, 650505, Yunnan, China
| | - Donggang Mou
- Pain Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, 650055, Yunnan, China
| | - Ling Zhu
- Orthopedics Department, Chenggong Hospital, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, 650505, Yunnan, China
| | - Jianping Zhou
- Orthopedics Department, Chenggong Hospital, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, 650505, Yunnan, China
| | - Qunying Yu
- Obstetrics Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650000, Yunnan, China
| | - Guangyuan Yang
- Kunming Medical University, Kunming, 650500, Yunnan, China
| | - Chaoli Luo
- Operating Room, Yunnan Pain Disease Hospital, Kunming, 650000, Yunnan, China
| | - Jianguo Meng
- Orthopedics Department, Guang Nan Hospital of Traditional Chinese Medcine, Guangnan, 663300, Yunnan, China
| | - Kewang Mao
- Orthopedics Department, Hua Ning Country Hospital, Kunming, 652800, Yunnan, China
| | - Jing Liu
- Orthopedics Department, Chenggong Hospital, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, 650505, Yunnan, China
| | - Bo Yan
- Orthopedics Department, Kunming City Resort District DaYu Street Community Health Service Center, Kunming, 650500, Yunnan, China
| | - Xuming Yang
- Orthopedics Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, 650055, Yunnan, China.
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Moreno-Blas D, Adell T, González-Estévez C. Autophagy in Tissue Repair and Regeneration. Cells 2025; 14:282. [PMID: 39996754 PMCID: PMC11853389 DOI: 10.3390/cells14040282] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/01/2025] [Accepted: 02/13/2025] [Indexed: 02/26/2025] Open
Abstract
Autophagy is a cellular recycling system that, through the sequestration and degradation of intracellular components regulates multiple cellular functions to maintain cellular homeostasis and survival. Dysregulation of autophagy is closely associated with the development of physiological alterations and human diseases, including the loss of regenerative capacity. Tissue regeneration is a highly complex process that relies on the coordinated interplay of several cellular processes, such as injury sensing, defense responses, cell proliferation, differentiation, migration, and cellular senescence. These processes act synergistically to repair or replace damaged tissues and restore their morphology and function. In this review, we examine the evidence supporting the involvement of the autophagy pathway in the different cellular mechanisms comprising the processes of regeneration and repair across different regenerative contexts. Additionally, we explore how modulating autophagy can enhance or accelerate regeneration and repair, highlighting autophagy as a promising therapeutic target in regenerative medicine for the development of autophagy-based treatments for human diseases.
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Affiliation(s)
| | | | - Cristina González-Estévez
- Department of Genetics, Microbiology and Statistics, School of Biology and Institute of Biomedicine (IBUB), University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain; (D.M.-B.); (T.A.)
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Li YT, Takaki E, Ouchi Y, Tamai K. Guided monocyte fate to FRβ/CD163 + S1 macrophage antagonises atopic dermatitis via fibroblastic matrices in mouse hypodermis. Cell Mol Life Sci 2024; 82:14. [PMID: 39720957 DOI: 10.1007/s00018-024-05543-2] [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: 05/08/2024] [Revised: 10/21/2024] [Accepted: 12/06/2024] [Indexed: 12/26/2024]
Abstract
Macrophages are versatile myeloid leukocytes with flexible cellular states to perform diverse tissue functions beyond immunity. This plasticity is however often hijacked by diseases to promote pathology. Scanning kinetics of macrophage states by single-cell transcriptomics and flow cytometry, we observed atopic dermatitis drastically exhausted a resident subtype S1. Characterized by FRβ/CD163 expression, S1 exhibited strong efferocytosis and chemoattracted monocytes and eosinophils. Here we have delineated mechanisms regulating monocyte decision to acquire S1 identity in skin. During M-CSF driven macrophage differentiation in healthy skin, FRβ was expressed via intrinsic control of STAT6 and ALK5 activities, and did not require heterotypic cellular crosstalk. In contrast, CD163 expression required exposure to fibroblastic secretion. This process depended on SHP1 activity and involved STAT5 inactivation. Suppressed STAT5 activity caused CD163 expression and rendered macrophage insensitive to further induction by fibroblasts. Parsing coculture experiments with in silico ligand expression, we identified laminin-α2 and type-V collagen secreted by hypodermal fibroblasts as CD163-driving factors. S1 identity loss in AD followed a stepwise cascade: reduced laminins availability first dampened CD163 expression, IL4 and TGFβ subsequently acted on CD163lo/- cells to downregulate FRβ. In AD skin, we showed that imitating this fibroblast-macrophage crosstalk with exogenous laminin-211 encouraged monocyte differentiation to S1 macrophages, fostered homeostatic commitment of extravasated eosinophils, and alleviated dermatitis. Hence, we demonstrated that reinforcing a steady-state cue from hypodermal fibroblasts could override maladaptive pressure on macrophage and restored tissue homeostasis.
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MESH Headings
- Dermatitis, Atopic/metabolism
- Dermatitis, Atopic/pathology
- Receptors, Cell Surface/metabolism
- Antigens, Differentiation, Myelomonocytic/metabolism
- Animals
- Antigens, CD/metabolism
- Antigens, CD/genetics
- Fibroblasts/metabolism
- Fibroblasts/pathology
- Macrophages/metabolism
- Monocytes/metabolism
- Mice
- Cell Differentiation
- STAT6 Transcription Factor/metabolism
- Skin/metabolism
- Skin/pathology
- Receptor, Transforming Growth Factor-beta Type I/metabolism
- Receptor, Transforming Growth Factor-beta Type I/genetics
- Mice, Inbred C57BL
- Macrophage Colony-Stimulating Factor/metabolism
- Eosinophils/metabolism
- Laminin/metabolism
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Affiliation(s)
- Yu-Tung Li
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
| | | | - Yuya Ouchi
- StemRIM Inc., Ibaraki, Osaka, 567-0085, Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
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Li H, Wei J, Li M, Li Y, Zhang T, Tian J, Liu X, Li K, Lin J. Biological characteristics of Muse cells derived from MenSCs and their application in acute liver injury and intracerebral hemorrhage diseases. Regen Ther 2024; 27:48-62. [PMID: 38496012 PMCID: PMC10940801 DOI: 10.1016/j.reth.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/16/2024] [Accepted: 03/03/2024] [Indexed: 03/19/2024] Open
Abstract
The increasing interest in multilineage differentiating stress-enduring (Muse) cells within the field of regenerative medicine is attributed to their exceptional homing capabilities, prolonged viability in adverse conditions, and enhanced three-germ-layer differentiate ability, surpassing their parent mesenchymal stem cells. Given their abundant sources, non-invasive collection procedure, and periodic availability, human menstrual blood-derived endometrium stem cells (MenSCs) have been extensively investigated as a potential resource for stem cell-based therapies. However, there is no established modality to isolate Muse cells from MenSCs and disparity in gene expression profiles between Muse cells and MenSCs remain unknown. In this study, Muse cells were isolated from MenSCs by long-time trypsin incubation method. Muse cells expressed pluripotency markers and could realize multilineage differentiation in vitro. Compared with MenSCs, Muse cells showed enhanced homing ability and superior therapeutic efficacy in animal models of acute liver injury (ALI) and intracerebral hemorrhage (ICH). Furthermore, the RNA-seq analysis offers insights into the mechanism underlying the disparity in trypsin resistance and migration ability between Muse and MenSCs cells. This research offers a significant foundation for further exploration of cell-based therapies using MenSCs-derived Muse cells in the context of various human diseases, highlighting their promising application in the field of regenerative medicine.
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Affiliation(s)
- Han Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Jinghui Wei
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Mingzhi Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Yaoqiang Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Tong Zhang
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Jialu Tian
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Xuejia Liu
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Kangjia Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Juntang Lin
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China
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Gila F, Alamdari-Palangi V, Rafiee M, Jokar A, Ehtiaty S, Dianatinasab A, Khatami SH, Taheri-Anganeh M, Movahedpour A, Fallahi J. Gene-edited cells: novel allogeneic gene/cell therapy for epidermolysis bullosa. J Appl Genet 2024; 65:705-726. [PMID: 38459407 DOI: 10.1007/s13353-024-00839-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/12/2024] [Accepted: 01/30/2024] [Indexed: 03/10/2024]
Abstract
Epidermolysis bullosa (EB) is a group of rare genetic skin fragility disorders, which are hereditary. These disorders are associated with mutations in at least 16 genes that encode components of the epidermal adhesion complex. Currently, there are no effective treatments for this disorder. All current treatment approaches focus on topical treatments to prevent complications and infections. In recent years, significant progress has been achieved in the treatment of the severe genetic skin blistering condition known as EB through preclinical and clinical advancements. Promising developments have emerged in the areas of protein and cell therapies, such as allogeneic stem cell transplantation; in addition, RNA-based therapies and gene therapy approaches have also become a reality. Stem cells obtained from embryonic or adult tissues, including the skin, are undifferentiated cells with the ability to generate, maintain, and replace fully developed cells and tissues. Recent advancements in preclinical and clinical research have significantly enhanced stem cell therapy, presenting a promising treatment option for various diseases that are not effectively addressed by current medical treatments. Different types of stem cells such as primarily hematopoietic and mesenchymal, obtained from the patient or from a donor, have been utilized to treat severe forms of diseases, each with some beneficial effects. In addition, extensive research has shown that gene transfer methods targeting allogeneic and autologous epidermal stem cells to replace or correct the defective gene are promising. These methods can regenerate and restore the adhesion of primary keratinocytes in EB patients. The long-term treatment of skin lesions in a small number of patients has shown promising results through the transplantation of skin grafts produced from gene-corrected autologous epidermal stem cells. This article attempts to summarize the current situation, potential development prospects, and some of the challenges related to the cell therapy approach for EB treatment.
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Affiliation(s)
- Fatemeh Gila
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahab Alamdari-Palangi
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maedeh Rafiee
- Department of Veterinary Sciences, University of Wyoming, Laramie, WY, USA
| | - Arezoo Jokar
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sajad Ehtiaty
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Aria Dianatinasab
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyyed Hossein Khatami
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Jafar Fallahi
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
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Niebergall-Roth E, Dieter K, Frank MH, Kluth MA. Systemic treatment of recessive dystrophic epidermolysis bullosa with mesenchymal stromal cells: a scoping review of the literature and conclusions for future clinical research. J DERMATOL TREAT 2024; 35:2419931. [PMID: 39551482 DOI: 10.1080/09546634.2024.2419931] [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: 09/10/2024] [Accepted: 10/16/2024] [Indexed: 11/19/2024]
Abstract
Background: The ability of mesenchymal stromal cells (MSCs) to facilitate regenerative responses in inflamed and injured tissues, coupled with preclinical data suggesting potential to restore defective collagen VII at the dermo-epidermal junction, has raised the hope that MSCs may provide an effective disease-modifying therapy for patients suffering from recessive dystrophic epidermolysis bullosa (RDEB). Methods: We present a descriptive analysis of the clinical research on systemic MSC administration to RDEB patients available in PubMed, including six early-phase studies and one case report, involving 59 patients who received 1-3 intravenous infusions of MSCs from various sources. Results: Based on 133 MSC infusions, a total of 44 mostly mild adverse events were reported as definitely, possibly or likely related to the study treatment, only two of which led to treatment discontinuation. Improvements were seen in skin manifestations, disease activity, pain, pruritus and quality of life, with considerable heterogeneity in reported outcome variables and measurement tools between studies, and large inter-patient variability within studies. Conclusions: Although the current evidence base is limited, reflecting the typical challenges of clinical research in rare diseases, the reported results suggest potential treatment benefits for patients and provide a rationale for continuing to pursue this therapeutic approach.
