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1
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Yang S, Li Y, Ruan R, Yu J, Zhu B, Lou H, Zhang X, Wang S. Exogenous TSG-6 treatment alleviates DSS-induced colitis in mice by modulating Pou2f3 and promoting tuft cells differentiation. Mol Med 2025; 31:157. [PMID: 40301757 PMCID: PMC12042439 DOI: 10.1186/s10020-025-01230-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 04/24/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND Whereas intestinal epithelial barrier dysfunction is implicated in inflammatory bowel disease (IBD), the underlying mechanisms remain elusive. Tumor necrosis factor α stimulated gene 6 (TSG-6) is a secretory protein with anti-inflammatory properties. Our previous research demonstrated TSG-6 can relieve intestinal inflammation and mucosal damage. However, the underlying mechanism and targets remain unclear. This research sought to explore how TSG-6 regulates the intestinal epithelial barrier and its mechanistic role in experimental colitis. METHODS IBD mouse model was generated using dextran sodium sulfate (DSS), with or without intraperitoneal injection of TSG-6(100 µg/kg or 200 µg/kg). The effects of TSG-6 on colonic inflammation and intestinal barrier function were investigated. Label-free quantitative proteomic analysis was performed on intestinal samples to explore the mechanism and therapeutic target of TSG-6. Molecular interactions were determined by co-immunoprecipitation (Co-IP) and immunofluorescence colocalization. RESULTS TSG-6 treatment significantly attenuated DSS-induced colitis symptoms and inflammatory cell infiltration. Microarray analysis revealed that TSG-6 decreased pro-inflammatory cytokine levels in colon tissue. TSG-6 restored the intestinal epithelial barrier through the promotion of intestinal epithelial cells (IECs) proliferation and mitigation of tight junctions (TJs) damage. Mechanistically, TSG-6 promoted tuft cells differentiation and increased interleukin-25 (IL-25) levels by directly binding to Pou class 2 homeobox 3(Pou2f3) and up-regulating its expression in the gut. CONCLUSIONS This study demonstrated TSG-6 as a positive regulator of tuft cells differentiation by interacting with Pou2f3, and the effectiveness of exogenous TSG-6 treatment on maintaining intestinal barrier integrity showed a promising potential for its clinical application.
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Affiliation(s)
- Shaopeng Yang
- Department of Endoscopy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Yuqi Li
- Department of Endoscopy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Rongwei Ruan
- Department of Endoscopy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Jiangping Yu
- Department of Endoscopy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Bo Zhu
- Department of Endoscopy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Haibin Lou
- Department of Endoscopy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Xiaolan Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China.
| | - Shi Wang
- Department of Endoscopy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.
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2
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Pani G. Bacteria, stem cells and cancer. Cancer Gene Ther 2025; 32:269-272. [PMID: 39915606 DOI: 10.1038/s41417-025-00876-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/16/2025] [Accepted: 01/29/2025] [Indexed: 03/28/2025]
Affiliation(s)
- Giovambattista Pani
- Department of Translational Medicine and Surgery, Faculty of Medicine, Università Cattolica del Sacro Cuore, Rome, Italy.
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
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3
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Aghayan AH, Mirazimi Y, Nasehi L, Atashi A. The toxic effects of neutrophil extracellular traps on mesenchymal stem cells. Mol Biol Rep 2024; 52:30. [PMID: 39614028 DOI: 10.1007/s11033-024-10134-2] [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: 04/15/2024] [Accepted: 11/23/2024] [Indexed: 12/01/2024]
Abstract
Sepsis, a systemic inflammatory response syndrome resulting from an uncontrolled inflammatory reaction to infection, remains without a definitive cure despite therapeutic advancements. Mesenchymal stem cells (MSCs), renowned for their capacity to alleviate inflammation and modulate the immune system, have emerged as a potential treatment avenue for sepsis. In sepsis pathophysiology, hyperactivated neutrophils release extracellular neutrophil traps (NETs). NETs are essential for eradicating pathogens; however, excessive formation leads to tissue damage. Given the limited knowledge regarding the impact of NETs on MSCs used in sepsis therapy and the established interaction between MSCs and NETs, this study investigates the effects of NETs on MSCs in vitro. NETs were isolated from stimulated neutrophils, and MSCs were sourced from umbilical cord blood. After co-culturing MSCs with isolated NETs, MSCs' viability, migration, intracellular antioxidant capacity, and changes in gene expression were analyzed. Following exposure to NETs, MSCs exhibited obvious apoptosis and necrosis. NETs disrupt MSCs' mitochondrial activity. Also, NETs upregulate the pro-apoptotic gene BAX and downregulate the anti-apoptotic gene BCL2 in MSCs. Additionally, NETs reduce MSCs' intracellular antioxidant capacity. Furthermore, MSC migration is significantly impaired by NETs. This study collectively demonstrates that NETs have toxic and detrimental effects on MSCs. These effects on MSCs indicate a potential barrier to their functionality and therapeutic efficacy. Therefore, it appears that reducing the undesirable effects of NETs could serve as a novel target to enhance the therapeutic efficacy of MSCs in septic patients.
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Affiliation(s)
- Amir Hossein Aghayan
- Student Research Committee, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Yasin Mirazimi
- Student Research Committee, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Leila Nasehi
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.
- Department of Medical Laboratory Sciences, School of Paramedical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Amir Atashi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran.
- Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, Shahroud, Iran.
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Zhao X, Wang Q, Wang W, Lu S. Increased neutrophil extracellular traps caused by diet-induced obesity delay fracture healing. FASEB J 2024; 38:e70126. [PMID: 39446097 PMCID: PMC11580727 DOI: 10.1096/fj.202401523r] [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: 07/03/2024] [Revised: 09/28/2024] [Accepted: 10/09/2024] [Indexed: 10/25/2024]
Abstract
Obesity, recognized as a risk factor for nonunion, detrimentally impacts bone health, with significant physical and economic repercussions for affected individuals. Nevertheless, the precise pathomechanisms by which obesity impairs fracture healing remain insufficiently understood. Multiple studies have identified neutrophil granulocytes as key players in the systemic immune response, being the predominant immune cells in early fracture hematomas. This study identified a previously unreported critical period for neutrophil infiltration into the callus. In vivo experiments demonstrated that diet-induced obesity (DIO) mice showed earlier neutrophil infiltration, along with increased formation of neutrophil extracellular traps (NETs), compared to control mice during the endochondral phase of fracture repair. Furthermore, Padi4 knockout was found to reduce NET formation and mitigate the fracture healing delays caused by high-fat diets. Mechanistically, in vitro analyses revealed that NETs, by activating NLRP3 inflammasomes, inhibited the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and concurrently promoted M1-like macrophage polarization. These findings establish a connection between NET formation during the endochondral phase and delayed fracture healing, suggesting that targeting NETs could serve as a promising therapeutic approach for addressing obesity-induced delays in fracture recovery.
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Affiliation(s)
- Xuan Zhao
- Department of Orthopedics, Xuanwu HospitalCapital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric DiseasesBeijingChina
| | - Qijun Wang
- Department of Orthopedics, Xuanwu HospitalCapital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric DiseasesBeijingChina
| | - Wei Wang
- Department of Orthopedics, Xuanwu HospitalCapital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric DiseasesBeijingChina
| | - Shibao Lu
- Department of Orthopedics, Xuanwu HospitalCapital Medical UniversityBeijingChina
- National Clinical Research Center for Geriatric DiseasesBeijingChina
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5
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Areny-Balagueró A, Camprubí-Rimblas M, Campaña-Duel E, Solé-Porta A, Ceccato A, Roig A, Laffey JG, Closa D, Artigas A. Priming Mesenchymal Stem Cells with Lipopolysaccharide Boosts the Immunomodulatory and Regenerative Activity of Secreted Extracellular Vesicles. Pharmaceutics 2024; 16:1316. [PMID: 39458645 PMCID: PMC11510928 DOI: 10.3390/pharmaceutics16101316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/27/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been proposed as an alternative to live-cell administration for Acute Respiratory Distress Syndrome (ARDS). MSC-EVs can be chiefly influenced by the environment to which the MSCs are exposed. Here, lipopolysaccharide (LPS) priming of MSCs was used as a strategy to boost the natural therapeutic potential of the EVs in acute lung injury (ALI). Methods: The regenerative and immunemodulatory effect of LPS-primed MSC-EVs (LPS-EVs) and non-primed MSC-EVs (C-EVs) were evaluated in vitro on alveolar epithelial cells and macrophage-like THP-1 cells. In vivo, ALI was induced in adult male rats by the intrapulmonary instillation of HCl and LPS. Rats (n = 8 to 22/group) were randomized to receive a single bolus (1 × 108 particles) of LPS-EVs, C-EVs, or saline. Lung injury severity was assessed at 72 h in lung tissue and bronchoalveolar lavage. Results: In vitro, LPS-EVs improved wound regeneration and attenuated the inflammatory response triggered by the P. aeruginosa infection, enhancing the M2 macrophage phenotype. In in vivo studies, LPS-EVs, but not C-EVs, significantly decreased the neutrophilic infiltration and myeloperoxidase (MPO) activity in lung tissue. Alveolar macrophages from LPS-EVs-treated animals exhibited a reduced expression of CXCL-1, a key neutrophil chemoattractant. However, both C-EVs and LPS-EVs reduced alveolar epithelial and endothelial permeability, mitigating lung damage. Conclusions: EVs from LPS-primed MSCs resulted in a better resolution of ALI, achieving a greater balance in neutrophil infiltration and activation, while avoiding the complete disruption of the alveolar barrier. This opens new avenues, paving the way for the clinical implementation of cell-based therapies.
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Affiliation(s)
- Aina Areny-Balagueró
- Critical Care Research Center, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.C.); (A.A.)
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Marta Camprubí-Rimblas
- Critical Care Research Center, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.C.); (A.A.)
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Elena Campaña-Duel
- Critical Care Research Center, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.C.); (A.A.)
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Anna Solé-Porta
- Institut de Ciència de Materials de Barcelona, ICMAB-CSIC, Campus UAB, 08193 Bellaterra, Spain; (A.S.-P.); (A.R.)
| | - Adrián Ceccato
- Critical Care Research Center, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.C.); (A.A.)
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto de Salud Carlos III, 28029 Madrid, Spain
- Intensive Care Unit, Hospital Universitari Sagrat Cor, Grupo Quironsalud, 08029 Barcelona, Spain
| | - Anna Roig
- Institut de Ciència de Materials de Barcelona, ICMAB-CSIC, Campus UAB, 08193 Bellaterra, Spain; (A.S.-P.); (A.R.)
| | - John G. Laffey
- REMEDI, CÚRAM Centre for Medical Device Research, University of Galway, H91 TK33 Galway, Ireland;
| | - Daniel Closa
- Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain;
| | - Antonio Artigas
- Critical Care Research Center, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain; (M.C.-R.); (E.C.-D.); (A.C.); (A.A.)