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Affiliation(s)
| | | | - Markus H Frank
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
- Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- School of Medical and Health Sciences, Edith Cowan University, Perth, Australia
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7
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Hokkoku D, Sasaki K, Kobayashi S, Shimbo T, Kitayama T, Yamazaki S, Yamamoto Y, Ouchi Y, Imamura H, Kado T, Toya K, Fujii W, Iwagami Y, Yamada D, Tomimaru Y, Noda T, Takahashi H, Tamai K, Doki Y, Eguchi H. High-mobility group box 1 fragment ameliorates chronic pancreatitis induced by caerulein in mice. J Gastroenterol 2024; 59:744-757. [PMID: 38727823 DOI: 10.1007/s00535-024-02112-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 04/26/2024] [Indexed: 07/29/2024]
Abstract
BACKGROUND Chronic pancreatitis (CP) is a progressive disease characterized by pancreatic fibrosis for which effective treatment options are lacking. Mesenchymal stem cells (MSCs) have shown potential for fibrosis treatment but face limitations in clinical application. The high-mobility group box 1 (HMGB1) fragment mobilizes MSCs from bone marrow into the blood and has emerged as a promising therapeutic agent for tissue regeneration in various pathological conditions. The aim of this study was to investigate the potential therapeutic effects of systemic administration of the HMGB1 fragment in a mouse model of CP. METHODS A caerulein-induced CP mouse model was used, and the HMGB1 fragment was administered by tail vein injection. Parameters such as body weight, pancreatic tissue damage, fibrosis, inflammatory cytokine expression, and collagen-related gene expression were evaluated using various assays, including immunohistochemistry, real-time PCR, serum analysis, and single-cell transcriptome analysis. And the migration of MSCs to the pancreas was evaluated using the parabiosis model. RESULTS Administration of the HMGB1 fragment was associated with significant improvements in pancreatic tissue damage and fibrosis. It suppressed the expression of inflammatory cytokines and activated platelet-derived growth factor receptor-α+ MSCs, leading to their accumulation in the pancreas. The HMGB1 fragment also shifted gene expression patterns associated with pancreatic fibrosis toward those of the normal pancreas. Systemic administration of the HMGB1 fragment demonstrated therapeutic efficacy in attenuating pancreatic tissue damage and fibrosis in a CP mouse model. CONCLUSION These findings highlight the potential of the HMGB1 fragment as a therapeutic target for the treatment of CP.
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Affiliation(s)
- Daiki Hokkoku
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan.
| | - Takashi Shimbo
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Osaka, Japan
| | - Tomomi Kitayama
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- StemRIM Inc, Ibaraki, Osaka, Japan
| | - Sho Yamazaki
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- StemRIM Inc, Ibaraki, Osaka, Japan
| | - Yukari Yamamoto
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuya Ouchi
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Osaka, Japan
| | - Hiroki Imamura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Takeshi Kado
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Keisuke Toya
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Wataru Fujii
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
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Minaga K, Otsuka Y, Watanabe T. High-mobility group box 1: friend or foe in pancreatitis. J Gastroenterol 2024; 59:758-759. [PMID: 38880788 DOI: 10.1007/s00535-024-02123-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 06/18/2024]
Affiliation(s)
- Kosuke Minaga
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Yasuo Otsuka
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
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Goto T, Nakamura Y, Ito Y, Miyagawa S. Regenerative medicine in cardiovascular disease. Regen Ther 2024; 26:859-866. [PMID: 39430582 PMCID: PMC11490749 DOI: 10.1016/j.reth.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/04/2024] [Accepted: 09/11/2024] [Indexed: 10/22/2024] Open
Abstract
Owing to the rapid increase in the number of people with severe heart failure, regenerative medicine is anticipated to play a role in overcoming the limitations inherent in existing surgical interventions. There are essentially two types of cardiac regenerative therapies for a failing heart. Cellular regenerative therapies using various stem cells improve the functional recovery of the heart mainly by cytokine paracrine effects. The implantation of induced pluripotent stem cell-derived cardiomyocytes can contribute not only to the inhibition of adverse heart remodeling by paracrine effects but also to the supply of newly born functional myocytes with the recipient myocardium as "mechanically working cells." Cell transplantation, including autologous myoblast transplantation, reduces heart failure exacerbations and benefits patients without the need for other treatment options. Although cellular therapy is currently the mainstream approach, it requires an in-house cell-processing center with an aseptic environment. In addition, these stem cells are usually introduced via several invasive delivery methods, including intracoronary administration, and cellular sheet implantation. Simplifying the culture methods for these cells is a crucial problem that needs to be resolved. Drug-induced regenerative therapy is another option that enhances self-endogenous regenerative systems in the human body and does not require invasive methods or cell cultures. Therefore, drug-induced regenerative therapies may overcome the disadvantages of these cellular therapies. The purpose of this report is to summarize cell transplantation therapy in the cardiovascular system and regenerative therapy for heart failure using an autologous endogenous regenerative system.
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Affiliation(s)
- Takasumi Goto
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Cardiovascular Surgery, Toyonaka Municipal Hospital, Osaka, Japan
| | - Yuki Nakamura
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshito Ito
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
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10
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(Ogi) Suzuki K, Okamoto T, Tamai K, Tabata Y, Hatano E. Enhancement of tracheal cartilage regeneration by local controlled release of stromal cell-derived factor 1α with gelatin hydrogels and systemic administration of high-mobility group box 1 peptide. Regen Ther 2024; 26:415-424. [PMID: 39070123 PMCID: PMC11282968 DOI: 10.1016/j.reth.2024.06.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 06/19/2024] [Accepted: 06/27/2024] [Indexed: 07/30/2024] Open
Abstract
Introduction This present study evaluated the effect of combination therapy with stromal cell-derived factor 1α (SDF-1α) and high-mobility group box 1 (HMGB1) peptide on the regeneration of tracheal injury in a rat model. Methods To improve this effect, SDF-1α was incorporated into a gelatin hydrogel, which was then applied to the damaged tracheal cartilage of rats for local release. Furthermore, HMGB1 peptide was repeatedly administered intravenously. Regeneration of damaged tracheal cartilage was evaluated in terms of cell recruitment. Results Mesenchymal stem cells (MSC) with C-X-C motif chemokine receptor 4 (CXCR4) were mobilized more into the injured area, and consequently the fastest tracheal cartilage regeneration was observed in the combination therapy group eight weeks after injury. Conclusions The present study demonstrated that combination therapy with gelatin hydrogel incorporating SDF-1α and HMGB1 peptide injected intravenously can enhance the recruitment of CXCR4-positive MSC, promoting the regeneration of damaged tracheal cartilage.
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Affiliation(s)
- Kumiko (Ogi) Suzuki
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
- Department of Biomaterials, Field of Tissue Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Tatsuya Okamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Japan
| | - Yasuhiko Tabata
- Department of Biomaterials, Field of Tissue Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
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11
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Lee SG, Kim SE, Jeong IH, Lee SE. Mechanism underlying pruritus in recessive dystrophic epidermolysis bullosa: Role of interleukin-31 from mast cells and macrophages. J Eur Acad Dermatol Venereol 2024; 38:895-903. [PMID: 38084871 DOI: 10.1111/jdv.19738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 10/26/2023] [Indexed: 04/26/2024]
Abstract
BACKGROUND Pruritus is a highly burdensome symptom in patients with epidermolysis bullosa, especially recessive dystrophic epidermolysis bullosa (RDEB); however, only a few studies have assessed the molecular pathogenesis of RDEB-associated pruritus. Interleukin (IL)-31 is a key cytokine implicated in pruritus associated with dermatologic diseases such as atopic dermatitis and prurigo nodularis. OBJECTIVE To investigate the role and cellular source of IL-31 in RDEB-associated pruritus. METHODS Serum and skin samples were obtained from 11 RDEB patients and 11 healthy controls. Pruritus visual analogue scale scores were determined. Serum levels of IL-31 and thymic stromal lymphopoietin (TSLP) were examined by enzyme-linked immunosorbent assay (ELISA). The expression of IL-31 and other pruritus mediators in the skin were examined through immunofluorescence staining, and their correlation with pruritus severity was analysed. RESULTS Serum IL-31 and TSLP were elevated in RDEB patients. IL-31 expression was increased in RDEB skin and positively correlated with pruritus severity. Most of the IL-31-expressing cells were mast cells, and some were CD206(+) M2-like macrophages. The number of substance P(+) cells was also increased in the patients' skin, and most of them were mast cells. The number of substance P(+) mast cells was correlated with the number of IL-31(+) dermal infiltrates. The number of IL-4Rα- and IL-13-expressing cells and expression of TSLP and periostin increased in RDEB skin, but without a correlation to pruritus score. CONCLUSION The increased production of skin IL-31 from mast cells and M2-like macrophages may be the mechanism underlying pruritus in RDEB.
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Affiliation(s)
- Sang Gyun Lee
- Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Song-Ee Kim
- Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - In-Hye Jeong
- Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Eun Lee
- Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
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12
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Okano J, Nakagawa T, Kojima H. Plasticity of bone marrow-derived cell differentiation depending on microenvironments in the skin. Front Physiol 2024; 15:1391640. [PMID: 38699142 PMCID: PMC11063383 DOI: 10.3389/fphys.2024.1391640] [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: 02/26/2024] [Accepted: 04/04/2024] [Indexed: 05/05/2024] Open
Abstract
Bone marrow-derived cells (BMDCs) are heterogeneous populations in which not only pluripotent stem cells, namely, hematopoietic stem cells (HSCs), mesenchymal stem cells (MSC) but also endothelial progenitor cells (EPC) are involved. BMDCs contribute to the maintenance of homeostasis and recovery from disrupted homeostasis as the immune, endocrine, and nervous systems. The skin is the largest organ in which various tissues, such as the epidermis, dermis, skin appendages (i.e., hair follicles), fats, muscles, and vessels, are tightly and systematically packed. It functions as a physical barrier to block the invasion of harmful substances and pathogenic microorganisms and properly regulate water evaporation. The skin is exposed to injuries from external stimuli because it is the outermost layer and owing to its specificity. Recovery from physical injuries and DNA mutations occurs constantly in the skin, but medical treatments are required for impaired wound healing. Recently, conservative treatments utilizing scaffolds have attracted attention as alternatives to surgical therapy, which is highly invasive. Against this background, numerous scaffolds are available in a clinical setting, although they have not surpassed surgery because of their distinct disadvantages. Here, we discuss the plasticity of BMDCs in the skin to maintain homeostasis, in addition to their critical roles on recovery from disrupted homeostasis. We also share our perspective on how scaffolds can be developed to establish scaffolds beyond surgery to regenerate skin structure during wound healing by maximally utilizing the plasticity of BMDCs.
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Affiliation(s)
- Junko Okano
- Department of Plastic and Reconstructive Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Takahiko Nakagawa
- Department of Regenerative Medicine Development, Shiga University of Medical Science, Otsu, Japan
| | - Hideto Kojima
- Department of Regenerative Medicine Development, Shiga University of Medical Science, Otsu, Japan
- Department of Biocommunication Development, Shiga University of Medical Science, Otsu, Japan
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13
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Fülle JB, de Almeida RA, Lawless C, Stockdale L, Yanes B, Lane EB, Garrod DR, Ballestrem C. Proximity Mapping of Desmosomes Reveals a Striking Shift in Their Molecular Neighborhood Associated With Maturation. Mol Cell Proteomics 2024; 23:100735. [PMID: 38342409 PMCID: PMC10943070 DOI: 10.1016/j.mcpro.2024.100735] [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: 05/04/2023] [Revised: 01/29/2024] [Accepted: 02/08/2024] [Indexed: 02/13/2024] Open
Abstract
Desmosomes are multiprotein adhesion complexes that link intermediate filaments to the plasma membrane, ensuring the mechanical integrity of cells across tissues, but how they participate in the wider signaling network to exert their full function is unclear. To investigate this, we carried out protein proximity mapping using biotinylation (BioID). The combined interactomes of the essential desmosomal proteins desmocollin 2a, plakoglobin, and plakophilin 2a (Pkp2a) in Madin-Darby canine kidney epithelial cells were mapped and their differences and commonalities characterized as desmosome matured from Ca2+ dependence to the mature, Ca2+-independent, hyper-adhesive state, which predominates in tissues. Results suggest that individual desmosomal proteins have distinct roles in connecting to cellular signaling pathways and that these roles alter substantially when cells change their adhesion state. The data provide further support for a dualistic concept of desmosomes in which the properties of Pkp2a differ from those of the other, more stable proteins. This body of data provides an invaluable resource for the analysis of desmosome function.