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto de Salud Carlos III, 28029 Madrid, Spain
- Servei de Medicina Intensiva, Corporació Sanitària i Universitària Parc Taulí, 08208 Sabadell, Spain
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Inagawa H, Nishizawa T, Kohchi C, Soma GI. Lipopolysaccharide Derived from Pantoea agglomerans Directly Promotes the Migration of Human Keratinocytes. In Vivo 2024; 38:2172-2178. [PMID: 39187364 PMCID: PMC11363747 DOI: 10.21873/invivo.13680] [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: 06/13/2024] [Revised: 07/08/2024] [Accepted: 07/09/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND/AIM Because the skin is exposed to the external environment, it is important that wound healing processes proceed and terminate rapidly to minimize the risk of infection. A previous case report described the promotion of wound healing by transdermal administration of lipopolysaccharide derived from Pantoea agglomerans (LPSp). However, whether the wound healing-promoting effect of LPSp was due to direct activity on skin cells or indirect effects involving macrophages remained unclear. Therefore, this study investigated the wound healing-promoting effect of LPSp, particularly the promotion of keratinocyte migration. MATERIALS AND METHODS The migration of HaCaT human keratinocytes over time with and without LPSp was assayed using a cell migration assay kit. Migration was also analyzed using HaCaT cells treated with LPSp and an antibody against Toll-like receptor (TLR) 4, a receptor for LPS. RESULTS Addition of LPSp significantly enhanced cell migration compared to no LPSp addition. Migration was inhibited by the addition of anti-TLR4 antibody. CONCLUSION LPSp acts directly on epidermal cells to promote migration and may be one mechanism by which LPSp promotes wound healing.
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Affiliation(s)
- Hiroyuki Inagawa
- Control of Innate Immunity, Collaborative Innovation Partnership, Kagawa, Japan
- Macrophi Inc., Kagawa, Japan
- Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
| | | | - Chie Kohchi
- Control of Innate Immunity, Collaborative Innovation Partnership, Kagawa, Japan
- Macrophi Inc., Kagawa, Japan
| | - Gen-Ichiro Soma
- Control of Innate Immunity, Collaborative Innovation Partnership, Kagawa, Japan;
- Macrophi Inc., Kagawa, Japan
- Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
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7
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Zhao H, Kumar P, Sobreira TJP, Smith M, Novick S, Johansson A, Luchniak A, Zhang A, Woollard KJ, Larsson N, Kawatkar A. Integrated Proteomics Characterization of NLRP3 Inflammasome Inhibitor MCC950 in Monocytic Cell Line Confirms Direct MCC950 Engagement with Endogenous NLRP3. ACS Chem Biol 2024; 19:962-972. [PMID: 38509779 DOI: 10.1021/acschembio.3c00777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Abstract
Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and selective small-molecule inhibitor of the NLRP3 pathway and has been validated in numerous species and disease models. Although the capacity of MCC950 to block NLRP3 signaling is well-established, it is still critical to identify the mechanism of action and molecular targets of MCC950 to inform and derisk drug development. Quantitative proteomics performed in disease-relevant systems provides a powerful method to study both direct and indirect pharmacological responses to small molecules to elucidate the mechanism of action and confirm target engagement. A comprehensive target deconvolution campaign requires the use of complementary chemical biology techniques. Here we applied two orthogonal chemical biology techniques: compressed Cellular Thermal Shift Assay (CETSA) and photoaffinity labeling chemoproteomics, performed under biologically relevant conditions with LPS-primed THP-1 cells, thereby deconvoluting, for the first time, the molecular targets of MCC950 using chemical biology techniques. In-cell chemoproteomics with inlysate CETSA confirmed the suspected mechanism as the disruption of inflammasome formation via NLRP3. Further cCETSA (c indicates compressed) in live cells mapped the stabilization of NLRP3 inflammasome pathway proteins, highlighting modulation of the targeted pathway. This is the first evidence of direct MCC950 engagement with endogenous NLRP3 in a human macrophage cellular system using discovery proteomics chemical biology techniques, providing critical information for inflammasome studies.
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Affiliation(s)
- Heng Zhao
- Discovery Biology, Discovery Sciences, R&D, AstraZeneca, 02451 Waltham, Massachusetts, United States
| | - Praveen Kumar
- Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, 02451 Waltham, Massachusetts, United States
| | | | - Mackenzie Smith
- Discovery Biology, Discovery Sciences, R&D, AstraZeneca, 02451 Waltham, Massachusetts, United States
| | - Steven Novick
- Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, 02451 Waltham, Massachusetts, United States
| | - Anders Johansson
- Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43183 Mölndal, Sweden
| | - Anna Luchniak
- Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, 43183 Mölndal, Sweden
| | - Andrew Zhang
- Discovery Biology, Discovery Sciences, R&D, AstraZeneca, 02451 Waltham, Massachusetts, United States
| | - Kevin J Woollard
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, CB2 OAA Cambridge, U.K
| | - Niklas Larsson
- Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, 43183 Mölndal, Sweden
| | - Aarti Kawatkar
- Discovery Biology, Discovery Sciences, R&D, AstraZeneca, 02451 Waltham, Massachusetts, United States
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8
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Szűcs D, Monostori T, Miklós V, Páhi ZG, Póliska S, Kemény L, Veréb Z. Licensing effects of inflammatory factors and TLR ligands on the regenerative capacity of adipose-derived mesenchymal stem cells. Front Cell Dev Biol 2024; 12:1367242. [PMID: 38606318 PMCID: PMC11007080 DOI: 10.3389/fcell.2024.1367242] [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: 01/08/2024] [Accepted: 03/15/2024] [Indexed: 04/13/2024] Open
Abstract
Introduction: Adipose tissue-derived mesenchymal stem cells are promising contributors to regenerative medicine, exhibiting the ability to regenerate tissues and modulate the immune system, which is particularly beneficial for addressing chronic inflammatory ulcers and wounds. Despite their inherent capabilities, research suggests that pretreatment amplifies therapeutic effectiveness. Methods: Our experimental design exposed adipose-derived mesenchymal stem cells to six inflammatory factors for 24 h. We subsequently evaluated gene expression and proteome profile alterations and observed the wound closure rate post-treatment. Results: Specific pretreatments, such as IL-1β, notably demonstrated an accelerated wound-healing process. Analysis of gene and protein expression profiles revealed alterations in pathways associated with tissue regeneration. Discussion: This suggests that licensed cells exhibit potentially higher therapeutic efficiency than untreated cells, shedding light on optimizing regenerative strategies using adipose tissue-derived stem cells.
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Affiliation(s)
- Diána Szűcs
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
| | - Tamás Monostori
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
| | | | - Zoltán G. Páhi
- Genome Integrity and DNA Repair Core Group, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), University of Szeged, Szeged, Hungary
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Szilárd Póliska
- Genomic Medicine and Bioinformatics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Lajos Kemény
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
- Hungarian Centre of Excellence for Molecular Medicine-USz Skin Research Group, University of Szeged, Szeged, Hungary
| | - Zoltán Veréb
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
- Biobank, University of Szeged, Szeged, Hungary
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9
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Gao M, Guo H, Dong X, Wang Z, Yang Z, Shang Q, Wang Q. Regulation of inflammation during wound healing: the function of mesenchymal stem cells and strategies for therapeutic enhancement. Front Pharmacol 2024; 15:1345779. [PMID: 38425646 PMCID: PMC10901993 DOI: 10.3389/fphar.2024.1345779] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/05/2024] [Indexed: 03/02/2024] Open
Abstract
A wound takes a long time to heal and involves several steps. Following tissue injury, inflammation is the primary cause of tissue regeneration and repair processes. As a result, the pathophysiological processes involving skin damage, healing, and remodeling depend critically on the control of inflammation. The fact that it is a feasible target for improving the prognosis of wound healing has lately become clear. Mesenchymal stem cells (MSCs) are an innovative and effective therapeutic option for wound healing due to their immunomodulatory and paracrine properties. By controlling the inflammatory milieu of wounds through immunomodulation, transplanted MSCs have been shown to speed up the healing process. In addition to other immunomodulatory mechanisms, including handling neutrophil activity and modifying macrophage polarization, there may be modifications to the activation of T cells, natural killer (NK) cells, and dendritic cells (DCs). Furthermore, several studies have shown that pretreating MSCs improves their ability to modulate immunity. In this review, we summarize the existing knowledge about how MSCs influence local inflammation in wounds by influencing immunity to facilitate the healing process. We also provide an overview of MSCs optimizing techniques when used to treat wounds.
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Affiliation(s)
| | | | | | | | | | | | - Qiying Wang
- Department of Plastic Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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10
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Roy R, Mahmud F, Zayas J, Kuzel TM, Reiser J, Shafikhani SH. Reduced Bioactive Microbial Products (Pathogen-Associated Molecular Patterns) Contribute to Dysregulated Immune Responses and Impaired Healing in Infected Wounds in Mice with Diabetes. J Invest Dermatol 2024; 144:387-397.e11. [PMID: 37619833 PMCID: PMC10840742 DOI: 10.1016/j.jid.2023.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/11/2023] [Accepted: 08/01/2023] [Indexed: 08/26/2023]
Abstract
Diabetic chronic ulcers are plagued with persistent nonresolving inflammation. However, diabetic wound environment early after injury suffers from inadequate inflammatory responses due to reductions in proinflammatory cytokines levels. Diabetic neutrophils have known impairments in bactericidal functions. We hypothesized that reduced bacterial killing by diabetic neutrophils, due to their bactericidal functional impairments, results in reduced bioactive bacterial products, known as pathogen-associated molecular patterns, which in turn contribute to reduced signaling through toll-like receptors, leading to inadequate production of proinflammatory cytokines in infected diabetic wound early after injury. We tested our hypothesis in db/db type 2 obese diabetic mouse wound infection model with Pseudomonas aeruginosa. Our data indicate that despite substantially higher levels of infection, toll-like receptor 4-mediated signaling is reduced in diabetic wounds early after injury owing to reduced bioactive levels of lipopolysaccharide. We further demonstrate that topical treatment with lipopolysaccharide enhances toll-like receptor 4 signaling, increases proinflammatory cytokine production, restores leukocyte trafficking, reduces infection burden, and stimulates healing in diabetic wounds. We posit that lipopolysaccharide may be a viable therapeutic option for the treatment of diabetic foot ulcers if it is applied topically after the surgical debridement process, which is intended to reset chronic ulcers into acute fresh wounds.
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Affiliation(s)
- Ruchi Roy
- Division of Hematology, Oncology and Cell Therapy, Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Foyez Mahmud
- Division of Hematology, Oncology and Cell Therapy, Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Janet Zayas
- Division of Hematology, Oncology and Cell Therapy, Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA; Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois, USA
| | - Timothy M Kuzel
- Division of Hematology, Oncology and Cell Therapy, Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA; Cancer Center, Rush University Medical Center, Chicago, Illinois, USA
| | - Jochen Reiser
- Division of Hematology, Oncology and Cell Therapy, Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Sasha H Shafikhani
- Division of Hematology, Oncology and Cell Therapy, Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA; Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois, USA; Cancer Center, Rush University Medical Center, Chicago, Illinois, USA.
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Liu X, Zhou Z, Zeng WN, Zeng Q, Zhang X. The role of toll-like receptors in orchestrating osteogenic differentiation of mesenchymal stromal cells and osteoimmunology. Front Cell Dev Biol 2023; 11:1277686. [PMID: 37941898 PMCID: PMC10629627 DOI: 10.3389/fcell.2023.1277686] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/11/2023] [Indexed: 11/10/2023] Open
Abstract
Osteoimmunology is a concept involving molecular and cellular crosstalk between the skeletal and immune systems. Toll-like receptors (TLRs) are widely expressed both on mesenchymal stromal cells (MSCs), the hematopoietic cells, and immune cells in the osteogenic microenvironment for bone development or repair. TLRs can sense both exogenous pathogen-associated molecular patterns (PAMPs) derived from microorganisms, and damage-associated molecular patterns (DAMPs) derived from normal cells subjected to injury, inflammation, or cell apoptosis under physiological or pathological conditions. Emerging studies reported that TLR signaling plays an important role in bone remodeling by directly impacting MSC osteogenic differentiation or osteoimmunology. However, how to regulate TLR signaling is critical and remains to be elucidated to promote the osteogenic differentiation of MSCs and new bone formation for bone tissue repair. This review outlines distinct TLR variants on MSCs from various tissues, detailing the impact of TLR pathway activation or inhibition on MSC osteogenic differentiation. It also elucidates TLR pathways' interplay with osteoclasts, immune cells, and extracellular vesicles (EVs) derived from MSCs. Furthermore, we explore biomaterial-based activation to guide MSCs' osteogenic differentiation. Therefore, understanding TLRs' role in this context has significant implications for advancing bone regeneration and repair strategies.
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Affiliation(s)
- Xiaoyang Liu
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Zongke Zhou
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Nan Zeng
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Qin Zeng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, China
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12
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Zhu M, Cao L, Melino S, Candi E, Wang Y, Shao C, Melino G, Shi Y, Chen X. Orchestration of Mesenchymal Stem/Stromal Cells and Inflammation During Wound Healing. Stem Cells Transl Med 2023; 12:576-587. [PMID: 37487541 PMCID: PMC10502569 DOI: 10.1093/stcltm/szad043] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 06/13/2023] [Indexed: 07/26/2023] Open
Abstract
Wound healing is a complex process and encompasses a number of overlapping phases, during which coordinated inflammatory responses following tissue injury play dominant roles in triggering evolutionarily highly conserved principals governing tissue repair and regeneration. Among all nonimmune cells involved in the process, mesenchymal stem/stromal cells (MSCs) are most intensely investigated and have been shown to play fundamental roles in orchestrating wound healing and regeneration through interaction with the ordered inflammatory processes. Despite recent progress and encouraging results, an informed view of the scope of this evolutionarily conserved biological process requires a clear understanding of the dynamic interplay between MSCs and the immune systems in the process of wound healing. In this review, we outline current insights into the ways in which MSCs sense and modulate inflammation undergoing the process of wound healing, highlighting the central role of neutrophils, macrophages, and T cells during the interaction. We also draw attention to the specific effects of MSC-based therapy on different pathological wound healing. Finally, we discuss how ongoing scientific advances in MSCs could be efficiently translated into clinical strategies, focusing on the current limitations and gaps that remain to be overcome for achieving preferred functional tissue regeneration.
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Affiliation(s)
- Mengting Zhu
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Lijuan Cao
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Sonia Melino
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Shanghai, People’s Republic of China
| | - Changshun Shao
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
| | - Gerry Melino
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
| | - Xiaodong Chen
- Wuxi Sinotide New Drug Discovery Institutes, Huishan Economic and Technological Development Zone, Wuxi, Jiangsu, People’s Republic of China
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13
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Szűcs D, Miklós V, Monostori T, Guba M, Kun-Varga A, Póliska S, Kis E, Bende B, Kemény L, Veréb Z. Effect of Inflammatory Microenvironment on the Regenerative Capacity of Adipose-Derived Mesenchymal Stem Cells. Cells 2023; 12:1966. [PMID: 37566046 PMCID: PMC10416993 DOI: 10.3390/cells12151966] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/12/2023] [Accepted: 07/22/2023] [Indexed: 08/12/2023] Open
Abstract
Adipose-derived mesenchymal stem cells are increasingly being used in regenerative medicine as cell therapy targets, including in the treatment of burns and ulcers. The regenerative potential of AD-MSCs and some of their immunological properties are known from in vitro studies; however, in clinical applications, cells are used in non-ideal conditions and can behave differently in inflammatory environments, affecting the efficacy and outcome of therapy. Our aim was to investigate and map the pathways that the inflammatory microenvironment can induce in these cells. High-throughput gene expression assays were performed on AD-MSCs activated with LPS and TNFα. Analysis of RNA-Seq data showed that control, LPS-treated and TNFα-treated samples exhibited distinct gene expression patterns. LPS treatment increased the expression of 926 genes and decreased the expression of 770 genes involved in cell division, DNA repair, the cell cycle, and several metabolic processes. TNFα treatment increased the expression of 174 genes and decreased the expression of 383 genes, which are related to cell division, the immune response, cell proliferation, and differentiation. We also map the biological pathways by further investigating the most altered genes using the Gene Ontology and KEGG databases. Secreted cytokines, which are important in the immunological response, were also examined at the protein level, and a functional assay was performed to assess wound healing. Activated AD-MSC increased the secretion of IL-6, IL-8 and CXCL-10, and also the closure of wounds. AD-MSCs presented accelerated wound healing under inflammation conditions, suggesting that we could use this cell in clinical application.
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Affiliation(s)
- Diána Szűcs
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
- Doctoral School of Clinical Medicine, University of Szeged, 6720 Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary
| | - Vanda Miklós
- Biobank, University of Szeged, 6720 Szeged, Hungary;
| | - Tamás Monostori
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary
| | - Melinda Guba
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary
| | - Anikó Kun-Varga
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
| | - Szilárd Póliska
- Genomic Medicine and Bioinformatics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary;
| | - Erika Kis
- Dermatosurgery and Plastic Surgery, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (E.K.); (B.B.)
| | - Balázs Bende
- Dermatosurgery and Plastic Surgery, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (E.K.); (B.B.)
| | - Lajos Kemény
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary
- Hungarian Centre of Excellence for Molecular Medicine-USz Skin Research Group, University of Szeged, 6720 Szeged, Hungary
| | - Zoltán Veréb
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (D.S.); (T.M.); (M.G.); (A.K.-V.); (L.K.)
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, 6720 Szeged, Hungary
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de Castro Roston JR, Reis IB, Luzo ÂCM, Roston MO, Durán N, Fávaro WJ. Evaluation of the tissue repair process and immunomodulatory action of Platelet-Rich Plasma (PRP) in the treatment of abdominal stretch marks. Tissue Cell 2023; 83:102132. [PMID: 37331321 DOI: 10.1016/j.tice.2023.102132] [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: 03/27/2023] [Revised: 06/01/2023] [Accepted: 06/08/2023] [Indexed: 06/20/2023]
Abstract
The aims of this study were to characterize and to compare the structural alterations of collagen and elastic fibers in the abdominal stretch marks of patients submitted to intralesional and per quadrant (region close to stretch marks) Platelet-Rich Plasma (PRP) treatment, as well as, to establish the possible mechanisms of action of this treatment involving toll-like receptors (TLRs) signaling pathways and growth factors. Incisional biopsies were collected from abdominal stretch marks with a 2 mm diameter punch in female patients, at the beginning of treatment, after 6 and 12 weeks of treatment, and submitted to morphological analyzes of elastic and collagen fibers, and immunohistochemistry for TLRs signaling pathways and growth factors. Our results demonstrated PRP per quadrant treatment was most effective in reducing the area of the abdominal stretch marks, with consequent stimulation of the synthesis and remodeling of collagen and elastic fibers. Also, PRP per quadrant treatment promoted an increase in TLR2 and TLR4 immunoreactivities, with consequent increase in TNF-α, VEGF and IGF-1. Based on the current findings, PRP constitutes a promising therapeutic approach in patients with stretch marks, since it promoted modulation of inflammatory cytokines and growth factors, with consequent remodeling of extracellular matrix, culminating with tissue improvement.
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Affiliation(s)
- José Ronaldo de Castro Roston
- Center of Immunotherapy and Inflammatory Diseases (CIDI), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil; Hospital Municipal "Dr. Mário Gatti", Department of Plastic Surgery, Campinas, São Paulo, Brazil.
| | - Ianny Brum Reis
- Center of Immunotherapy and Inflammatory Diseases (CIDI), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | | | - Milena Olivieri Roston
- Center of Immunotherapy and Inflammatory Diseases (CIDI), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Nelson Durán
- Center of Immunotherapy and Inflammatory Diseases (CIDI), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Wagner José Fávaro
- Center of Immunotherapy and Inflammatory Diseases (CIDI), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
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15
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Dixit K, Bora H, Lakshmi Parimi J, Mukherjee G, Dhara S. Biomaterial mediated immunomodulation: An interplay of material environment interaction for ameliorating wound regeneration. J Biomater Appl 2023; 37:1509-1528. [PMID: 37069479 DOI: 10.1177/08853282231156484] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Abstract
Chronic wounds are the outcome of an imbalanced inflammatory response caused by sustenance of immune microenvironment. In this context, tissue engineered graft played great role in healing wounds but faced difficulty in scar remodelling, immune rejection and poor vascularization. All the limitations faced are somewhere linked with the immune cells involved in healing. In this consideration, immunomodulatory biomaterials bridge a large gap with the delivery of modulating factors for triggering key inflammatory cells responsible towards interplay in the wound micro-environment. Inherent physico-chemical properties of biomaterials substantially determine the nature of cell-materials interaction thereby facilitating differential cytokine gradient involved in activation or suppression of inflammatory signalling pathways, and followed by surface marker expression. This review aims to systematically describe the interplay of immune cells involved in different phases in the wound microenvironment and biomaterials. Additionally, it also focuses on modulating innate immune cell responses in the context of triggering the halted phase of the wound healing, i.e., inflammatory phase. The various strategies are highlighted for modulation of wound microenvironment towards wound regeneration including stem cells, cytokines, growth factors, vitamins, and anti-inflammatory agents to induce interactive ability of biomaterials with immune cells. The last section focuses on prospective approaches and current potential strategies for wound regeneration. This includes the development of different models to bridge the gap between mouse models and human patients. Emerging new tools to study inflammatory response owing to biomaterials and novel strategies for modulation of monocyte and macrophage behaviour in the wound environment are also discussed.