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Affiliation(s)
- Judith B Fülle
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
| | | | - Craig Lawless
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
| | - Liam Stockdale
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
| | - Bian Yanes
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
| | - E Birgitte Lane
- Skin Research Institute of Singapore, Agency of Science Technology and Research (A∗STAR), Singapore, Singapore
| | - David R Garrod
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
| | - Christoph Ballestrem
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
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14
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Kumar V, Stewart JH. Obesity, bone marrow adiposity, and leukemia: Time to act. Obes Rev 2024; 25:e13674. [PMID: 38092420 DOI: 10.1111/obr.13674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/07/2023] [Accepted: 11/13/2023] [Indexed: 02/28/2024]
Abstract
Obesity has taken the face of a pandemic with less direct concern among the general population and scientific community. However, obesity is considered a low-grade systemic inflammation that impacts multiple organs. Chronic inflammation is also associated with different solid and blood cancers. In addition, emerging evidence demonstrates that individuals with obesity are at higher risk of developing blood cancers and have poorer clinical outcomes than individuals in a normal weight range. The bone marrow is critical for hematopoiesis, lymphopoiesis, and myelopoiesis. Therefore, it is vital to understand the mechanisms by which obesity-associated changes in BM adiposity impact leukemia development. BM adipocytes are critical to maintain homeostasis via different means, including immune regulation. However, obesity increases BM adiposity and creates a pro-inflammatory environment to upregulate clonal hematopoiesis and a leukemia-supportive environment. Obesity further alters lymphopoiesis and myelopoiesis via different mechanisms, which dysregulate myeloid and lymphoid immune cell functions mentioned in the text under different sequentially discussed sections. The altered immune cell function during obesity alters hematological malignancies and leukemia susceptibility. Therefore, obesity-induced altered BM adiposity, immune cell generation, and function impact an individual's predisposition and severity of leukemia, which should be considered a critical factor in leukemia patients.
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Affiliation(s)
- Vijay Kumar
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - John H Stewart
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Morehouse School of Medicine, Atlanta, Georgia, USA
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15
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Kikuchi Y, Tamakoshi T, Ishida R, Kobayashi R, Mori S, Ishida-Yamamoto A, Fujimoto M, Kaneda Y, Tamai K. Gene-Modified Blister Fluid-Derived Mesenchymal Stromal Cells for Treating Recessive Dystrophic Epidermolysis Bullosa. J Invest Dermatol 2023; 143:2447-2455.e8. [PMID: 37302620 DOI: 10.1016/j.jid.2023.05.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/29/2023] [Accepted: 05/11/2023] [Indexed: 06/13/2023]
Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis caused by variants in COL7A1-encoded type VII collagen, a major component of anchoring fibrils. In this study, we developed an ex vivo gene therapy for RDEB using autologous mesenchymal stromal cells (MSCs). On the basis of our previous studies, we first attempted to isolate MSCs from the blister fluid of patients with RDEB and succeeded in obtaining cells with a set of MSC characteristics from all 10 patients. We termed these cells blister fluid-derived MSCs. Blister fluid-derived MSCs were genetically modified and injected into skins of type VII collagen-deficient neonatal mice transplanted onto immunodeficient mice, resulting in continuous and widespread expression of type VII collagen at the dermal-epidermal junction, particularly when administered into blisters. When injected intradermally, the efforts were not successful. The gene-modified blister fluid-derived MSCs could be cultured as cell sheets and applied to the dermis with an efficacy equivalent to that of intrablister administration. In conclusion, we successfully developed a minimally invasive and highly efficient ex vivo gene therapy for RDEB. This study shows the successful application of gene therapy in the RDEB mouse model for both early blistering skin and advanced ulcerative lesions.
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Affiliation(s)
- Yasushi Kikuchi
- Department of Stem Cell Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan; Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Tomoki Tamakoshi
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan
| | | | | | - Shiho Mori
- Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Japan; Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan
| | | | - Manabu Fujimoto
- Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Yasufumi Kaneda
- Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Katsuto Tamai
- Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Japan; Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan.
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16
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Ye M, Dewi L, Liao YC, Nicholls A, Huang CY, Kuo CH. DNA oxidation after exercise: a systematic review and meta-analysis. Front Physiol 2023; 14:1275867. [PMID: 38028771 PMCID: PMC10644354 DOI: 10.3389/fphys.2023.1275867] [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: 08/10/2023] [Accepted: 10/09/2023] [Indexed: 12/01/2023] Open
Abstract
Purpose: 8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a byproduct of DNA oxidation resulting from free radical attacks. Paradoxically, treatment with 8-OHdG accelerates tissue healing. The aim of this study is to quantify the 8-OHdG response after a single session of exercise in both trained and untrained adults. Methods: A systematic review and meta-analysis of exercise intervention studies measuring changes in blood 8-OHdG following resistance exercise and aerobic exercise were conducted. The literature search included Web of Science, PubMed, BASE, and Scopus, with publications up to February 2023 included. Subgroup analysis of training status was also conducted. Results: Sixteen studies involving 431 participants met the eligibility criteria. Resistance exercise showed a medium effect on increasing circulating 8-OHdG levels (SMD = 0.66, p < 0.001), which was similar for both trained and untrained participants. However, studies on aerobic exercise presented mixed results. For trained participants, a small effect of aerobic exercise on increasing circulating 8-OHdG levels was observed (SMD = 0.42; p < 0.001). In contrast, for untrained participants, a large effect of decreasing circulating 8-OHdG levels was observed, mostly after long-duration aerobic exercise (SMD = -1.16; p < 0.05). Similar to resistance exercise, high-intensity aerobic exercise (5-45 min, ≥75% VO2max) significantly increased circulating 8-OHdG levels, primarily in trained participants. Conclusion: Pooled results from the studies confirm an increase in circulating 8-OHdG levels after resistance exercise. However, further studies are needed to fully confirm the circulating 8-OHdG response to aerobic exercise. Increases in 8-OHdG after high-intensity aerobic exercise are observed only in trained individuals, implicating its role in training adaptation. Systematic Review Registration: [https://Systematicreview.gov/], identifier [CRD42022324180].
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Affiliation(s)
- Mengxin Ye
- College of Physical Education and Science, Zhejiang Normal University, Jinhua, China
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan
| | - Luthfia Dewi
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan
| | - Yu-Chieh Liao
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan
| | - Andrew Nicholls
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondria Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Chia-Hua Kuo
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan
- School of Physical Education and Sports Science, Soochow University, Suzhou, China
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17
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Chang Q, Fujio M, Tsuboi M, Bian H, Wakasugi M, Hibi H. High-mobility group box 1 accelerates distraction osteogenesis healing via the recruitment of endogenous stem/progenitor cells. Cytotherapy 2023:S1465-3249(23)00960-X. [PMID: 37354151 DOI: 10.1016/j.jcyt.2023.05.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 05/25/2023] [Accepted: 05/29/2023] [Indexed: 06/26/2023]
Abstract
BACKGROUND AIMS While distraction osteogenesis (DO) achieves substantial bone regeneration, prolonged fixation may lead to infections. Existing stem cell and physical therapies have limitations, requiring the development of novel therapeutic approaches. Here, we evaluated high-mobility group box 1 (HMGB1) as a novel therapeutic target for DO treatment. METHODS Micro-computed tomography (Micro-CT) analysis and histological staining of samples obtained from tibial DO model mice was performed. Transwell migration, wound healing, and proliferation assays were also performed on cultured human mesenchymal stem cells (hMSCs) and human umbilival vein endothelial cells (HUVECs). Tube formation assay was performed on HUVECs, whereas osteogenic differentiation assay was performed on hMSCs. RESULTS Micro-CT analysis and histological staining of mouse samples revealed that HMGB1 promotes bone regeneration during DO via the recruitment of PDGFRα and Sca-1 positve (PαS+) cells and endothelial progenitor cells. Furthermore, HMGB1 accelerated angiogenesis during DO, promoted the migration and osteogenic differentiation of hMSCs as well as the proliferation, migration and angiogenesis of HUVECs in vitro. CONCLUSIONS Our findings suggest that HMGB1 has a positive influence on endogenous stem/progenitor cells, representing a novel therapeutic target for the acceleration of DO-driven bone regeneration.
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Affiliation(s)
- Qi Chang
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Masahito Fujio
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Makoto Tsuboi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Huiting Bian
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Masashi Wakasugi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Hideharu Hibi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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18
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Hou PC, del Agua N, Lwin SM, Hsu CK, McGrath JA. Innovations in the Treatment of Dystrophic Epidermolysis Bullosa (DEB): Current Landscape and Prospects. Ther Clin Risk Manag 2023; 19:455-473. [PMID: 37337559 PMCID: PMC10277004 DOI: 10.2147/tcrm.s386923] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/02/2023] [Indexed: 06/21/2023] Open
Abstract
Dystrophic epidermolysis bullosa (DEB) is one of the major types of EB, a rare hereditary group of trauma-induced blistering skin disorders. DEB is caused by inherited pathogenic variants in the COL7A1 gene, which encodes type VII collagen, the major component of anchoring fibrils which maintain adhesion between the outer epidermis and underlying dermis. DEB can be subclassified into dominant (DDEB) and recessive (RDEB) forms. Generally, DDEB has a milder phenotype, while RDEB patients often have more extensive blistering, chronic inflammation, skin fibrosis, and a propensity for squamous cell carcinoma development, collectively impacting on daily activities and life expectancy. At present, best practice treatments are mostly supportive, and thus there is a considerable burden of disease with unmet therapeutic need. Over the last 20 years, considerable translational research efforts have focused on either trying to cure DEB by direct correction of the COL7A1 gene pathology, or by modifying secondary inflammation to lessen phenotypic severity and improve patient symptoms such as poor wound healing, itch, and pain. In this review, we provide an overview and update on various therapeutic innovations for DEB, including gene therapy, cell-based therapy, protein therapy, and disease-modifying and symptomatic control agents. We outline the progress and challenges for each treatment modality and identify likely prospects for future clinical impact.
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Affiliation(s)
- Ping-Chen Hou
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Nathalie del Agua
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan
| | - Su M Lwin
- St John’s Institute of Dermatology, School of Basic and Medical Biosciences, King’s College London, London, UK
| | - Chao-Kai Hsu
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan
| | - John A McGrath
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan
- St John’s Institute of Dermatology, School of Basic and Medical Biosciences, King’s College London, London, UK
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19
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Hara T, Shimbo T, Masuda T, Kitayama T, Fujii M, Hanawa M, Yokota K, Endo M, Tomimatsu T, Kimura T, Tamai K. High-mobility group box-1 peptide ameliorates bronchopulmonary dysplasia by suppressing inflammation and fibrosis in a mouse model. Biochem Biophys Res Commun 2023; 671:357-365. [PMID: 37329659 DOI: 10.1016/j.bbrc.2023.06.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 06/08/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND This study aimed to examine the effect of the HMGB1 peptide on Bronchopulmonary dysplasia (BPD)-related lung injury in a mouse model. RESULTS HMGB1 peptide ameliorates lung injury by suppressing the release of inflammatory cytokines and decreasing soluble collagen levels in the lungs. Single-cell RNA sequencing showed that the peptide suppressed the hyperoxia-induced inflammatory signature in macrophages and the fibrotic signature in fibroblasts. These changes in the transcriptome were confirmed using protein assays. CONCLUSION Systemic administration of HMGB1 peptide exerts anti-inflammatory and anti-fibrotic effects in a mouse model of BPD. This study provides a foundation for the development of new and effective therapies for BPD.
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Affiliation(s)
- Takeya Hara
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Takashi Shimbo
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Osaka, Japan
| | - Tatsuo Masuda
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Osaka, Japan
| | - Tomomi Kitayama
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; StemRIM Inc., Ibaraki, Osaka, Japan
| | - Makoto Fujii
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Osaka, Japan; Department of Children's and Women's Health, Division of Health Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | | | | | - Masayuki Endo
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Osaka, Japan; Department of Children's and Women's Health, Division of Health Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
| | - Takuji Tomimatsu
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Tadashi Kimura
- Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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20
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Zhao P, Dang Z, Liu M, Guo D, Luo R, Zhang M, Xie F, Zhang X, Wang Y, Pan S, Ma X. Molecular hydrogen promotes wound healing by inducing early epidermal stem cell proliferation and extracellular matrix deposition. Inflamm Regen 2023; 43:22. [PMID: 36973725 PMCID: PMC10044764 DOI: 10.1186/s41232-023-00271-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/26/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND Despite progress in developing wound care strategies, there is currently no treatment that promotes the self-tissue repair capabilities. H2 has been shown to effectively protect cells and tissues from oxidative and inflammatory damage. While comprehensive effects and how H2 functions in wound healing remains unknown, especially for the link between H2 and extracellular matrix (ECM) deposition and epidermal stem cells (EpSCs) activation. METHODS Here, we established a cutaneous aseptic wound model and applied a high concentration of H2 (66% H2) in a treatment chamber. Molecular mechanisms and the effects of healing were evaluated by gene functional enrichment analysis, digital spatial profiler analysis, blood perfusion/oxygen detection assay, in vitro tube formation assay, enzyme-linked immunosorbent assay, immunofluorescent staining, non-targeted metabonomic analysis, flow cytometry, transmission electron microscope, and live-cell imaging. RESULTS We revealed that a high concentration of H2 (66% H2) greatly increased the healing rate (3 times higher than the control group) on day 11 post-wounding. The effect was not dependent on O2 or anti-reactive oxygen species functions. Histological and cellular experiments proved the fast re-epithelialization in the H2 group. ECM components early (3 days post-wounding) deposition were found in the H2 group of the proximal wound, especially for the dermal col-I, epidermal col-III, and dermis-epidermis-junction col-XVII. H2 accelerated early autologous EpSCs proliferation (1-2 days in advance) and then differentiation into myoepithelial cells. These epidermal myoepithelial cells could further contribute to ECM deposition. Other beneficial outcomes include sustained moist healing, greater vascularization, less T-helper-1 and T-helper-17 cell-related systemic inflammation, and better tissue remodelling. CONCLUSION We have discovered a novel pattern of wound healing induced by molecular hydrogen treatment. This is the first time to reveal the direct link between H2 and ECM deposition and EpSCs activation. These H2-induced multiple advantages in healing may be related to the enhancement of cell viability in various cells and the maintenance of mitochondrial functions at a basic level in the biological processes of life.
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Affiliation(s)
- Pengxiang Zhao
- Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, People's Republic of China
- Beijing Molecular Hydrogen Research Center, Beijing, 100124, People's Republic of China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, 100124, People's Republic of China
| | - Zheng Dang
- Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, People's Republic of China
- Beijing Molecular Hydrogen Research Center, Beijing, 100124, People's Republic of China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, 100124, People's Republic of China
| | - Mengyu Liu
- Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, People's Republic of China
- Beijing Molecular Hydrogen Research Center, Beijing, 100124, People's Republic of China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, 100124, People's Republic of China
| | - Dazhi Guo
- Department of Hyperbaric Oxygen, Sixth Medical Center of PLA General Hospital, Beijing, 100048, People's Republic of China
| | - Ruiliu Luo
- Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, People's Republic of China
- Beijing Molecular Hydrogen Research Center, Beijing, 100124, People's Republic of China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, 100124, People's Republic of China
| | - Mingzi Zhang
- Department of Plastic Surgery, Peking Union Medical College Hospital (Dongdan campus), No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, People's Republic of China
| | - Fei Xie
- Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, People's Republic of China
- Beijing Molecular Hydrogen Research Center, Beijing, 100124, People's Republic of China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, 100124, People's Republic of China
| | - Xujuan Zhang
- Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, People's Republic of China
- Beijing Molecular Hydrogen Research Center, Beijing, 100124, People's Republic of China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, 100124, People's Republic of China
| | - Youbin Wang
- Department of Plastic Surgery, Peking Union Medical College Hospital (Dongdan campus), No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, People's Republic of China
| | - Shuyi Pan
- Department of Hyperbaric Oxygen, Sixth Medical Center of PLA General Hospital, Beijing, 100048, People's Republic of China
| | - Xuemei Ma
- Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, People's Republic of China.
- Beijing Molecular Hydrogen Research Center, Beijing, 100124, People's Republic of China.
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing, 100124, People's Republic of China.
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21
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Niti A, Koliakos G, Michopoulou A. Stem Cell Therapies for Epidermolysis Bullosa Treatment. Bioengineering (Basel) 2023; 10:bioengineering10040422. [PMID: 37106609 PMCID: PMC10135837 DOI: 10.3390/bioengineering10040422] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/25/2023] [Accepted: 03/26/2023] [Indexed: 03/29/2023] Open
Abstract
Epidermolysis bullosa (EB) includes a group of rare skin diseases characterized by skin fragility with bullous formation in the skin, in response to minor mechanical injury, as well as varying degrees of involvement of the mucous membranes of the internal organs. EB is classified into simplex, junctional, dystrophic and mixed. The impact of the disease on patients is both physical and psychological, with the result that their quality of life is constantly affected. Unfortunately, there are still no approved treatments available to confront the disease, and treatment focuses on improving the symptoms with topical treatments to avoid complications and other infections. Stem cells are undifferentiated cells capable of producing, maintaining and replacing terminally differentiated cells and tissues. Stem cells can be isolated from embryonic or adult tissues, including skin, but are also produced by genetic reprogramming of differentiated cells. Preclinical and clinical research has recently greatly improved stem cell therapy, making it a promising treatment option for various diseases in which current medical treatments fail to cure, prevent progression, or alleviate symptoms. So far, stem cells from different sources, mainly hematopoietic and mesenchymal, autologous or heterologous have been used for the treatment of the most severe forms of the disease each one of them with some beneficial effects. However, the mechanisms through which stem cells exert their beneficial role are still unknown or incompletely understood and most importantly further research is required to evaluate the effectiveness and safety of these treatments. The transplantation of skin grafts to patients produced by gene-corrected autologous epidermal stem cells has been proved to be rather successful for the treatment of skin lesions in the long term in a limited number of patients. Nevertheless, these treatments do not address the internal epithelia-related complications manifested in patients with more severe forms.
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22
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Choi JY, Jin X, Kim H, Koh S, Cho HJ, Kim BG. High Mobility Group Box 1 as an Autocrine Chemoattractant for Oligodendrocyte Lineage Cells in White Matter Stroke. Stroke 2023; 54:575-586. [PMID: 36490365 DOI: 10.1161/strokeaha.122.041414] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The migration of oligodendrocyte precursor cells (OPC) is a key process of remyelination, which is essential for the treatment of white matter stroke. This study aimed to investigate the role of HMGB1 (high mobility group box 1), a damage-associated molecular pattern released from dying oligodendrocytes, as an autocrine chemoattractant that promotes OPC migration. METHODS The migratory capacity of primary cultured OPCs was measured using the Boyden chamber assay. The downstream pathway of HMGB1-mediated OPC migration was specified by siRNA-induced knockdown or pharmacological blockade of TLR2 (toll-like receptor 2), RAGE (receptor for advanced glycation end product), Src, ERK1/2 (extracellular signal-regulated kinase1/2), and FAK (focal adhesion kinase). Conditioned media were collected from oxygen-glucose deprivation-treated oligodendrocytes, and the impact on OPC migration was assessed. Lesion size and number of intralesional Olig2(+) cells were analyzed in an in vivo model of white matter stroke with N5-(1-iminoethyl)-L-ornithine (L-NIO). RESULTS HMGB1 treatment promoted OPC migration. HMGB1 antagonism reversed such effects to untreated levels. Among the candidates for the downstream signal of HMGB1-mediated migration, the knockdown of TLR2 rather than that of RAGE attenuated the migration-promoting effect of HMGB1. Further specification of the HMGB1-TLR2 axis revealed that the phosphorylation of ERK1/2 and its downstream molecule FAK, rather than of Src, was decreased in TLR2-knockdown OPCs, and pharmacological inhibition of ERK1/2 and FAK led to decreased OPC migration. Oxygen-glucose deprivation-conditioned media promoted OPC migration, suggesting the autocrine chemoattractant function of HMGB1. In vivo, TLR2(-/-)-mice showed lesser intralesional Olig2(+) cells compared to wild-type controls in response to L-NIO induced ischemic injury regardless of HMGB1 administration. CONCLUSIONS HMGB1, through the TLR2-ERK1/2-FAK axis, functions as an autocrine chemoattractant to promote OPC migration, which is an initial and indispensable step in remyelination. Thus, a novel treatment strategy for white matter stroke based on the HMGB1-TLR2 axis in the oligodendrocyte lineage could be feasible.
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Affiliation(s)
- Jun Young Choi
- Department of Brain science, Ajou University School of Medicine, Republic of Korea (J.Y.C., X.J., H.K., S.K., H.J.C., B.G.K.).,Department of Neurology, Ajou University School of Medicine, Republic of Korea (J.Y.C., S.K., B.G.K.)
| | - Xuelian Jin
- Department of Brain science, Ajou University School of Medicine, Republic of Korea (J.Y.C., X.J., H.K., S.K., H.J.C., B.G.K.).,Neuroscience graduate program, Ajou University Graduate School of Medicine, Republic of Korea (X.J., H.K., S.K.).,Department of Nephrology, Suqian First Hospital, Jiangsu, China (X.J.)
| | - Hanki Kim
- Department of Brain science, Ajou University School of Medicine, Republic of Korea (J.Y.C., X.J., H.K., S.K., H.J.C., B.G.K.).,Neuroscience graduate program, Ajou University Graduate School of Medicine, Republic of Korea (X.J., H.K., S.K.)
| | - Seungyon Koh
- Department of Brain science, Ajou University School of Medicine, Republic of Korea (J.Y.C., X.J., H.K., S.K., H.J.C., B.G.K.).,Department of Neurology, Ajou University School of Medicine, Republic of Korea (J.Y.C., S.K., B.G.K.).,Neuroscience graduate program, Ajou University Graduate School of Medicine, Republic of Korea (X.J., H.K., S.K.)
| | - Hyo Jin Cho
- Department of Brain science, Ajou University School of Medicine, Republic of Korea (J.Y.C., X.J., H.K., S.K., H.J.C., B.G.K.)
| | - Byung Gon Kim
- Department of Brain science, Ajou University School of Medicine, Republic of Korea (J.Y.C., X.J., H.K., S.K., H.J.C., B.G.K.).,Department of Neurology, Ajou University School of Medicine, Republic of Korea (J.Y.C., S.K., B.G.K.)
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23
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Moriyama H, Moriyama M, Ozawa T, Tsuruta D, Hayakawa T. Differentiation of Human Adipose-Derived Mesenchymal Stromal/Stem Cells into Insulin-Producing Cells with A Single Tet-Off Lentiviral Vector System. CELL JOURNAL 2022; 24:705-714. [PMID: 36527342 PMCID: PMC9790068 DOI: 10.22074/cellj.2022.557533.1063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Indexed: 01/05/2023]
Abstract
OBJECTIVE Human adipose-derived mesenchymal stromal/stem cells (hASC) constitute an attractive source of stem cells for cell-based therapies in regenerative medicine and tissue engineering as they are easy to acquire from lipoaspirate, expansion, and genetic modification ex vivo. The combination of Pdx-1, MafA, and NeuroD1 has been indicated to possess the ability to reprogram various types of cells into insulin-producing cells. The aim of this study is to investigate whether MafA and NeuroD1 would cooperate with Pdx-1 in the differentiation of hASC into insulin-producing cells. MATERIALS AND METHODS In this experimental study, we generated polycistronic expression vectors expressing Pdx1 and MafA/NeuroD1 with a reporter from a human EF-1α promoter using 2A peptides in a single tet-off lentiviral vector system. Briefly, hASC were transduced with the lentiviral vectors and allowed to differentiate into insulin-producing cells in vitro and in vivo. Thereafter, RNA expression, dithizone staining, and immunofluorescent analysis were conducted. RESULTS Cleaved transcriptional factors from a single tet-off lentiviral vector were functionally equivalent to their native proteins and strictly regulated by doxycycline (Dox). Insulin gene expression in hASC transduced with Pdx1, Pdx1/ MafA, and Pdx1/NeuroD1 in differentiation medium were successfully increased by 1.89 ± 0.39, 4.81 ± 0.98, 5.51 ± 0.63, respectively, compared to venus-transduced, control hASC. These cells could form dithizone-positive cell clusters in vitro and were found to express insulin in vivo. CONCLUSION Using our single tet-off lentiviral vector system, Pdx-1 and MafA/NeuroD1 could be simultaneously expressed in the absence of Dox. Further, this system allowed the differentiation of hASC into insulin-producing cells.