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Affiliation(s)
- Krishna Dixit
- Biomaterials and Tissue Engineering Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
- Immunology and Inflammation Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Hema Bora
- Biomaterials and Tissue Engineering Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Jhansi Lakshmi Parimi
- Biomaterials and Tissue Engineering Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Gayatri Mukherjee
- Immunology and Inflammation Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Santanu Dhara
- Biomaterials and Tissue Engineering Laboratory, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
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16
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Xenogeneic mesenchymal stem cell biocurative improves skin wounds healing in diabetic mice by increasing mast cells and the regenerative profile. Regen Ther 2023; 22:79-89. [PMID: 36712958 PMCID: PMC9841355 DOI: 10.1016/j.reth.2022.12.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/19/2022] [Accepted: 12/22/2022] [Indexed: 01/11/2023] Open
Abstract
Introduction Diabetes mellitus (DM) is a chronic disease and a major cause of mortality and morbidity worldwide. The hyperglycemia caused by DM induces micro and macrovascular complications that lead, among other consequences, to chronic wounds and amputations. Cell therapy and tissue engineering constitute recent therapeutic alternatives to improve wound healing in diabetic patients. The current study aimed to analyze the effectiveness of biocuratives containing human mesenchymal stem cells (MSCs) associated with a hydrogel matrix in the wound healing process and related inflammatory cell profile in diabetic mice. Methods Biocuratives containing MSCs were constructed by 3D bioprinting, and applied to skin wounds on the back of streptozotocin (STZ)-induced type 1 diabetic (T1D) mice. The healing process, after the application of biocuratives with or without MSCs was histologically analyzed. In parallel, genes related to growth factors, mast cells (MC), M1 and M2 macrophage profiles were evaluated by RT-PCR. Macrophages were characterized by flow cytometry, and MC by toluidine blue staining and flow cytometry. Results Mice with T1D exhibited fewer skin MC and delayed wound healing when compared to the non-diabetic group. Treatment with the biocuratives containing MSCs accelerated wound healing and improved skin collagen deposition in diabetic mice. Increased TGF-β gene expression and M2 macrophage-related markers were also detected in skin of diabetic mice that received MSCs-containing biocuratives. Finally, MSCs upregulated IL-33 gene expression and augmented the number of MC in the skin of diabetic mice. Conclusion These results reveal the therapeutic potential of biocuratives containing MSCs in the healing of skin wounds in diabetic mice, providing a scientific base for future treatments in diabetic patients.
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17
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Niebergall-Roth E, Frank NY, Ganss C, Frank MH, Kluth MA. Skin-Derived ABCB5 + Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine. Int J Mol Sci 2022; 24:66. [PMID: 36613507 PMCID: PMC9820160 DOI: 10.3390/ijms24010066] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/16/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
The ATP-binding cassette superfamily member ABCB5 identifies a subset of skin-resident mesenchymal stem cells (MSCs) that exhibit potent immunomodulatory and wound healing-promoting capacities along with superior homing ability. The ABCB5+ MSCs can be easily accessed from discarded skin samples, expanded, and delivered as a highly homogenous medicinal product with standardized potency. A range of preclinical studies has suggested therapeutic efficacy of ABCB5+ MSCs in a variety of currently uncurable skin and non-skin inflammatory diseases, which has been substantiated thus far by distinct clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. Therefore, skin-derived ABCB5+ MSCs have the potential to provide a breakthrough at the forefront of MSC-based therapies striving to fulfill current unmet medical needs. The most recent milestones in this regard are the approval of a phase III pivotal trial of ABCB5+ MSCs for treatment of recessive dystrophic and junctional epidermolysis bullosa by the US Food and Drug Administration, and national market access of ABCB5+ MSCs (AMESANAR®) for therapy-refractory chronic venous ulcers under the national hospital exemption pathway in Germany.
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Affiliation(s)
| | - Natasha Y. Frank
- Department of Medicine, VA Boston Healthcare System, Boston, MA 02132, USA
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Christoph Ganss
- TICEBA GmbH, 69120 Heidelberg, Germany
- RHEACELL GmbH & Co. KG, 69120 Heidelberg, Germany
| | - Markus H. Frank
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- School of Medical and Health Sciences, Edith Cowan University, Perth 6027, Australia
| | - Mark A. Kluth
- TICEBA GmbH, 69120 Heidelberg, Germany
- RHEACELL GmbH & Co. KG, 69120 Heidelberg, Germany
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18
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Linnemann C, Nussler AK, Histing T, Ehnert S. Febrile-Range Hyperthermia Can Prevent Toxic Effects of Neutrophil Extracellular Traps on Mesenchymal Stem Cells. Int J Mol Sci 2022; 23:16208. [PMID: 36555846 PMCID: PMC9786713 DOI: 10.3390/ijms232416208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/30/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Fracture healing is characterized by an inflammatory phase directly after fracture which has a strong impact on the healing outcome. Neutrophils are strong contributors here and can release neutrophil extracellular traps (NETs). NETs are found after trauma, originally thought to capture pathogens. However, they can lead to tissue damage and impede wound healing processes. Their role in fracture healing remains unclear. In this study, the effect of isolated NETs on the function of bone-forming mesenchymal stem cells (SCP-1 cells) was examined. NETs were isolated from stimulated healthy neutrophils and viability, migration, and differentiation of SCP-1 cells were analyzed after the addition of NETs. NETs severely impaired the viability of SCP-1 cells, induced necrosis and already nontoxic concentrations reduced migration significantly. Short-term incubation with NETs had a persistent negative effect on osteogenic differentiation, as measured by AP activity and matrix formation. The addition of DNase or protease inhibitors failed to reverse the negative effect of NETs, whereas a short febrile-range temperature treatment successfully reduced the toxicity and membrane destruction. Thus, the possible modification of the negative effects of NETs in fracture hematomas could be an interesting new target to improve bone healing, particularly in patients with chronic diseases such as diabetes.
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Affiliation(s)
| | | | | | - Sabrina Ehnert
- Siegfried Weller Institute for Trauma Research, BG Unfallklinik Tübingen, Eberhard Karls Universität Tuebingen, 72076 Tuebingen, Germany
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19
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Wang Y, Fang J, Liu B, Shao C, Shi Y. Reciprocal regulation of mesenchymal stem cells and immune responses. Cell Stem Cell 2022; 29:1515-1530. [DOI: 10.1016/j.stem.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/19/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022]
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Sarsenova M, Kim Y, Raziyeva K, Kazybay B, Ogay V, Saparov A. Recent advances to enhance the immunomodulatory potential of mesenchymal stem cells. Front Immunol 2022; 13:1010399. [PMID: 36211399 PMCID: PMC9537745 DOI: 10.3389/fimmu.2022.1010399] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/07/2022] [Indexed: 11/19/2022] Open
Abstract
Considering the unique therapeutic potential of mesenchymal stem cells (MSCs), including their immunosuppressive and immunomodulatory properties as well as their ability to improve tissue regeneration, these cells have attracted the attention of scientists and clinicians for the treatment of different inflammatory and immune system mediated disorders. However, various clinical trials using MSCs for the therapeutic purpose are conflicting and differ from the results of promising preclinical studies. This inconsistency is caused by several factors such as poor migration and homing capacities, low survival rate, low level of proliferation and differentiation, and donor-dependent variation of the cells. Enhancement and retention of persistent therapeutic effects of the cells remain a challenge to overcome in MSC-based therapy. In this review, we summarized various approaches to enhance the clinical outcomes of MSC-based therapy as well as revised current and future perspectives for the creation of cellular products with improved potential for diverse clinical applications.
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Affiliation(s)
- Madina Sarsenova
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Yevgeniy Kim
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Kamila Raziyeva
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Bexultan Kazybay
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Vyacheslav Ogay
- Laboratory of Stem Cells, National Center for Biotechnology, Nur-Sultan, Kazakhstan
| | - Arman Saparov
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
- *Correspondence: Arman Saparov,
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Yuan Q, Zhao B, Cao YH, Yan JC, Sun LJ, Liu X, Xu Y, Wang XY, Wang B. BCR-Associated Protein 31 Regulates Macrophages Polarization and Wound Healing Function via Early Growth Response 2/C/EBPβ and IL-4Rα/C/EBPβ Pathways. THE JOURNAL OF IMMUNOLOGY 2022; 209:1059-1070. [DOI: 10.4049/jimmunol.2200044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 07/11/2022] [Indexed: 01/04/2023]
Abstract
Abstract
The BCR-associated protein 31 (BAP31), a transmembrane protein in the endoplasmic reticulum, participates in the regulation of immune cells, such as microglia and T cells, and has potential functions in macrophages that remain to be unexplored. In this study, we designed and bred macrophage-specific BAP31 knockdown mice to detect the polarization and functions of macrophages. The results revealed that M2 macrophage-associated genes were suppressed in mouse bone marrow–derived macrophages of Lyz2 Cre-BAP31flox/flox mice. Multiple macrophage-associated transcription factors were demonstrated to be able to be regulated by BAP31. Among these factors, C/EBPβ was the most significantly decreased and was regulated by early growth response 2. BAP31 could also affect C/EBPβ via modulating IL-4Rα ubiquitination and proteasome degradation in IL-4–stimulated macrophages. Furthermore, we found that BAP31 affects macrophages functions, including angiogenesis and skin fibrosis, during the wound healing process through IL-4Rα, as confirmed by infection with adeno-associated virus–short hairpin (sh)-IL-4Rα in Lyz2 Cre-BAP31flox/flox mice. Our findings indicate a novel mechanism of BAP31 in regulating macrophages and provide potential solutions for the prevention and treatment of chronic wounds.