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Affiliation(s)
- Hiroyuki Moriyama
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan,Pharmaceutical Research and Technology InstituteKindai University3-4-1 KowakaeHigashi-OsakaOsaka 577-8502Japan
| | - Mariko Moriyama
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
| | - Toshiyuki Ozawa
- Department of Dermatology, Graduate School of Medicine, Osaka Metropolita University, 1-4-3 Asahimachi, Abeno-Ku,
Osaka 545-8585, Japan
| | - Daisuke Tsuruta
- Department of Dermatology, Graduate School of Medicine, Osaka Metropolita University, 1-4-3 Asahimachi, Abeno-Ku,
Osaka 545-8585, Japan
| | - Takao Hayakawa
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
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24
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Ishii Y, Tsuchiya A, Natsui K, Koseki Y, Takeda N, Tomiyoshi K, Yamazaki F, Yoshida Y, Shimbo T, Tamai K, Terai S. Synthesized HMGB1 peptide prevents the progression of inflammation, steatosis, fibrosis, and tumor occurrence in a non-alcoholic steatohepatitis mouse model. Hepatol Res 2022; 52:985-997. [PMID: 35932481 DOI: 10.1111/hepr.13825] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 12/12/2022]
Abstract
AIM Non-alcoholic steatohepatitis (NASH) with fibrosis eventually leads to cirrhosis and hepatocellular carcinoma. Thus, the development of therapies other than dietary restriction and exercise, particularly those that suppress steatosis and fibrosis of the liver and have a long-term beneficial effect, is necessary. We aimed to evaluate the therapeutic effects of the HMGB1 peptide synthesized from box A using the melanocortin-4 receptor-deficient (Mc4r-KO) NASH model mouse. METHODS We performed short- and long-term administration of this peptide and evaluated the effects on steatosis, fibrosis, and carcinogenesis using Mc4r-KO mice. We also analyzed the direct effect of this peptide on macrophages and hepatic stellate cells in vitro and performed lipidomics and metabolomics techniques to evaluate the effect. RESULTS Although this peptide did not show direct effects on macrophages and hepatic stellate cells in vitro, in the short-term administration model, we could confirm the reduction of liver damage, steatosis, and fibrosis progression. The results of lipidomics and metabolomics suggested that the peptide might ameliorate NASH by promoting lipolysis via the activation of fatty acid β-oxidation and improving insulin resistance. In the long-term administration model, this peptide prevented progression to cirrhosis but retained the steatosis state, that is, the peptide prevents the progression to "burnt-out NASH." This peptide inhibited carcinogenesis by about one-third. CONCLUSION This HMGB1 peptide can reduce liver damage, improve fibrosis and steatosis, and inhibit carcinogenesis, suggesting that the peptide would be a new treatment candidate for NASH and can contribute to the long-term prognosis for patients with NASH.
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Affiliation(s)
- Yui Ishii
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kazuki Natsui
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Youhei Koseki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Nobutaka Takeda
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kei Tomiyoshi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Fusako Yamazaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yuki Yoshida
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Takashi Shimbo
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.,StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Osaka, Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
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25
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Matsuno Y, Yanagihara M, Ueno K, Saito T, Kurazumi H, Suzuki R, Katsura S, Oga A, Hamano K. Dry preserved multilayered fibroblast cell sheets are a new manageable tool for regenerative medicine to promote wound healing. Sci Rep 2022; 12:12519. [PMID: 35869108 PMCID: PMC9307603 DOI: 10.1038/s41598-022-16345-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 07/08/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractThis study investigated the therapeutic effects of dry-preserved multi-layered fibroblast cell sheets (dry sheets) on cutaneous ulcers. Dry sheets were prepared by air-drying multi-layered fibroblast cell sheets (living sheets) to cease their life activities. Before in vivo application, we tested the release of growth factors into the medium to examine the mechanisms of dry sheets in wound healing. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were released from both dry and living sheets, while high levels of fibroblast growth factor-2 (FGF-2) and high mobility group box 1 (HMGB1) protein were only from dry sheets. An in vitro fibroblast proliferation assay revealed that the dry sheet eluate significantly enhanced cell proliferation and VEGF and HGF production compared with living sheet eluate. FGF-2-neutralizing antibodies significantly blocked this proliferative response. In wounds created on diabetic mice, the dry sheet-treatment groups using autologous or allogeneic cells showed significantly accelerated wound closure compared with that in the no-treatment group. The storage stability of the dry sheet was better at refrigeration temperature than at room temperature and remained stable for at least 4 weeks. Our data indicated that allogeneic dry sheets represent a promising new tool for regenerative medicine that promotes wound healing.
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26
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Li H, Wei J, Liu X, Zhang P, Lin J. Muse cells: ushering in a new era of stem cell-based therapy for stroke. Stem Cell Res Ther 2022; 13:421. [PMID: 35986359 PMCID: PMC9389783 DOI: 10.1186/s13287-022-03126-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 08/07/2022] [Indexed: 11/10/2022] Open
Abstract
AbstractStem cell-based regenerative therapies have recently become promising and advanced for treating stroke. Mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) have received the most attention for treating stroke because of the outstanding paracrine function of MSCs and the three-germ-layer differentiation ability of iPSCs. However, the unsatisfactory homing ability, differentiation, integration, and survival time in vivo limit the effectiveness of MSCs in regenerative medicine. The inherent tumorigenic property of iPSCs renders complete differentiation necessary before transplantation, which is complicated and expensive and affects the consistency among cell batches. Multilineage differentiating stress-enduring (Muse) cells are natural pluripotent stem cells in the connective tissues of nearly every organ and thus are considered nontumorigenic. A single Muse cell can differentiate into all three-germ-layer, preferentially migrate to damaged sites after transplantation, survive in hostile environments, and spontaneously differentiate into tissue-compatible cells, all of which can compensate for the shortcomings of MSCs and iPSCs. This review summarizes the recent progress in understanding the biological properties of Muse cells and highlights the differences between Muse cells and other types of stem cells. Finally, we summarized the current research progress on the application of Muse cells on stroke and challenges from bench to bedside.
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27
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Hong SA, Kim SE, Lee AY, Hwang GH, Kim JH, Iwata H, Kim SC, Bae S, Lee SE. Therapeutic base editing and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa. Mol Ther 2022; 30:2664-2679. [PMID: 35690907 PMCID: PMC9372317 DOI: 10.1016/j.ymthe.2022.06.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 05/09/2022] [Accepted: 06/06/2022] [Indexed: 12/17/2022] Open
Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). For fibroblasts from two patients (Pat1 and Pat2), we applied adenine base editors (ABEs) to correct the pathogenic mutation of COL7A1 or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the COL7A1 mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that transfer of edited patient-derived skin equivalents (i.e., RDEB keratinocytes and PE-corrected RDEB fibroblasts from the RDEB patient) into the skin of immunodeficient mice led to C7 deposition and anchoring fibril formation within the dermal-epidermal junction, suggesting that base editing and prime editing could be feasible strategies for ex vivo gene editing to treat RDEB.
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Affiliation(s)
- Sung-Ah Hong
- Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Song-Ee Kim
- Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 06273, South Korea
| | - A-Young Lee
- Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 06273, South Korea
| | - Gue-Ho Hwang
- Department of Chemistry, Hanyang University, Seoul 04763, South Korea
| | - Jong Hoon Kim
- Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 06273, South Korea
| | - Hiroaki Iwata
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Soo-Chan Kim
- Department of Dermatology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin 16995, South Korea
| | - Sangsu Bae
- Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, South Korea; Department of Biomedical Sciences, Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, South Korea.
| | - Sang Eun Lee
- Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 06273, South Korea.
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28
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Hasegawa K, Fujimoto T, Mita C, Furumoto H, Inoue M, Ikegami K, Kitayama T, Yamamoto Y, Shimbo T, Yamazaki T, Tamai K. Single-cell transcriptome analysis of fractional CO 2 laser efficiency in treating a mouse model of alopecia. Lasers Surg Med 2022; 54:1167-1176. [PMID: 35916125 DOI: 10.1002/lsm.23590] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 07/03/2022] [Accepted: 07/16/2022] [Indexed: 11/06/2022]
Abstract
OBJECTIVES Hair loss, including alopecia, is a common dermatological issue worldwide. At present, the application of fractional carbon dioxide (CO2 ) laser in the treatment of alopecia has been documented; however, the results vary between reports. These varying results may be due to the limited knowledge of cellular action in laser-irradiated skin. The objective of this study was to investigate the molecular and cellular mechanisms of laser treatment under effective conditions for hair cycle initiation. METHODS A fractional CO2 laser was applied and optimized to initiate the hair cycle in a mouse model of alopecia. Several cellular markers were analyzed in the irradiated skin using immunofluorescence staining. Cellular populations and their comprehensive gene expression were analyzed using single-cell RNA sequencing and bioinformatics. RESULTS The effective irradiation condition for initiating the hair cycle was found to be 15 mJ energy/spot, which generates approximately 500 μm depth columns, but does not penetrate the dermis, only reaching approximately 1 spot/mm2 . The proportion of macrophage clusters significantly increased upon irradiation, whereas the proportion of fibroblast clusters decreased. The macrophages strongly expressed C-C chemokine receptor type 2 (Ccr2), which is known to be a key signal for injury-induced hair growth. CONCLUSIONS We found that fractional CO2 laser irradiation recruited Ccr2 positive macrophages, and induced hair regrowth in a mouse alopecia model. These findings may contribute to the development of stable and effective fractional laser irradiation conditions for human alopecia treatment.
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Affiliation(s)
- Kouichi Hasegawa
- Drug Discovery Department, StemRIM Incorporation, Osaka, Japan.,StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan
| | | | - Chihiro Mita
- Drug Discovery Department, StemRIM Incorporation, Osaka, Japan.,StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan
| | - Hidehiro Furumoto
- Drug Discovery Department, StemRIM Incorporation, Osaka, Japan.,StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan
| | - Masako Inoue
- Drug Discovery Department, StemRIM Incorporation, Osaka, Japan.,StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan
| | - Kentaro Ikegami
- Drug Discovery Department, StemRIM Incorporation, Osaka, Japan.,StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan
| | - Tomomi Kitayama
- Drug Discovery Department, StemRIM Incorporation, Osaka, Japan.,StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan.,Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yukari Yamamoto
- Drug Discovery Department, StemRIM Incorporation, Osaka, Japan.,StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan
| | - Takashi Shimbo
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan.,Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takehiko Yamazaki
- Drug Discovery Department, StemRIM Incorporation, Osaka, Japan.,StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan
| | - Katsuto Tamai
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Osaka, Japan.,Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan
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29
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Diversity of the Origin of Cancer Stem Cells in Oral Squamous Cell Carcinoma and Its Clinical Implications. Cancers (Basel) 2022; 14:cancers14153588. [PMID: 35892847 PMCID: PMC9332248 DOI: 10.3390/cancers14153588] [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: 06/23/2022] [Revised: 07/17/2022] [Accepted: 07/21/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Oral squamous cell carcinoma (OSCC) histopathologically accounts for ≥90% of oral cancer. In this review article, we focus on the diversity of the origin of OSCC and also discuss cancer stem cells (CSCs). CSCs are a subset of cancer cells that occupy a very small portion of the cancer mass and have characteristics of stem cells. When gene abnormalities accumulate in somatic stem cells, those cells transform into CSCs. CSCs as the origin of cancer then autonomously grow and develop into cancer. The histopathological phenotype of cancer cells is determined by the original characteristics of the somatic stem cells and/or surrounding environment. OSCC may be divided into the following three categories with different malignancy based on the origin of CSCs: cancer from oral epithelial stem cell-derived CSCs, cancer from stem cells in salivary gland-derived CSCs, and cancer from bone marrow-derived stem cell-derived CSCs. Abstract Oral squamous cell carcinoma (OSCC) histopathologically accounts for ≥90% of oral cancer. Many clinicopathological risk factors for OSCC have also been proposed, and postoperative therapy is recommended in guidelines based on cancer stage and other risk factors. However, even if the standard treatment is provided according to the guidelines, a few cases rapidly recur or show cervical and distant metastasis. In this review article, we focus on the diversity of the origin of OSCC. We also discuss cancer stem cells (CSCs) as a key player to explain the malignancy of OSCC. CSCs are a subset of cancer cells that occupy a very small portion of the cancer mass and have characteristics of stem cells. When gene abnormalities accumulate in somatic stem cells, those cells transform into CSCs. CSCs as the origin of cancer then autonomously grow and develop into cancer. The histopathological phenotype of cancer cells is determined by the original characteristics of the somatic stem cells and/or surrounding environment. OSCC may be divided into the following three categories with different malignancy based on the origin of CSCs: cancer from oral epithelial stem cell-derived CSCs, cancer from stem cells in salivary gland-derived CSCs, and cancer from bone marrow-derived stem cell-derived CSCs.
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30
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Satoh TK. The role of HMGB1 in inflammatory skin diseases. J Dermatol Sci 2022; 107:58-64. [PMID: 35907655 DOI: 10.1016/j.jdermsci.2022.07.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/06/2022] [Accepted: 07/10/2022] [Indexed: 01/22/2023]
Abstract
High-mobility group box 1 protein (HMGB1) is a highly abundant, non-histone nuclear protein that can serve as an alarmin to promote the pathogenesis of inflammatory diseases. In response to various stimuli, HMGB1 can translocate from the nucleus to the cytoplasm as well as the extracellular space through passive or active release, accompanied with different post-translational modifications. Depending on the redox state of three cysteine residues, HMGB1 determines its activity to induce cytokine production or tissue repair through binding with several different receptors. In addition, HMGB1 can form immunostimulatory complexes with cytokines and other endogenous/exogenous molecules and synergistically enhance their biological effect. Cell death is an important source of HMGB1 and major cell death forms such as apoptosis, necrosis and pyroptosis can modulate the redox state of HMGB1. In various human skin diseases as well as animal models, HMGB1 levels in cytoplasm, tissue and blood are increased and blockade of HMGB1 attenuates disease severity in animal models. These findings indicate that HMGB1 can serve as a unique biomarker as well as a target of new therapy in many inflammatory skin diseases.
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Affiliation(s)
- Takashi K Satoh
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Frauenlobstrasse, Munich, Germany.
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31
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Ishida Y, Nosaka M, Kondo T. Bone Marrow-Derived Cells and Wound Age Estimation. Front Med (Lausanne) 2022; 9:822572. [PMID: 35155503 PMCID: PMC8828650 DOI: 10.3389/fmed.2022.822572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/03/2022] [Indexed: 12/20/2022] Open
Abstract
Appropriate technology as well as specific target cells and molecules are key factors for determination of wound vitality or wound age in forensic practice. Wound examination is one of the most important tasks for forensic pathologists and is indispensable to distinguish antemortem wounds from postmortem damage. For vital wounds, estimating the age of the wound is also essential in determining how the wound is associated with the cause of death. We investigated bone marrow-derived cells as promising markers and their potential usefulness in forensic applications. Although examination of a single marker cannot provide high reliability and objectivity in estimating wound age, evaluating the appearance combination of bone marrow-derived cells and the other markers may allow for a more objective and accurate estimation of wound age.
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Affiliation(s)
- Yuko Ishida
- *Correspondence: Yuko Ishida ; orcid.org/0000-0001-6104-7599
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Kikuchi S, Uchida D, Takahashi K, Yoshida Y, Tochikubo-Suzuki A, Nakatsu T, Higuchi M, Azuma N, Kato K. Wound Healing on the Cutting Plane of Ankle Bones after Incomplete Revascularization for Chronic Limb-Threatening Ischemia in an Elderly Patient: A Case Report. Ann Vasc Dis 2022; 15:201-205. [PMID: 36310735 PMCID: PMC9558140 DOI: 10.3400/avd.cr.22-00049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/18/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic limb-threatening ischemia (CLTI) is an important issue for elderly patients with peripheral artery disease. Here, we present the case of a 91-year-old man with CLTI, residing in a rural district. The onset of CLTI rapidly deprived him of ambulation because of a foot infection. Given that he had difficulty with long-distance transportation, limb salvage for extensive tissue loss was performed at a district facility, based on his and his family’s request. Finally, skin grafting on the cutting plane of the right ankle bones resulted in wound healing in six months after incomplete revascularization and multiple minor amputations.
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Affiliation(s)
| | - Daiki Uchida
- Department of Vascular Surgery, Asahikawa Medical University
| | | | - Yuri Yoshida
- Department of Vascular Surgery, Asahikawa Medical University
| | | | - Tomoki Nakatsu
- Department of Vascular Surgery, Asahikawa Medical University
| | | | - Nobuyoshi Azuma
- Department of Vascular Surgery, Asahikawa Medical University
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Natsuga K, Shinkuma S, Hsu CK, Fujita Y, Ishiko A, Tamai K, McGrath JA. Current topics in Epidermolysis bullosa: Pathophysiology and therapeutic challenges. J Dermatol Sci 2021; 104:164-176. [PMID: 34916041 DOI: 10.1016/j.jdermsci.2021.11.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 11/06/2021] [Indexed: 12/14/2022]
Abstract
Epidermolysis bullosa (EB) is a group of inherited skin and mucosal fragility disorders resulting from mutations in genes encoding basement membrane zone (BMZ) components or proteins that maintain the integrity of BMZ and adjacent keratinocytes. More than 30 years have passed since the first causative gene for EB was identified, and over 40 genes are now known to be responsible for the protean collection of mechanobullous diseases included under the umbrella term of EB. Through the elucidation of disease mechanisms using human skin samples, animal models, and cultured cells, we have now reached the stage of developing more effective therapeutics for EB. This review will initially focus on what is known about blister wound healing in EB, since recent and emerging basic science data are very relevant to clinical translation and therapeutic strategies for patients. We then place these studies in the context of the latest information on gene therapy, read-through therapy, and cell therapy that provide optimism for improved clinical management of people living with EB.
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Affiliation(s)
- Ken Natsuga
- Department of Dermatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Hokkaido, Japan.
| | - Satoru Shinkuma
- Department of Dermatology, Nara Medical University School of Medicine, Kashihara, Japan
| | - Chao-Kai Hsu
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan
| | - Yasuyuki Fujita
- Department of Dermatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Hokkaido, Japan; Department of Dermatology, Sapporo City General Hospital, Sapporo, Japan
| | - Akira Ishiko
- Department of Dermatology, Toho University School of Medicine, Tokyo, Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan
| | - John A McGrath
- St. John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, United Kingdom
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Availability of mRNA Obtained from Peripheral Blood Mononuclear Cells for Testing Mutation Consequences in Dystrophic Epidermolysis Bullosa. Int J Mol Sci 2021; 22:ijms222413369. [PMID: 34948168 PMCID: PMC8709150 DOI: 10.3390/ijms222413369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 11/16/2022] Open
Abstract
Dystrophic epidermolysis bullosa (DEB) is an inheritable blistering disease caused by mutations in COL7A1, which encodes type VII collagen. To address the issue of genotype-phenotype correlations in DEB, analyzing the consequences of COL7A1 mutations using mRNA is indispensable. Herein we established a novel method for testing the effect of mutations in DEB using COL7A1 mRNA extracted from peripheral blood mononuclear cells (PBMCs). We investigated the consequences of four COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T, c.7270C > T and c.2527C > T) in three Japanese individuals with recessive DEB. The novel method detected the consequences of two recurrent COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T) and a novel COL7A1 mutation (c.7270C > T) accurately. In addition, it detected aberrant splicing resulting from a COL7A1 mutation (c.2527C > T) which was previously reported as a nonsense mutation. Furthermore, we revealed that type VII collagen-expressing cells in PBMCs have similar cell surface markers as mesenchymal stem cells; they were CD105+, CD29+, CD45-, and CD34-, suggesting that a small number of mesenchymal stem cells or mesenchymal stromal cells are circulating in the peripheral blood, which enables us to detect COL7A1 mRNA in PBMCs. Taken together, our novel method for analyzing mutation consequences using mRNA obtained from PBMCs in DEB will significantly contribute to genetic diagnoses and novel therapies for DEB.
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Abstract
Epidermolysis bullosa (EB) is a heterogeneous group of rare inherited blistering skin disorders characterized by skin fragility following minor trauma, usually present since birth. EB can be categorized into four classical subtypes, EB simplex, junctional EB, dystrophic EB and Kindler EB, distinguished on clinical features, plane of blister formation in the skin, and molecular pathology. Treatment for EB is mostly supportive, focusing on wound care and patient symptoms such as itch or pain. However, therapeutic advances have also been made in targeting the primary genetic abnormalities as well as the secondary inflammatory footprint of EB. Pre-clinical or clinical testing of gene therapies (gene replacement, gene editing, RNA-based therapy, natural gene therapy), cell-based therapies (fibroblasts, bone marrow transplantation, mesenchymal stromal cells, induced pluripotential stem cells), recombinant protein therapies, and small molecule and drug repurposing approaches, have generated new hope for better patient care. In this article, we review advances in translational research that are impacting on the quality of life for people living with different forms of EB and which offer hope for improved clinical management.
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Alven A, Lema C, Redfern RL. Impact of Low Humidity on Damage-associated Molecular Patterns at the Ocular Surface during Dry Eye Disease. Optom Vis Sci 2021; 98:1231-1238. [PMID: 34510151 PMCID: PMC8585693 DOI: 10.1097/opx.0000000000001802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
SIGNIFICANCE Dry eye is one of the leading causes for individuals to seek eye care, whereas the pathogenesis is poorly understood. One mechanism in which dry eye inflammation may ensue is by the release of damage-associated molecular patterns (DAMPs) by damaged cells to stimulate the production of cytokines and matrix metalloproteinases. Examining DAMP levels on the ocular surface during dry eye disease (DED) will increase our understanding of their potential involvement in the pathogenesis of DED. PURPOSE This study aimed to quantitate DAMPs, high-mobility group box 1 (HMGB1), and heat shock proteins on the ocular surface of normal and dry eye subjects and to examine the impact of low-humidity environment (LHE) on DAMPs and inflammation in dry eye subjects. METHODS Basal tears (10 to 20 μL) and conjunctival impression cytology samples were analyzed for HMGB1, HSP-27, HSP-60, HSP-70, and HSP-90α by ELISA or Luminex assays in normal (n = 15) and DED (n = 15) subjects. In addition, a subset of DED subjects were exposed to LHE for 2 hours. The level of DAMPs in the tear film was evaluated by ELISA or Luminex assay. Interleukin 6, interleukin 8, or metalloproteinase (MMP) 9 mRNA were quantitated by real-time polymerase chain reaction from conjunctival impression cytology samples. RESULTS Compared with age-matched normal subjects, HMGB1 was significantly elevated in the tear film of DED subjects (P = .03), whereas there was no significant difference in heat shock proteins. Conjunctival impression cytology samples revealed no significant difference in intracellular DAMP levels between both groups. After exposure to an LHE, there was an increase in corneal staining (P = .005), HSP-60 levels in the tear film (P = .01), and MMP-9 mRNA in the conjunctiva (P = .001). CONCLUSIONS Dry eye subjects had higher levels of HMGB1 in their tear film. Exposure to an LHE worsened corneal staining, increased conjunctival MMP-9 mRNA expression, and increased tear film HSP-60 levels. Larger studies are needed to understand the involvement of DAMPs in stimulating dry eye inflammation.
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Affiliation(s)
- Alyce Alven
- The Ocular Surface Institute, College of Optometry, University of Houston, Houston, Texas
| | - Carolina Lema
- The Ocular Surface Institute, College of Optometry, University of Houston, Houston, Texas
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Riedl J, Popp C, Eide C, Ebens C, Tolar J. Mesenchymal stromal cells in wound healing applications: role of the secretome, targeted delivery and impact on recessive dystrophic epidermolysis bullosa treatment. Cytotherapy 2021; 23:961-973. [PMID: 34376336 PMCID: PMC8569889 DOI: 10.1016/j.jcyt.2021.06.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/25/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are multi-potent stromal-derived cells capable of self-renewal that possess several advantageous properties for wound healing, making them of interest to the field of dermatology. Research has focused on characterizing the unique properties of MSCs, which broadly revolve around their regenerative and more recently discovered immunomodulatory capacities. Because of ease of harvesting and expansion, differentiation potential and low immunogenicity, MSCs have been leading candidates for tissue engineering and regenerative medicine applications for wound healing, yet results from clinical studies have been variable, and promising pre-clinical work has been difficult to reproduce. Therefore, the specific mechanisms of how MSCs influence the local microenvironment in distinct wound etiologies warrant further research. Of specific interest in MSC-mediated healing is harnessing the secretome, which is composed of components known to positively influence wound healing. Molecules released by the MSC secretome can promote re-epithelialization and angiogenesis while inhibiting fibrosis and microbial invasion. This review focuses on the therapeutic interest in MSCs with regard to wound healing applications, including burns and diabetic ulcers, with specific attention to the genetic skin disease recessive dystrophic epidermolysis bullosa. This review also compares various delivery methods to support skin regeneration in the hopes of combating the poor engraftment of MSCs after delivery, which is one of the major pitfalls in clinical studies utilizing MSCs.
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Affiliation(s)
- Julia Riedl
- Medical Scientist Training Program (MD/PhD), University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA
| | - Courtney Popp
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Cindy Eide
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Christen Ebens
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.