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Affiliation(s)
- Qing Yuan
- College of Life Science and Health, Northeastern University, Hunnan Xinqu, Shenyang, Liaoning, China
| | - Bo Zhao
- College of Life Science and Health, Northeastern University, Hunnan Xinqu, Shenyang, Liaoning, China
| | - Yu-hua Cao
- College of Life Science and Health, Northeastern University, Hunnan Xinqu, Shenyang, Liaoning, China
| | - Jia-cheng Yan
- College of Life Science and Health, Northeastern University, Hunnan Xinqu, Shenyang, Liaoning, China
| | - Li-jun Sun
- College of Life Science and Health, Northeastern University, Hunnan Xinqu, Shenyang, Liaoning, China
| | - Xia Liu
- College of Life Science and Health, Northeastern University, Hunnan Xinqu, Shenyang, Liaoning, China
| | - Yang Xu
- College of Life Science and Health, Northeastern University, Hunnan Xinqu, Shenyang, Liaoning, China
| | - Xiao-yu Wang
- College of Life Science and Health, Northeastern University, Hunnan Xinqu, Shenyang, Liaoning, China
| | - Bing Wang
- College of Life Science and Health, Northeastern University, Hunnan Xinqu, Shenyang, Liaoning, China
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22
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Vadakke‐Madathil S, Chaudhry HW. Concepts of Cell Therapy and Myocardial Regeneration. Interv Cardiol 2022. [DOI: 10.1002/9781119697367.ch30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
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Liu Y, Zhang X, Chen S, Wang J, Yu S, Li Y, Xu M, Aboubacar H, Li J, Shan T, Wang J, Cao G. Gut-derived lipopolysaccharide promotes alcoholic hepatosteatosis and subsequent hepatocellular carcinoma by stimulating neutrophil extracellular traps through TLR4. Clin Mol Hepatol 2022; 28:522-539. [PMID: 35508957 PMCID: PMC9293619 DOI: 10.3350/cmh.2022.0039] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 05/01/2022] [Indexed: 11/23/2022] Open
Abstract
Background/Aims Binge drinking leads to many disorders, including alcoholic hepatosteatosis, which is characterized by intrahepatic neutrophil infiltration and increases the risk of hepatocellular carcinoma (HCC). Molecular mechanisms may involve the migration of bacterial metabolites from the gut to the liver and the activation of neutrophil extracellular traps (NETs). Methods Serum samples from both binge drinking and alcohol-avoiding patients were analyzed. Mouse models of chronic plus binge alcohol-induced hepatosteatosis and HCC models were used. Results A marker of NETs formation, lipopolysaccharide (LPS), was significantly higher in alcoholic hepatosteatosis and HCC patients and mice than in controls. Intrahepatic inflammation markers and HCC-related cytokines were decreased in mice with reduced NET formation due to neutrophil elastase (NE) deletion, and liver-related symptoms of alcohol were also alleviated in NE knockout mice. Removal of intestinal bacteria with antibiotics led to decreases in markers of NETs formation and inflammatory cytokines upon chronic alcohol consumption, and development of alcoholic hepatosteatosis and HCC was also attenuated. These functions were restored upon supplementation with the bacterial product LPS. When mice lacking toll-like receptor 4 (TLR4) received chronic alcohol feeding, intrahepatic markers of NETs formation decreased, and hepatosteatosis and HCC were alleviated. Conclusions Formation of NETs following LPS stimulation of TLR4 upon chronic alcohol use leads to increased alcoholic steatosis and subsequent HCC.
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Affiliation(s)
- Yang Liu
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Xin Zhang
- Department of Infectious Diseases, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Shuo Chen
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Jiazhong Wang
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Shuo Yu
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China.,Bioinspired Engineering and Biomechanics Center, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Yiming Li
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Meng Xu
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Harouna Aboubacar
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Junhui Li
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Tao Shan
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Jixin Wang
- Department of Infectious Diseases, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Gang Cao
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
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Rippon MG, Westgate S, Rogers AA. Implications of endotoxins in wound healing: a narrative review. J Wound Care 2022; 31:380-392. [PMID: 35579309 DOI: 10.12968/jowc.2022.31.5.380] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Bacterial toxins are thought to play a role in delayed wound healing in critically colonised and infected wounds. Endotoxins are released from Gram-negative bacteria when they are lysed by host phagocytic cells during an immune response, or by antimicrobial agents, potentially leading to a detrimental effect on the host tissues. Endotoxins can affect all aspects of the wound healing process, leading to delayed healing and contributing to wound chronicity. Release of endotoxins by bacteria can also have serious systemic effects (for example, septic shock) that can lead to high levels of patient mortality. This review summarises the role and implications on wound healing of bacterial endotoxins, describing the impact of endotoxins on the various phases of the wound healing response. There is a paucity of in vivo/clinical evidence linking endotoxins attributed to a wound (via antibiotic treatment) or their release from infecting bacteria with parameters of delayed wound healing. Future work should investigate if this link is apparent and determine the mechanism(s) by which such detrimental effects occur, offering an opportunity to identify possible treatment pathways. This paper describes the phenomenon of antimicrobial-induced endotoxin release and summarises the use of wound dressings to reduce wound bioburden without inducing microbial death and subsequent release of endotoxins, thus limiting their detrimental effects.
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Affiliation(s)
- Mark G Rippon
- University of Huddersfield, Queensgate, Huddersfield, UK
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Zhang Z, Nie P, Yang W, Ma X, Chen Z, Wei H. Lipopolysaccharide-preconditioned allogeneic adipose-derived stem cells improve erectile function in a rat model of bilateral cavernous nerve injury. Basic Clin Androl 2022; 32:5. [PMID: 35337262 PMCID: PMC8953072 DOI: 10.1186/s12610-022-00156-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 02/26/2022] [Indexed: 01/15/2023] Open
Abstract
Background Erectile dysfunction (ED) often occurs due to cavernous nerve injury (CNI) after colorectal surgery. Cell-based therapies have great potential for the treatment of CNI-related ED; however, it needs to be optimised. In this study, we explored the therapeutic effects of lipopolysaccharide-preconditioned allogeneic adipose-derived stem cells (L-ADSCs) on CNI-induced ED in rats. Results The results of this in vitro study revealed that low-dose lipopolysaccharide could increase the viability of ADSCs, inhibit caspase 3 activation induced by hydrogen peroxide and promote cell migration. Compared with the ADSC supernatant, the L-ADSC supernatant could better reduce fibrosis in the corpus cavernosum smooth muscle cells induced by transforming growth factor-beta 1 protein. In the in vivo study, it was compared to ADSCs therapy, where the L-ADSCs therapy indicated that could better improve erectile function by increasing smooth muscle content and alleviating penile fibrosis in rats 2 weeks after CNI. The outcome may be related to the increase in the hepatocyte growth factor content in the corpus cavernosum and myelin basic protein in the major pelvic ganglion. Conclusions L-ADSC treatment may be a promising approach for restoring erectile function after CNI. Supplementary Information The online version contains supplementary material available at 10.1186/s12610-022-00156-w.
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Affiliation(s)
- Zhenbin Zhang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
| | - Pan Nie
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
| | - Wende Yang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
| | - Xiaolei Ma
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
| | - Zehong Chen
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China
| | - Hongbo Wei
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China.
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Upregulation of CD14 in mesenchymal stromal cells accelerates lipopolysaccharide-induced response and enhances antibacterial properties. iScience 2022; 25:103759. [PMID: 35141503 PMCID: PMC8814754 DOI: 10.1016/j.isci.2022.103759] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 08/04/2021] [Accepted: 01/07/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have broad-ranging therapeutic properties, including the ability to inhibit bacterial growth and resolve infection. However, the genetic mechanisms regulating these antibacterial properties in MSCs are largely unknown. Here, we utilized a systems-based approach to compare MSCs from different genetic backgrounds that displayed differences in antibacterial activity. Although both MSCs satisfied traditional MSC-defining criteria, comparative transcriptomics and quantitative membrane proteomics revealed two unique molecular profiles. The antibacterial MSCs responded rapidly to bacterial lipopolysaccharide (LPS) and had elevated levels of the LPS co-receptor CD14. CRISPR-mediated overexpression of endogenous CD14 in MSCs resulted in faster LPS response and enhanced antibacterial activity. Single-cell RNA sequencing of CD14-upregulated MSCs revealed a shift in transcriptional ground state and a more uniform LPS-induced response. Our results highlight the impact of genetic background on MSC phenotypic diversity and demonstrate that overexpression of CD14 can prime these cells to be more responsive to bacterial challenge.
MSCs from different genetic backgrounds have distinct responses to bacteria Upregulating CD14 in MSCs enhances LPS-induced response and antibacterial traits CD14 upregulation homogenizes MSC transcriptional profiles across individual cells
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27
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Huang Y, Liu Q, Liu L, Huo F, Guo S, Tian W. Lipopolysaccharide-Preconditioned Dental Follicle Stem Cells Derived Small Extracellular Vesicles Treating Periodontitis via Reactive Oxygen Species/Mitogen-Activated Protein Kinase Signaling-Mediated Antioxidant Effect. Int J Nanomedicine 2022; 17:799-819. [PMID: 35228798 PMCID: PMC8882029 DOI: 10.2147/ijn.s350869] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 01/29/2022] [Indexed: 12/23/2022] Open
Abstract
Purpose Lipopolysaccharide (LPS) pretreatment can enhance the therapeutic effect of dental follicle stem cells-derived small extracellular vesicles (DFC-sEV) for periodontitis, and this study aimed to investigate the underlying mechanisms and clinical application Of LPS-preconditioned DFC-sEV in periodontitis. Methods The protein spectrum of DFC-sEV before and after LPS pretreatment was determined by liquid chromatography-tandem mass spectrometry and bioinformatic analysis. Their effects on inflammatory periodontal ligament stem cells (PDLSCs) and macrophages were investigated for cell proliferation, migration, type 2 macrophage (M2) polarization, and intracellular reactive oxygen species (ROS) levels separately. In addition, the regulation of ROS/Jun amino-terminal kinases (JNK) and ROS/extracellular signal-related kinases (ERK) signaling by LPS-preconditioned DFC-sEV was also studied to reveal the antioxidant mechanism. In vivo, two kinds of DFC-sEV loaded with 0.2% hyaluronic acid (HA) gel were applied for canine periodontitis to evaluate the therapeutic potential. Results The proteomic analysis showed that thirty-eight proteins were differentially expressed in LPS-preconditioned DFC-sEV, and interestingly, the highly expressed proteins were mainly involved in antioxidant and enzyme-regulating activities. In addition to promoting PDLSCs and macrophage proliferation, LPS-preconditioned DFC-sEV inhibited intracellular ROS as an antioxidant. It reduced the RANKL/OPG ratio of PDLSCs by inhibiting ROS/JNK signaling under inflammatory conditions and promoted macrophages to polarize toward the M2 phenotype via ROS/ERK signaling. Furthermore, LPS-preconditioned DFC-sEV loaded with the HA injectable system could sustainably release sEV and enhance the therapeutic efficacy for periodontitis in canines. Conclusion LPS-preconditioned DFC-sEV could be effectively used as an auxiliary method for periodontitis treatment via antioxidant effects in a subgingival environment, and loading it with HA is feasible and effective for clinical applications.
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Affiliation(s)
- Yanli Huang
- State Key Laboratory of Oral Disease & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Qian Liu
- State Key Laboratory of Oral Disease & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
- Department of Periodontics, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Li Liu
- State Key Laboratory of Oral Disease & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
- Department of Periodontics, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Fangjun Huo
- State Key Laboratory of Oral Disease & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Shujuan Guo
- State Key Laboratory of Oral Disease & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
- Department of Periodontics, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
- Correspondence: Shujuan Guo; Weidong Tian, Tel/Fax +86 028 8550 3499, Email ;
| | - Weidong Tian
- State Key Laboratory of Oral Disease & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
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Wu X, Jin S, Ding C, Wang Y, He D, Liu Y. Mesenchymal Stem Cell-Derived Exosome Therapy of Microbial Diseases: From Bench to Bed. Front Microbiol 2022; 12:804813. [PMID: 35046923 PMCID: PMC8761948 DOI: 10.3389/fmicb.2021.804813] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022] Open
Abstract
Microbial diseases are a global health threat, leading to tremendous casualties and economic losses. The strategy to treat microbial diseases falls into two broad categories: pathogen-directed therapy (PDT) and host-directed therapy (HDT). As the typical PDT, antibiotics or antiviral drugs directly attack bacteria or viruses through discerning specific molecules. However, drug abuse could result in antimicrobial resistance and increase infectious disease morbidity. Recently, the exosome therapy, as a HDT, has attracted extensive attentions for its potential in limiting infectious complications and targeted drug delivery. Mesenchymal stem cell-derived exosomes (MSC-Exos) are the most broadly investigated. In this review, we mainly focus on the development and recent advances of the application of MSC-Exos on microbial diseases. The review starts with the difficulties and current strategies in antimicrobial treatments, followed by a comprehensive overview of exosomes in aspect of isolation, identification, contents, and applications. Then, the underlying mechanisms of the MSC-Exo therapy in microbial diseases are discussed in depth, mainly including immunomodulation, repression of excessive inflammation, and promotion of tissue regeneration. In addition, we highlight the latest progress in the clinical translation of the MSC-Exo therapy, by summarizing related clinical trials, routes of administration, and exosome modifications. This review will provide fundamental insights and future perspectives on MSC-Exo therapy in microbial diseases from bench to bedside.
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Affiliation(s)
| | | | | | | | | | - Yan Liu
- Laboratory of Biomimetic Nanomaterials, Department of Orthodontics, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology and Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health and NMPA Key Laboratory for Dental Materials, Beijing, China
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29
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Malhotra P, Shukla M, Meena P, Kakkar A, Khatri N, Nagar RK, Kumar M, Saraswat SK, Shrivastava S, Datt R, Pandey S. Mesenchymal stem cells are prospective novel off-the-shelf wound management tools. Drug Deliv Transl Res 2022; 12:79-104. [PMID: 33580481 DOI: 10.1007/s13346-021-00925-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2021] [Indexed: 12/12/2022]
Abstract
Chronic/non-healing cutaneous wounds pose a debilitating burden on patients and healthcare system. Presently, treatment modalities are rapidly shifting pace from conventional methods to advanced wound care involving cell-based therapies. Mesenchymal stem cells (MSCs) have come across as a prospective option due to its pleiotropic functions viz. non-immunogenicity, multipotency, multi-lineage plasticity and secretion of growth factors, cytokines, microRNAs (miRNA), exosomes, and microvesicles as part of their secretome for assisting wound healing. We outline the therapeutic role played by MSCs and its secretome in suppressing tissue inflammation, causing immunomodulation, aiding angiogenesis and assisting in scar-free wound healing. We further assess the mechanism of action by which MSCs contribute in manifesting tissue repair. The review flows ahead in exploring factors that influence healing behavior including effect of multiple donor sites, donor age and health status, tissue microenvironment, and in vitro expansion capability. Moving ahead, we overview the advancements achieved in extending the lifespan of cells upon implantation, influence of genetic modifications aimed at altering MSC cargo, and evaluating bioengineered matrix-assisted delivery methods toward faster healing in preclinical and clinical models. We also contribute toward highlighting the challenges faced in commercializing cell-based therapies as standard of care treatment regimens. Finally, we strongly advocate and highlight its application as a futuristic technology for revolutionizing tissue regeneration.
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Affiliation(s)
- Poonam Malhotra
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India
| | - Manish Shukla
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India
| | - Poonam Meena
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India
| | - Anupama Kakkar
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India
| | - Nitin Khatri
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India
| | - Rakesh K Nagar
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India
| | - Mukesh Kumar
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India
| | - Sumit K Saraswat
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India
| | - Supriya Shrivastava
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India
| | - Rajan Datt
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India
| | - Siddharth Pandey
- Department of Life Sciences, Datt Mediproducts Private Ltd, Roz Ka Meo Industrial Area, Distt. Mewat, Nuh, 122103, Haryana, India.
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Chapman PA, Gilbert CB, Devine TJ, Hudson DT, Ward J, Morgan XC, Beck CW. Manipulating the microbiome alters regenerative outcomes in Xenopus laevis tadpoles via lipopolysaccharide signalling. Wound Repair Regen 2022; 30:636-651. [PMID: 35212086 PMCID: PMC9790228 DOI: 10.1111/wrr.13003] [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: 12/03/2021] [Revised: 01/23/2022] [Accepted: 01/28/2022] [Indexed: 12/30/2022]
Abstract
Xenopus laevis tadpoles can regenerate functional tails, containing the spinal cord, notochord, muscle, fin, blood vessels and nerves, except for a brief refractory period at around 1 week of age. At this stage, amputation of the tadpole's tail may either result in scarless wound healing or the activation of a regeneration programme, which replaces the lost tissues. We recently demonstrated a link between bacterial lipopolysaccharides and successful tail regeneration in refractory stage tadpoles and proposed that this could result from lipopolysaccharides binding to Toll-like receptor 4 (TLR4). Here, we have used 16S rRNA sequencing to show that the tadpole skin microbiome is highly variable between sibships and that the community can be altered by raising embryos in the antibiotic gentamicin. Six Gram-negative genera, including Delftia and Chryseobacterium, were over-represented in tadpoles that underwent tail regeneration. Lipopolysaccharides purified from a commensal Chryseobacterium spp. XDS4, an exogenous Delftia spp. or Escherichia coli, could significantly increase the number of antibiotic-raised tadpoles that attempted regeneration. Conversely, the quality of regeneration was impaired in native-raised tadpoles exposed to the antagonistic lipopolysaccharide of Rhodobacter sphaeroides. Editing TLR4 using CRISPR/Cas9 also reduced regeneration quality, but not quantity, at the level of the cohort. However, we found that the editing level of individual tadpoles was a poor predictor of regenerative outcome. In conclusion, our results suggest that variable regeneration in refractory stage tadpoles depends at least in part on the skin microbiome and lipopolysaccharide signalling, but that signalling via TLR4 cannot account for all of this effect.
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Affiliation(s)
| | | | - Thomas J. Devine
- Department of Microbiology and ImmunologyUniversity of OtagoDunedinNew Zealand
| | - Daniel T. Hudson
- Department of ZoologyUniversity of OtagoDunedinNew Zealand,Department of Microbiology and ImmunologyUniversity of OtagoDunedinNew Zealand
| | - Joanna Ward
- Department of ZoologyUniversity of OtagoDunedinNew Zealand
| | - Xochitl C. Morgan
- Department of Microbiology and ImmunologyUniversity of OtagoDunedinNew Zealand
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Modulation of Mesenchymal Stem Cells for Enhanced Therapeutic Utility in Ischemic Vascular Diseases. Int J Mol Sci 2021; 23:ijms23010249. [PMID: 35008675 PMCID: PMC8745455 DOI: 10.3390/ijms23010249] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells are multipotent stem cells isolated from various tissue sources, including but not limited to bone marrow, adipose, umbilical cord, and Wharton Jelly. Although cell-mediated mechanisms have been reported, the therapeutic effect of MSCs is now recognized to be primarily mediated via paracrine effects through the secretion of bioactive molecules, known as the “secretome”. The regenerative benefit of the secretome has been attributed to trophic factors and cytokines that play neuroprotective, anti-angiogenic/pro-angiogenic, anti-inflammatory, and immune-modulatory roles. The advancement of autologous MSCs therapy can be hindered when introduced back into a hostile/disease environment. Barriers include impaired endogenous MSCs function, limited post-transplantation cell viability, and altered immune-modulatory efficiency. Although secretome-based therapeutics have gained popularity, many translational hurdles, including the heterogeneity of MSCs, limited proliferation potential, and the complex nature of the secretome, have impeded the progress. This review will discuss the experimental and clinical impact of restoring the functional capabilities of MSCs prior to transplantation and the progress in secretome therapies involving extracellular vesicles. Modulation and utilization of MSCs–secretome are most likely to serve as an effective strategy for promoting their ultimate success as therapeutic modulators.
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32
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Marofi F, Alexandrovna KI, Margiana R, Bahramali M, Suksatan W, Abdelbasset WK, Chupradit S, Nasimi M, Maashi MS. MSCs and their exosomes: a rapidly evolving approach in the context of cutaneous wounds therapy. Stem Cell Res Ther 2021; 12:597. [PMID: 34863308 PMCID: PMC8642895 DOI: 10.1186/s13287-021-02662-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/14/2021] [Indexed: 12/18/2022] Open
Abstract
Currently, mesenchymal stem/stromal stem cell (MSC) therapy has become a promising option for accelerating cutaneous wound healing. In vivo reports have outlined the robust competences of MSCs to offer a solid milieu by inhibition of inflammatory reactions, which in turn, enables skin regeneration. Further, due to their great potential to stimulate angiogenesis and also facilitate matrix remodeling, MSCs hold substantial potential as future therapeutic strategies in this context. The MSCs-induced wound healing is thought to mainly rely on the secretion of a myriad of paracrine factors in addition to their direct differentiation to skin-resident cells. Besides, MSCs-derived exosomes as nanoscale and closed membrane vesicles have recently been suggested as an effective and cell-free approach to support skin regeneration, circumventing the concerns respecting direct application of MSCs. The MSCs-derived exosomes comprise molecular components including lipid, proteins, DNA, microRNA, and also mRNA, which target molecular pathways and also biological activities in recipient cells (e.g., endothelial cell, keratinocyte, and fibroblast). The secreted exosome modifies macrophage activation, stimulates angiogenesis, and instigates keratinocytes and dermal fibroblast proliferations as well as migrations concurrently regulate inherent potential of myofibroblast for adjustment of turnover of the ECM. In the present review, we will focus on the recent findings concerning the application of MSCs and their derivative exosome to support wound healing and skin regeneration, with special focus on last decade in vivo reports.