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Li YT, Yamazaki S, Takaki E, Ouchi Y, Kitayama T, Tamai K. PDGFRα-lineage origin directs monocytes to trafficking proficiency to support peripheral immunity. Eur J Immunol 2021; 52:204-221. [PMID: 34708880 PMCID: PMC9299050 DOI: 10.1002/eji.202149479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/11/2021] [Accepted: 10/25/2021] [Indexed: 12/03/2022]
Abstract
Multiple embryonic precursors give rise to leukocytes in adults while the lineage‐based functional impacts are underappreciated. Mesodermal precursors expressing PDGFRα appear transiently during E7.5‐8.5 descend to a subset of Lin–Sca1+Kit+ hematopoietic progenitors found in adult BM. By analyzing a PDGFRα‐lineage tracing mouse line, we here report that PDGFRα‐lineage BM F4/80+SSClo monocytes/macrophages are solely Ly6C+LFA‐1hiMac‐1hi monocytes enriched on the abluminal sinusoidal endothelium while Ly6C–LFA‐1loMac‐1lo macrophages are mostly from non‐PDGFRα‐lineage in vivo. Monocytes with stronger integrin profiles outcompete macrophages for adhesion on an endothelial monolayer or surfaces coated with ICAM‐1‐Fc or VCAM‐1‐Fc. Egress of PDGFRα‐lineage‐rich monocytes and subsequent differentiation to peripheral macrophages spatially segregates them from non‐PDGFRα‐lineage BM‐resident macrophages and allows functional specialization since macrophages derived from these egressing monocytes differ in morphology, phenotype, and functionality from BM‐resident macrophages in culture. Extravasation preference for blood PDGFRα‐lineage monocytes varies by tissues and governs the local lineage composition of macrophages. More PDGFRα‐lineage classical monocytes infiltrated into skin and colon but not into peritoneum. Accordingly, transcriptomic analytics indicated augmented inflammatory cascades in dermatitis skin of BM‐chimeric mice harbouring only PDGFRα‐lineage leukocytes. Thus, the PDGFRα‐lineage origin biasedly generates monocytes predestined for BM exit to support peripheral immunity following extravasation and macrophage differentiation.
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Affiliation(s)
- Yu-Tung Li
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan
| | | | | | | | | | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan
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Nojiri S, Tsuchiya A, Natsui K, Takeuchi S, Watanabe T, Kojima Y, Watanabe Y, Kamimura H, Ogawa M, Motegi S, Iwasawa T, Sato T, Kumagai M, Ishii Y, Kitayama T, Li YT, Ouchi Y, Shimbo T, Takamura M, Tamai K, Terai S. Synthesized HMGB1 peptide attenuates liver inflammation and suppresses fibrosis in mice. Inflamm Regen 2021; 41:28. [PMID: 34565478 PMCID: PMC8474861 DOI: 10.1186/s41232-021-00177-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/25/2021] [Indexed: 11/20/2022] Open
Abstract
The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.
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Affiliation(s)
- Shunsuke Nojiri
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Kazuki Natsui
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Suguru Takeuchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Takayuki Watanabe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Yuichi Kojima
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Yusuke Watanabe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Satoko Motegi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Takahiro Iwasawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Takeki Sato
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Masaru Kumagai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Yui Ishii
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Tomomi Kitayama
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871 Japan
- StemRIM Inc., Saito Bio-Incubator 3F 7-7-15, Saito-Asagi, Ibaraki City, Osaka, 567-0085 Japan
| | - Yu-Tung Li
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Yuya Ouchi
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871 Japan
- StemRIM Inc., Saito Bio-Incubator 3F 7-7-15, Saito-Asagi, Ibaraki City, Osaka, 567-0085 Japan
| | - Takashi Shimbo
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871 Japan
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, 2-8, Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Masaaki Takamura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
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Zhang J, Li F, Augi T, Williamson KM, Onishi K, Hogan MV, Neal MD, Wang JHC. Platelet HMGB1 in Platelet-Rich Plasma (PRP) promotes tendon wound healing. PLoS One 2021; 16:e0251166. [PMID: 34529657 PMCID: PMC8445483 DOI: 10.1371/journal.pone.0251166] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 08/24/2021] [Indexed: 11/18/2022] Open
Abstract
Platelet-rich plasma (PRP) is a widely used autologous treatment for tendon injuries in clinics. Platelets (PLTs) are a major source of high mobility group box1 (HMGB1) that is gaining attention as a chemoattractant that can recruit stem cells to the wound area to enhance healing of injured tissues; however, the contribution of PLT HMGB1 in wounded tendon healing remains unexplored. This study investigated the effect of PLT HMGB1 within PRP on tendon healing using PLT HMGB1 knockout (KO) and GFP mice. A window defect was created in the patellar tendons of both groups of mice, and wounds were treated with either saline, PRP isolated from PLT HMGB1-KO mice, or PRP isolated from GFP mice. Seven days post-treatment, animals were sacrificed and analyzed by gross inspection, histology, and immunostaining for characteristic signs of tendon healing and repair. Our results showed that in comparison to mice treated with PRP from PLT HMGB1-KO mice, wounds treated with PRP from GFP mice healed faster and exhibited a better organization in tendon structure. Mice treated with PRP from PLT HMGB1-KO mice produced tendon tissue with large premature wound areas and low cell densities. However, wounds of PLT HMGB1-KO mice showed better healing with PRP from HMGB1-KO mice compared to saline treatment. Moreover, wounds treated with PRP from GFP mice had increased extracellular HMGB1, decreased CD68, increased stem cell markers CD146 and CD73, and increased collagen III protein expression levels compared to those treated with PRP from PLT HMGB1-KO mice. Thus, PLT HMGB1 within PRP plays an important role in tendon wound healing by decreasing inflammation, increasing local HMGB1 levels, and recruiting stem cells to the wound area in the tendon. Our findings also suggest that the efficacy of PRP treatment for tendon injuries in clinics may depend on PLT HMGB1 within PRP preparations.
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Affiliation(s)
- Jianying Zhang
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Feng Li
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Tyler Augi
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Kelly M. Williamson
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Kentaro Onishi
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - MaCalus V. Hogan
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Matthew D. Neal
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - James H.-C. Wang
- MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States of America
- * E-mail:
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Fujimura Y, Watanabe M, Ohno K, Kobayashi Y, Takashima S, Nakamura H, Kosumi H, Wang Y, Mai Y, Lauria A, Proserpio V, Ujiie H, Iwata H, Nishie W, Nagayama M, Oliviero S, Donati G, Shimizu H, Natsuga K. Hair follicle stem cell progeny heal blisters while pausing skin development. EMBO Rep 2021; 22:e50882. [PMID: 34085753 DOI: 10.15252/embr.202050882] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 12/13/2022] Open
Abstract
Injury in adult tissue generally reactivates developmental programs to foster regeneration, but it is not known whether this paradigm applies to growing tissue. Here, by employing blisters, we show that epidermal wounds heal at the expense of skin development. The regenerated epidermis suppresses the expression of tissue morphogenesis genes accompanied by delayed hair follicle (HF) growth. Lineage tracing experiments, cell proliferation dynamics, and mathematical modeling reveal that the progeny of HF junctional zone stem cells, which undergo a morphological transformation, repair the blisters while not promoting HF development. In contrast, the contribution of interfollicular stem cell progeny to blister healing is small. These findings demonstrate that HF development can be sacrificed for the sake of epidermal wound regeneration. Our study elucidates the key cellular mechanism of wound healing in skin blistering diseases.
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Affiliation(s)
- Yu Fujimura
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Mika Watanabe
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Department of Life Sciences and Systems Biology, Molecular Biotechnology Centre, University of Turin, Turin, Italy
| | - Kota Ohno
- Research Institute for Electronic Science, Hokkaido University, Sapporo, Japan
| | - Yasuaki Kobayashi
- Research Institute for Electronic Science, Hokkaido University, Sapporo, Japan
| | - Shota Takashima
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hideki Nakamura
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hideyuki Kosumi
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yunan Wang
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yosuke Mai
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Andrea Lauria
- Department of Life Sciences and Systems Biology, Molecular Biotechnology Centre, University of Turin, Turin, Italy.,Italian Institute for Genomic Medicine, Candiolo, Italy
| | - Valentina Proserpio
- Italian Institute for Genomic Medicine, Candiolo, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Hideyuki Ujiie
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiroaki Iwata
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Wataru Nishie
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masaharu Nagayama
- Research Institute for Electronic Science, Hokkaido University, Sapporo, Japan
| | - Salvatore Oliviero
- Department of Life Sciences and Systems Biology, Molecular Biotechnology Centre, University of Turin, Turin, Italy.,Italian Institute for Genomic Medicine, Candiolo, Italy
| | - Giacomo Donati
- Department of Life Sciences and Systems Biology, Molecular Biotechnology Centre, University of Turin, Turin, Italy
| | - Hiroshi Shimizu
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Ken Natsuga
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Sakihama H, Lee GR, Chin BY, Csizmadia E, Gallo D, Qi Y, Gagliani N, Wang H, Bach FH, Otterbein LE. Carbon Monoxide Suppresses Neointima Formation in Transplant Arteriosclerosis by Inhibiting Vascular Progenitor Cell Differentiation. Arterioscler Thromb Vasc Biol 2021; 41:1915-1927. [PMID: 33853347 PMCID: PMC8159904 DOI: 10.1161/atvbaha.120.315558] [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] [Indexed: 11/16/2022]
Abstract
[Figure: see text].
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MESH Headings
- Animals
- Aorta, Thoracic/enzymology
- Aorta, Thoracic/pathology
- Aorta, Thoracic/transplantation
- Arteriosclerosis/enzymology
- Arteriosclerosis/genetics
- Arteriosclerosis/pathology
- Arteriosclerosis/prevention & control
- Bone Marrow Transplantation
- Carbon Monoxide/pharmacology
- Cell Differentiation/drug effects
- Cells, Cultured
- Disease Models, Animal
- Heme Oxygenase-1/genetics
- Heme Oxygenase-1/metabolism
- Kinetics
- Male
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/enzymology
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/enzymology
- Myocytes, Smooth Muscle/pathology
- Neointima
- Receptor, Platelet-Derived Growth Factor beta/metabolism
- Stem Cells/drug effects
- Stem Cells/enzymology
- Stem Cells/pathology
- Transplantation Chimera
- Vascular Remodeling/drug effects
- Mice
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Affiliation(s)
- Hideyasu Sakihama
- Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215
- Hokkaido University, Sapporo, Hokkaido, Japan
| | - Ghee Rye Lee
- Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215
| | | | - Eva Csizmadia
- Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215
| | - David Gallo
- Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215
| | - Yilin Qi
- Agios Pharmaceuticals, Cambridge, MA
| | - Nicola Gagliani
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg Germany
| | - Hongjun Wang
- Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215
| | - Fritz H. Bach
- Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215
| | - Leo E. Otterbein
- Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215
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Abstract
Epidermolysis bullosa (EB) is a group of rare genetic disorders for which significant progress has been achieved in the development of molecular therapies in the last few decades. Such therapies require knowledge of mutant genes and specific mutations, some of them being allele specific. A relatively large number of clinical trials are ongoing and ascertaining the clinical efficacy of gene, protein or cell therapies or of repurposed drugs, mainly in recessive dystrophic EB. It is expected that some new drugs may emerge in the near future and that combinations of different approaches may result in improved treatment outcomes for individuals with EB.
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44
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A Review of Acquired Autoimmune Blistering Diseases in Inherited Epidermolysis Bullosa: Implications for the Future of Gene Therapy. Antibodies (Basel) 2021; 10:antib10020019. [PMID: 34067512 PMCID: PMC8161452 DOI: 10.3390/antib10020019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/24/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
Gene therapy serves as a promising therapy in the pipeline for treatment of epidermolysis bullosa (EB). However, with great promise, the risk of autoimmunity must be considered. While EB is a group of inherited blistering disorders caused by mutations in various skin proteins, autoimmune blistering diseases (AIBD) have a similar clinical phenotype and are caused by autoantibodies targeting skin antigens. Often, AIBD and EB have the same protein targeted through antibody or mutation, respectively. Moreover, EB patients are also reported to carry anti-skin antibodies of questionable pathogenicity. It has been speculated that activation of autoimmunity is both a consequence and cause of further skin deterioration in EB due to a state of chronic inflammation. Herein, we review the factors that facilitate the initiation of autoimmune and inflammatory responses to help understand the pathogenesis and therapeutic implications of the overlap between EB and AIBD. These may also help explain whether corrections of highly immunogenic portions of protein through gene therapy confers a greater risk towards developing AIBD.