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Affiliation(s)
- Faroogh Marofi
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Master’s Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Mahta Bahramali
- Biotechnology Department, University of Tehran, Tehran, Iran
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, 10210 Thailand
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Supat Chupradit
- Department of Occupational Therapy, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200 Thailand
| | | | - Marwah Suliman Maashi
- Stem Cells and Regenerative Medicine Unit at King Fahad Medical Research Centre, Jeddah, Saudi Arabia
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Infante A, Rodríguez CI. Cell and Cell-Free Therapies to Counteract Human Premature and Physiological Aging: MSCs Come to Light. J Pers Med 2021; 11:1043. [PMID: 34683184 PMCID: PMC8541473 DOI: 10.3390/jpm11101043] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022] Open
Abstract
The progressive loss of the regenerative potential of tissues is one of the most obvious consequences of aging, driven by altered intercellular communication, cell senescence and niche-specific stem cell exhaustion, among other drivers. Mesenchymal tissues, such as bone, cartilage and fat, which originate from mesenchymal stem cell (MSC) differentiation, are especially affected by aging. Senescent MSCs show limited proliferative capacity and impairment in key defining features: their multipotent differentiation and secretory abilities, leading to diminished function and deleterious consequences for tissue homeostasis. In the past few years, several interventions to improve human healthspan by counteracting the cellular and molecular consequences of aging have moved closer to the clinic. Taking into account the MSC exhaustion occurring in aging, advanced therapies based on the potential use of young allogeneic MSCs and derivatives, such as extracellular vesicles (EVs), are gaining attention. Based on encouraging pre-clinical and clinical data, this review assesses the strong potential of MSC-based (cell and cell-free) therapies to counteract age-related consequences in both physiological and premature aging scenarios. We also discuss the mechanisms of action of these therapies and the possibility of enhancing their clinical potential by exposing MSCs to niche-relevant signals.
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Affiliation(s)
- Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, 48903 Barakaldo, Spain
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, 48903 Barakaldo, Spain
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Theeuwes WF, van den Bosch MHJ, Thurlings RM, Blom AB, van Lent PLEM. The role of inflammation in mesenchymal stromal cell therapy in osteoarthritis, perspectives for post-traumatic osteoarthritis: a review. Rheumatology (Oxford) 2021; 60:1042-1053. [PMID: 33410465 DOI: 10.1093/rheumatology/keaa910] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/26/2020] [Accepted: 12/15/2020] [Indexed: 12/12/2022] Open
Abstract
OA is a complex and highly prevalent degenerative disease affecting the whole joint, in which factors like genetic predisposition, gender, age, obesity and traumas contribute to joint destruction. ∼50-80% of OA patients develop synovitis. OA-associated risk factors contribute to joint instability and the release of cartilage matrix fragments, activating the synovium to release pro-inflammatory factors and catabolic enzymes in turn damaging the cartilage and creating a vicious circle. Currently, no cure is available for OA. Mesenchymal stromal cells (MSCs) have been tested in OA for their chondrogenic and anti-inflammatory properties. Interestingly, MSCs are most effective when administered during synovitis. This review focusses on the interplay between joint inflammation and the immunomodulation by MSCs in OA. We discuss the potential of MSCs to break the vicious circle of inflammation and describe current perspectives and challenges for clinical application of MSCs in treatment and prevention of OA, focussing on preventing post-traumatic OA.
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Affiliation(s)
- Wessel F Theeuwes
- Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | | | - Rogier M Thurlings
- Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Arjen B Blom
- Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Peter L E M van Lent
- Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands
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35
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Sharma A, Chakraborty A, Jaganathan BG. Review of the potential of mesenchymal stem cells for the treatment of infectious diseases. World J Stem Cells 2021; 13:568-593. [PMID: 34249228 PMCID: PMC8246252 DOI: 10.4252/wjsc.v13.i6.568] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/07/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
The therapeutic value of mesenchymal stem cells (MSCs) for the treatment of infectious diseases and the repair of disease-induced tissue damage has been explored extensively. MSCs inhibit inflammation, reduce pathogen load and tissue damage encountered during infectious diseases through the secretion of antimicrobial factors for pathogen clearance and they phagocytose certain bacteria themselves. MSCs dampen tissue damage during infection by downregulating the levels of pro-inflammatory cytokines, and inhibiting the excessive recruitment of neutrophils and proliferation of T cells at the site of injury. MSCs aid in the regeneration of damaged tissue by differentiating into the damaged cell types or by releasing paracrine factors that direct tissue regeneration, differentiation, and wound healing. In this review, we discuss in detail the various mechanisms by which MSCs help combat pathogens, tissue damage associated with infectious diseases, and challenges in utilizing MSCs for therapy.
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Affiliation(s)
- Amit Sharma
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | - Anuja Chakraborty
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | - Bithiah Grace Jaganathan
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
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36
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Li M, Hou Q, Zhong L, Zhao Y, Fu X. Macrophage Related Chronic Inflammation in Non-Healing Wounds. Front Immunol 2021; 12:681710. [PMID: 34220830 PMCID: PMC8242337 DOI: 10.3389/fimmu.2021.681710] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/27/2021] [Indexed: 12/14/2022] Open
Abstract
Persistent hyper-inflammation is a distinguishing pathophysiological characteristic of chronic wounds, and macrophage malfunction is considered as a major contributor thereof. In this review, we describe the origin and heterogeneity of macrophages during wound healing, and compare macrophage function in healing and non-healing wounds. We consider extrinsic and intrinsic factors driving wound macrophage dysregulation, and review systemic and topical therapeutic approaches for the restoration of macrophage response. Multidimensional analysis is highlighted through the integration of various high-throughput technologies, used to assess the diversity and activation states as well as cellular communication of macrophages in healing and non-healing wound. This research fills the gaps in current literature and provides the promising therapeutic interventions for chronic wounds.
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Affiliation(s)
- Meirong Li
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4 Medical Center, PLA General Hospital and PLA Medical College, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, PLA General Hospital, Beijing, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
- Central Laboratory, Trauma Treatment Center, Central Laboratory, Chinese PLA General Hospital, Hainan Hospital, Sanya, China
| | - Qian Hou
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4 Medical Center, PLA General Hospital and PLA Medical College, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, PLA General Hospital, Beijing, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Lingzhi Zhong
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4 Medical Center, PLA General Hospital and PLA Medical College, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, PLA General Hospital, Beijing, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Yali Zhao
- Central Laboratory, Trauma Treatment Center, Central Laboratory, Chinese PLA General Hospital, Hainan Hospital, Sanya, China
| | - Xiaobing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4 Medical Center, PLA General Hospital and PLA Medical College, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, PLA General Hospital, Beijing, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
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Infante A, Gener B, Vázquez M, Olivares N, Arrieta A, Grau G, Llano I, Madero L, Bueno AM, Sagastizabal B, Gerovska D, Araúzo‐Bravo MJ, Astigarraga I, Rodríguez CI. Reiterative infusions of MSCs improve pediatric osteogenesis imperfecta eliciting a pro-osteogenic paracrine response: TERCELOI clinical trial. Clin Transl Med 2021; 11:e265. [PMID: 33463067 PMCID: PMC7805402 DOI: 10.1002/ctm2.265] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/04/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility, with a wide range in the severity of clinical manifestations. The majority of cases are due to mutations in the COL1A1 or COL1A2 genes, which encode type I collagen. Mesenchymal stem cells (MSCs), as the progenitors of the osteoblasts, the main type I collagen secreting cell type in the bone, have been proposed and tested as an innovative therapy for OI with promising but transient outcomes. METHODS To overcome the short-term effect of MSCs therapy, we performed a phase I clinical trial based on reiterative infusions of histocompatible MSCs, administered in a 2.5-year period, in two pediatric patients affected by severe and moderate OI. The aim of this study was to assess the safety and effectiveness of this cell therapy in nonimmunosuppressed OI patients. The host response to MSCs was studied by analyzing the sera from OI patients, collected before, during, and after the cell therapy. RESULTS We first demonstrated that the sequential administration of MSCs was safe and improved the bone parameters and quality of life of OI patients along the cell treatment plus 2-year follow-up period. Moreover, the study of the mechanism of action indicated that MSCs therapy elicited a pro-osteogenic paracrine response in patients, especially noticeable in the patient affected by severe OI. CONCLUSIONS Our results demonstrate the feasibility and potential of reiterative MSCs infusion for two pediatric OI and highlight the paracrine response shown by patients as a consequence of MSCs treatment.