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45
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Tartaglia G, Cao Q, Padron ZM, South AP. Impaired Wound Healing, Fibrosis, and Cancer: The Paradigm of Recessive Dystrophic Epidermolysis Bullosa. Int J Mol Sci 2021; 22:5104. [PMID: 34065916 PMCID: PMC8151646 DOI: 10.3390/ijms22105104] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a devastating skin blistering disease caused by mutations in the gene encoding type VII collagen (C7), leading to epidermal fragility, trauma-induced blistering, and long term, hard-to-heal wounds. Fibrosis develops rapidly in RDEB skin and contributes to both chronic wounds, which emerge after cycles of repetitive wound and scar formation, and squamous cell carcinoma-the single biggest cause of death in this patient group. The molecular pathways disrupted in a broad spectrum of fibrotic disease are also disrupted in RDEB, and squamous cell carcinomas arising in RDEB are thus far molecularly indistinct from other sub-types of aggressive squamous cell carcinoma (SCC). Collectively these data demonstrate RDEB is a model for understanding the molecular basis of both fibrosis and rapidly developing aggressive cancer. A number of studies have shown that RDEB pathogenesis is driven by a radical change in extracellular matrix (ECM) composition and increased transforming growth factor-beta (TGFβ) signaling that is a direct result of C7 loss-of-function in dermal fibroblasts. However, the exact mechanism of how C7 loss results in extensive fibrosis is unclear, particularly how TGFβ signaling is activated and then sustained through complex networks of cell-cell interaction not limited to the traditional fibrotic protagonist, the dermal fibroblast. Continued study of this rare disease will likely yield paradigms relevant to more common pathologies.
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Affiliation(s)
- Grace Tartaglia
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S. 10th Street, BLSB 406, Philadelphia, PA 19107, USA; (G.T.); (Q.C.); (Z.M.P.)
| | - Qingqing Cao
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S. 10th Street, BLSB 406, Philadelphia, PA 19107, USA; (G.T.); (Q.C.); (Z.M.P.)
| | - Zachary M. Padron
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S. 10th Street, BLSB 406, Philadelphia, PA 19107, USA; (G.T.); (Q.C.); (Z.M.P.)
- The Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Andrew P. South
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S. 10th Street, BLSB 406, Philadelphia, PA 19107, USA; (G.T.); (Q.C.); (Z.M.P.)
- The Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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46
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Xiao Y, Sun Y, Liu W, Zeng F, Shi J, Li J, Chen H, Tu C, Xu Y, Tan Z, Gong F, Shu X, Zheng F. HMGB1 Promotes the Release of Sonic Hedgehog From Astrocytes. Front Immunol 2021; 12:584097. [PMID: 33868221 PMCID: PMC8047406 DOI: 10.3389/fimmu.2021.584097] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 03/15/2021] [Indexed: 12/26/2022] Open
Abstract
High mobility group box 1 protein (HMGB1) is known to be a trigger of inflammation in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, it may play a different role in some way. Here we investigated the effect of HMGB1 on promoting sonic hedgehog (shh) release from astrocytes as well as the possible signal pathway involved in it. Firstly, shh increased in astrocytes after administration of recombinant HMGB1 or decreased after HMGB1 was blocked when stimulated by homogenate of the onset stage of EAE. Moreover, the expression of HMGB1 receptors, toll-like receptor (TLR) 2 and receptor for advanced glycation end products (RAGE) increased after HMGB1 administration in primary astrocytes. However, the enhancing effect of HMGB1 on shh release from astrocytes was suppressed only after RAGE was knocked out or blocked. Mechanistically, HMGB1 functioned by activating RAGE-mediated JNK, p38, stat3 phosphorylation. Moreover, HMGB1 could induce shh release in EAE. Additionally, intracerebroventricular injection of recombinant shh protein on the onset stage of EAE alleviated the progress of disease and decreased demylination, compared to the mice with normal saline treatment. Overall, HMGB1 promoted the release of shh from astrocytes through signal pathway JNK, p38 and stat3 mediated by receptor RAGE, which may provide new insights of HMGB1 function in EAE.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/pharmacology
- Astrocytes/cytology
- Astrocytes/drug effects
- Astrocytes/metabolism
- Cells, Cultured
- Disease Models, Animal
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/prevention & control
- Female
- Glycyrrhizic Acid/pharmacology
- HMGB1 Protein/genetics
- HMGB1 Protein/pharmacology
- Hedgehog Proteins/metabolism
- Mice, Inbred C57BL
- Mice, Knockout
- Multiple Sclerosis/genetics
- Multiple Sclerosis/metabolism
- Multiple Sclerosis/prevention & control
- Receptor for Advanced Glycation End Products/genetics
- Receptor for Advanced Glycation End Products/metabolism
- Recombinant Proteins/pharmacology
- Signal Transduction/drug effects
- Mice
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Affiliation(s)
- Yifan Xiao
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Medicine, Institutes of Biomedical Sciences, Jianghan University, Wuhan, China
| | - Yan Sun
- Wuhan Institute for Neuroscience and Neuroengineering, South-Central University for Nationalities, Wuhan, China
- Department of Neurobiology, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Wei Liu
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
- School of Medicine, Institutes of Biomedical Sciences, Jianghan University, Wuhan, China
| | - FanFan Zeng
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junyu Shi
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Li
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huoying Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Chang Tu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yong Xu
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zheng Tan
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feili Gong
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiji Shu
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
- School of Medicine, Institutes of Biomedical Sciences, Jianghan University, Wuhan, China
| | - Fang Zheng
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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47
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Bar J, Sarig O, Lotan-Pompan M, Dassa B, Miodovnik M, Weinberger A, Sprecher E, Segal E, Samuelov L. Evidence for cutaneous dysbiosis in dystrophic epidermolysis bullosa. Clin Exp Dermatol 2021; 46:1223-1229. [PMID: 33682945 DOI: 10.1111/ced.14592] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 01/10/2021] [Accepted: 02/01/2021] [Indexed: 01/02/2023]
Abstract
BACKGROUND The human microbiome project addresses the relationship between bacterial flora and the human host, in both healthy and diseased conditions. The skin is an ecosystem with multiple niches, each featuring unique physiological conditions and thus hosting different bacterial populations. The skin microbiome has been implicated in the pathogenesis of many dermatoses. Given the role of dysbiosis in the pathogenesis of inflammation, which is prominent in dystrophic epidermolysis bullosa (DEB), we undertook a study on the skin microbiome. AIM To characterize the skin microbiome in a series of patients with DEB. METHODS This was a case-control study of eight patients with DEB and nine control cases enrolled between June 2017 and November 2018. The skin of patients with DEB was sampled at three different sites: untreated wound, perilesional skin and normal-appearing (uninvolved) skin. Normal skin on the forearm was sampled from age-matched healthy controls (HCs). We used a dedicated DNA extraction protocol to isolate microbial DNA, which was then analysed using next-generation microbial 16S rRNA sequencing. Data were analysed using a series of advanced bioinformatics tools. RESULTS The wounds, perilesional and uninvolved skin of patients with DEB demonstrated reduced bacterial diversity compared with HCs, with the flora in DEB wounds being the least diverse. We found an increased prevalence of staphylococci species in the lesional and perilesional skin of patients with DEB, compared with their uninvolved, intact skin. Similarly, the uninvolved skin of patients with DEB displayed increased staphylococcal content and significantly different microbiome diversities (other than staphylococci) compared with HC skin. CONCLUSIONS These findings suggest the existence of a unique DEB-associated skin microbiome signature, which could be targeted by specific pathogen-directed therapies. Moreover, altering the skin microbiome with increasing colonization of bacteria associated with nonchronic wounds may potentially facilitate wound healing in patients with DEB.
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Affiliation(s)
- J Bar
- Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - O Sarig
- Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - M Lotan-Pompan
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.,Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - B Dassa
- Bioinformatics Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - M Miodovnik
- Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - A Weinberger
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.,Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - E Sprecher
- Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - E Segal
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.,Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - L Samuelov
- Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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48
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Iwai S, Okada A, Sasano K, Endo M, Yamazaki S, Wang X, Shimbo T, Tomimatsu T, Kimura T, Tamai K. Controlled induction of immune tolerance by mesenchymal stem cells transferred by maternal microchimerism. Biochem Biophys Res Commun 2021; 539:83-88. [PMID: 33461067 DOI: 10.1016/j.bbrc.2020.12.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 12/11/2020] [Indexed: 12/20/2022]
Abstract
Feto-maternal immune tolerance is established during pregnancy; however, its mechanism and maintenance remain underexplored. Here, we investigated whether mesenchymal stem/stromal cells (MSCs) as non-inherited maternal antigens (NIMAs) transferred by maternal microchimerism could induce immune tolerance. We showed that MSCs had a potential equivalent to hematopoietic stem and progenitor cells (HSPCs) to induce immune tolerance and that MSCs were essential to induce tolerance to MSC-specific antigens. Furthermore, we demonstrated that MSCs as NIMAs transferred by maternal microchimerism could induce robust immune tolerance that can be further enhanced using a drug. Our data shed light on induction of immune tolerance and serve as a foundation to develop new therapies using maternally derived cells for autoimmune or genetic diseases.
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Affiliation(s)
- Sayuri Iwai
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Aiko Okada
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kei Sasano
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Masayuki Endo
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Japan; Department of Children's and Women's Health, Division of Health Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
| | - Sho Yamazaki
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan; StemRIM Inc, Ibaraki, Osaka, Japan
| | - Xin Wang
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan; StemRIM Inc, Ibaraki, Osaka, Japan
| | - Takashi Shimbo
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan; StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Japan
| | - Takuji Tomimatsu
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tadashi Kimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan.
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49
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Hasegawa T, Nakashiro KI, Fukumoto C, Hyodo T, Sawatani Y, Shimura M, Kamimura R, Kuribayashi N, Fujita A, Uchida D, Kawamata H. Oral squamous cell carcinoma may originate from bone marrow-derived stem cells. Oncol Lett 2021; 21:170. [PMID: 33552287 PMCID: PMC7798092 DOI: 10.3892/ol.2021.12431] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/21/2020] [Indexed: 01/11/2023] Open
Abstract
Molecules that demonstrate a clear association with the aggressiveness of oral squamous cell carcinoma (OSCC) have not yet been identified. The current study hypothesized that tumor cells in OSCC have three different origins: Epithelial stem cells, oral tissue stem cells from the salivary gland and bone marrow (BM) stem cells. It was also hypothesized that carcinomas derived from less-differentiated stem cells have a greater malignancy. In the present study, sex chromosome analysis by fluorescence in situ hybridization and/or microdissection PCR was performed in patients with OSCC that developed after hematopoietic stem cell transplantation (HSCT) from the opposite sex. OSCC from 3 male patients among the 6 total transplanted patients were considered to originate from donor-derived BM cells. A total of 2/3 patients had distant metastasis, resulting in a poor prognosis. In a female patient with oral potentially malignant disorder who underwent HSCT, there were 10.7% Y-containing cells in epithelial cells, suggesting that some epithelial cells were from the donor. Subsequently, gene expression patterns in patients with possible BM stem cell-derived OSCC were compared with those in patients with normally developed OSCC by microarray analysis. A total of 3 patients with BM stem cell-derived OSCC exhibited a specific pattern of gene expression. Following cluster analysis by the probes identified on BM stem cell-derived OSCC, 2 patients with normally developed OSCC were included in the cluster of BM stem cell-derived OSCC. If the genes that could discriminate the origin of OSCC were identified, OSCCs were classified into the three aforementioned categories. If diagnosis can be performed based on the origin of the cancer cells, a more specific therapeutic strategy may be implemented to improve prognosis. This would be a paradigm shift in diagnostic and therapeutic strategies for OSCC.
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Affiliation(s)
- Tomonori Hasegawa
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Koh-Ichi Nakashiro
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan
| | - Chonji Fukumoto
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Toshiki Hyodo
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Yuta Sawatani
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Michiko Shimura
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Ryouta Kamimura
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Nobuyuki Kuribayashi
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan
| | - Atsushi Fujita
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
| | - Daisuke Uchida
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan
| | - Hitoshi Kawamata
- Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan
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50
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Rubanenko M, Manturova N, Ustiugov A, Porshina O, Petunina V, Zorin V, Zorina A, Palinkash A. Epidermolysis bullosa. Possible methods of treatment. KLINICHESKAYA DERMATOLOGIYA I VENEROLOGIYA 2021; 20:22. [DOI: 10.17116/klinderma20212004122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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