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Affiliation(s)
- Arantza Infante
- Stem Cells and Cell Therapy LaboratoryBiocruces Bizkaia Health Research InstituteCruces University HospitalBarakaldoSpain
| | - Blanca Gener
- Stem Cells and Cell Therapy LaboratoryBiocruces Bizkaia Health Research InstituteCruces University HospitalBarakaldoSpain
- Service of GeneticsCruces University HospitalBarakaldoSpain
| | - Miguel Vázquez
- Department of PediatricsBiocruces Bizkaia Health Research InstituteCruces University HospitalBarakaldoSpain
| | - Nerea Olivares
- Department of Biochemistry, Immunology UnitCruces University HospitalBarakaldoSpain
| | - Arantza Arrieta
- Department of Biochemistry, Immunology UnitCruces University HospitalBarakaldoSpain
| | - Gema Grau
- Department of PediatricsBiocruces Bizkaia Health Research InstituteCruces University HospitalBarakaldoSpain
| | - Isabel Llano
- Service of GeneticsCruces University HospitalBarakaldoSpain
| | - Luis Madero
- Department of Pediatric Hematology, Oncology and Stem CellsNiño Jesús University Children´s HospitalMadridSpain
| | - Ana Maria Bueno
- Department of Orthopedic SurgeryGetafe University HospitalMadridSpain
| | | | - Daniela Gerovska
- Computational Biology and Systems Biomedicine Research GroupBiodonostia Health Research InstituteDonostiaSpain
| | - Marcos J Araúzo‐Bravo
- Computational Biology and Systems Biomedicine Research GroupBiodonostia Health Research InstituteDonostiaSpain
| | - Itziar Astigarraga
- Department of PediatricsBiocruces Bizkaia Health Research InstituteCruces University HospitalBarakaldoSpain
- Department of PediatricsBasque Country University UPV/EHULeioaSpain
| | - Clara I. Rodríguez
- Stem Cells and Cell Therapy LaboratoryBiocruces Bizkaia Health Research InstituteCruces University HospitalBarakaldoSpain
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Najar M, Martel-Pelletier J, Pelletier JP, Fahmi H. Novel insights for improving the therapeutic safety and efficiency of mesenchymal stromal cells. World J Stem Cells 2020; 12:1474-1491. [PMID: 33505596 PMCID: PMC7789128 DOI: 10.4252/wjsc.v12.i12.1474] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/13/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have attracted great interest in the field of regenerative medicine. They can home to damaged tissue, where they can exert pro-regenerative and anti-inflammatory properties. These therapeutic effects involve the secretion of growth factors, cytokines, and chemokines. Moreover, the functions of MSCs could be mediated by extracellular vesicles (EVs) that shuttle various signaling messengers. Although preclinical studies and clinical trials have demonstrated promising therapeutic results, the efficiency and the safety of MSCs need to be improved. After transplantation, MSCs face harsh environmental conditions, which likely dampen their therapeutic efficacy. A possible strategy aiming to improve the survival and therapeutic functions of MSCs needs to be developed. The preconditioning of MSCs ex vivo would strength their capacities by preparing them to survive and to better function in this hostile environment. In this review, we will discuss several preconditioning approaches that may improve the therapeutic capacity of MSCs. As stated above, EVs can recapitulate the beneficial effects of MSCs and may help avoid many risks associated with cell transplantation. As a result, this novel type of cell-free therapy may be safer and more efficient than the whole cell product. We will, therefore, also discuss current knowledge regarding the therapeutic properties of MSC-derived EVs.
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Affiliation(s)
- Mehdi Najar
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada.
| | - Johanne Martel-Pelletier
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Jean Pierre Pelletier
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Hassan Fahmi
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
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39
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The Cutaneous Wound Innate Immunological Microenvironment. Int J Mol Sci 2020; 21:ijms21228748. [PMID: 33228152 PMCID: PMC7699544 DOI: 10.3390/ijms21228748] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/17/2020] [Accepted: 11/17/2020] [Indexed: 12/17/2022] Open
Abstract
The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound repair and protection from invading pathogens are essential processes in successful skin barrier regeneration. To repair and protect wounds, skin promotes the development of a specific and complex immunological microenvironment within and surrounding the disrupted tissue. This immune microenvironment includes both innate and adaptive processes, including immune cell recruitment to the wound and secretion of extracellular factors that can act directly to promote wound closure and wound antimicrobial defense. Recent work has shown that this immune microenvironment also varies according to the specific context of the wound: the microbiome, neuroimmune signaling, environmental effects, and age play roles in altering the innate immune response to wounding. This review will focus on the role of these factors in shaping the cutaneous microenvironment and how this ultimately impacts the immune response to wounding.
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40
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Shi W, Guo S, Liu L, Liu Q, Huo F, Ding Y, Tian W. Small Extracellular Vesicles from Lipopolysaccharide-Preconditioned Dental Follicle Cells Promote Periodontal Regeneration in an Inflammatory Microenvironment. ACS Biomater Sci Eng 2020; 6:5797-5810. [PMID: 33320548 DOI: 10.1021/acsbiomaterials.0c00882] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Lipopolysaccharide (LPS)-induced inflammatory microenvironment can enhance the dental follicle cells (DFCs) proliferation, differentiation, and adhesion abilities beneficial to periodontal regeneration, which possibly attributes the success to exosomes according to recent studies. This study aimed to investigate the therapeutic efficacy and underlying mechanisms of LPS-preconditioned DFC-derived small extracellular vesicles (sEVs), which enriched exosomes for periodontal regeneration in an inflammatory microenvironment. LPS preconditioning could significantly increase the secretion of sEVs derived from DFCs. Both LPS-preconditioned dental follicle cell-derived sEV (L-D-sEV) and DFC-derived sEV (D-sEV) promoted the proliferation of periodontal ligament cells from periodontitis (p-PDLCs) with a dose-dependent and saturable manner and also enhanced the migration and differentiation of p-PDLCs. Furthermore, L-D-sEV showed a modest benefit than D-sEV to promote p-PDLCs differentiation. In vivo, an L-D-sEV-loaded hydrogel applied in the treatment of periodontitis was beneficial to repair lost alveolar bone in the early stage of treatment and to maintain the level of alveolar bone in the late stage of treatment in experimental periodontitis rats, which could partly decrease the expression of the RANKL/OPG ratio. In conclusion, L-D-sEV was beneficial to p-PDLCs forming an integrity periodontal tissue. The biological injectable L-D-sEV-loaded hydrogel could be used as a treatment method for experimental periodontitis in rats, promoting periodontal tissue regeneration and providing a new alternative cell therapy method for periodontal tissue regeneration.
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Affiliation(s)
- Weiwei Shi
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Shujuan Guo
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Li Liu
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Qian Liu
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Fangjun Huo
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yi Ding
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Weidong Tian
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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41
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Jiang D, Scharffetter-Kochanek K. Mesenchymal Stem Cells Adaptively Respond to Environmental Cues Thereby Improving Granulation Tissue Formation and Wound Healing. Front Cell Dev Biol 2020; 8:697. [PMID: 32850818 PMCID: PMC7403200 DOI: 10.3389/fcell.2020.00697] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Granulation tissue formation constitutes a key step during wound healing of the skin and other organs. Granulation tissue concomitantly initiates regenerative M2 macrophages polarization, fibroblast proliferation, myofibroblast differentiation with subsequent contraction of the wound, new vessel formation, and matrix deposition. Impaired granulation tissue formation either leads to delayed wound healing or excessive scar formation, conditions with high morbidity and mortality. Accumulating evidence has demonstrated that mesenchymal stem cell (MSC)-based therapy is a promising strategy to ameliorate defects in granulation tissue formation and to successfully treat non-healing chronic wounds. In this review we give an updated overview of how therapeutically administered MSCs ensure a balanced granulation tissue formation, and furthermore discuss the cellular and molecular mechanisms underlying the adaptive responses of MSCs to cue in their direct neighborhood. Improved understanding of the interplay between the exogenous MSCs and their niche in granulation tissue will foster the development of MSC-based therapies tailored for difficult-to-treat non-healing wounds.
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Affiliation(s)
- Dongsheng Jiang
- Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Munich, Germany
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42
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Rahmani-Kukia N, Abbasi A, Abtahi Froushani SM, Shahgaldi S, Mokarram P. The effects of 17 Beta-Estradiol primed mesenchymal stem cells on the biology of co-cultured neutrophil. Int Immunopharmacol 2020; 84:106602. [PMID: 32417655 DOI: 10.1016/j.intimp.2020.106602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 04/15/2020] [Accepted: 05/11/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Mesenchymal stem cells (MSCs) can influence immune effector cells. It is proved that MSCs respond to various Toll-like receptor (TLR) ligands, which could ultimately result in changes in their immunomodulatory effects. Neutrophils play an essential role in the first line defense system and their function can be regulated by MSCs. Estrogen is a female hormone that contributes to sex differences in several immune-related diseases. With regard to the stated facts, this research aims to elucidate the effects of estrogen treatment on the ability of TLR4-primed MSCs to regulate neutrophil functions. METHODS Following isolation and characterization, MSCs were stimulated with LPS as a TLR4 ligand and subsequently incubated with different concentrations (0, 10, 20 and 40 nM) of estrogen for 48 hrs. Then, MSCs were co-cultured with neutrophils to investigate the vitality and function of the co-cultured neutrophils. RESULTS Our results indicated that TLR4-primed MSCs could decrease the viability and neutral red uptake potential of co-cultured neutrophils. Furthermore, neutrophils co-cultured with TLR4-primed MSCs exhibited a decrease in the respiratory burst intensity after being challenged with opsonized yeast. Interestingly, treating TLR4-primed MSCs with estrogen reversed the observed alterations in neutrophil functions. CONCLUSION It appears that estrogen can alter the interaction between MSCs and neutrophils.
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Affiliation(s)
- Nasim Rahmani-Kukia
- Department of biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | | | - Shahab Shahgaldi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pooneh Mokarram
- Autophagy Research Center, Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran
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43
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Munir S, Basu A, Maity P, Krug L, Haas P, Jiang D, Strauss G, Wlaschek M, Geiger H, Singh K, Scharffetter-Kochanek K. TLR4-dependent shaping of the wound site by MSCs accelerates wound healing. EMBO Rep 2020; 21:e48777. [PMID: 32162777 PMCID: PMC7202058 DOI: 10.15252/embr.201948777] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 12/13/2022] Open
Abstract
We here address the question whether the unique capacity of mesenchymal stem cells to re‐establish tissue homeostasis depends on their potential to sense pathogen‐associated molecular pattern and, in consequence, mount an adaptive response in the interest of tissue repair. After injection of MSCs primed with the bacterial wall component LPS into murine wounds, an unexpected acceleration of healing occurs, clearly exceeding that of non‐primed MSCs. This correlates with a fundamental reprogramming of the transcriptome in LPS‐treated MSCs as deduced from RNAseq analysis and its validation. A network of genes mediating the adaptive response through the Toll‐like receptor 4 (TLR4) pathway responsible for neutrophil and macrophage recruitment and their activation profoundly contributes to enhanced wound healing. In fact, injection of LPS‐primed MSCs silenced for TLR4 fails to accelerate wound healing. These unprecedented findings hold substantial promise to refine current MSC‐based therapies for difficult‐to‐treat wounds.
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Affiliation(s)
- Saira Munir
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
| | - Abhijit Basu
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
| | - Pallab Maity
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany.,Aging Research Center (ARC), Ulm, Germany
| | - Linda Krug
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany.,Aging Research Center (ARC), Ulm, Germany
| | - Philipp Haas
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
| | - Dongsheng Jiang
- Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Munich, Germany
| | - Gudrun Strauss
- Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, Germany
| | - Meinhard Wlaschek
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
| | - Hartmut Geiger
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany.,Aging Research Center (ARC), Ulm, Germany.,Institute of Molecular Medicine and Stem Cell Aging, Ulm University, Ulm, Germany.,Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Karmveer Singh
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany.,Aging Research Center (ARC), Ulm, Germany
| | - Karin Scharffetter-Kochanek
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany.,Aging Research Center (ARC), Ulm, Germany
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