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Zununi Vahed S, Hejazian SM, Bakari WN, Landon R, Gueguen V, Meddahi-Pellé A, Anagnostou F, Barzegari A, Pavon-Djavid G. Milking mesenchymal stem cells: Updated protocols for cell lysate, secretome, and exosome extraction, and comparative analysis of their therapeutic potential. Methods 2025; 238:40-60. [PMID: 40058715 DOI: 10.1016/j.ymeth.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 02/28/2025] [Accepted: 03/04/2025] [Indexed: 03/21/2025] Open
Abstract
The potential of the cell lysate, secretome, and extracellular vesicles (EVs) of mesenchymal stem cells (MSCs) to modulate the immune response and promote tissue regeneration has positioned them as a promising option for cell-free therapy. Currently, many clinical trials in stem cells-derived EVs and secretome are in progress various diseases and sometimes the results are failing. The major challenge on this roadmap is the lack of a standard extraction method for exosome, secretome, and lysate. The most optimal method for obtaining the secretome of MSCs for clinical utilization involves a comprehensive approach that includes non-destructive collection methods, time optimization, multiple collection rounds, optimization of culture conditions, and quality control measures. Further research and clinical studies are warranted to validate and refine these methods for safe and effective utilization of the MSC exosome, secretome, and lysate in various clinical applications. To address these challenges, it is imperative to establish a standardized and unified methodology to ensure reliable evaluation of these extractions in clinical trials. This review seeks to outline the pros and cons of methods for the preparation of MSCs-derived exosome, and secretome/lysate, and comparative analysis of their therapeutic potential.
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Affiliation(s)
| | | | - William Ndjidda Bakari
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France; Université Paris Cité, CNRS UMR7052, INSERM U1271, ENVA, B3OA, F-75010 Paris, France
| | - Rebecca Landon
- Université Paris Cité, CNRS UMR7052, INSERM U1271, ENVA, B3OA, F-75010 Paris, France
| | - Virginie Gueguen
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France
| | - Anne Meddahi-Pellé
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France
| | - Fani Anagnostou
- Université Paris Cité, CNRS UMR7052, INSERM U1271, ENVA, B3OA, F-75010 Paris, France
| | - Abolfazl Barzegari
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Pharmaceutical Nanotechnology (RCPN), Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Graciela Pavon-Djavid
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France.
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Giannasi C, Cadelano F, Della Morte E, Baserga C, Mazzucato C, Niada S, Baj A. Unlocking the Therapeutic Potential of Adipose-Derived Stem Cell Secretome in Oral and Maxillofacial Medicine: A Composition-Based Perspective. BIOLOGY 2024; 13:1016. [PMID: 39765683 PMCID: PMC11673083 DOI: 10.3390/biology13121016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/27/2024] [Accepted: 12/03/2024] [Indexed: 01/03/2025]
Abstract
The adipose-derived stem cell (ADSC) secretome is widely studied for its immunomodulatory and regenerative properties, yet its potential in maxillofacial medicine remains largely underexplored. This review takes a composition-driven approach, beginning with a list of chemokines, cytokines, receptors, and inflammatory and growth factors quantified in the ADSC secretome to infer its potential applications in this medical field. First, a review of the literature confirmed the presence of 107 bioactive factors in the secretome of ADSCs or other types of mesenchymal stem cells. This list was then analyzed using the Search Tool for Retrieval of Interacting Genes/Proteins (STRING) software, revealing 844 enriched biological processes. From these, key processes were categorized into three major clinical application areas: immunoregulation (73 factors), bone regeneration (13 factors), and wound healing and soft tissue regeneration (27 factors), with several factors relevant to more than one area. The most relevant molecules were discussed in the context of existing literature to explore their therapeutic potential based on available evidence. Among these, TGFB1, IL10, and CSF2 have been shown to modulate immune and inflammatory responses, while OPG, IL6, HGF, and TIMP1 contribute to bone regeneration and tissue repair. Although the ADSC secretome holds great promise in oral and maxillofacial medicine, further research is needed to optimize its application and validate its clinical efficacy.
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Affiliation(s)
- Chiara Giannasi
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20100 Milan, Italy; (F.C.); (A.B.)
- IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy; (E.D.M.); (C.B.); (C.M.)
| | - Francesca Cadelano
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20100 Milan, Italy; (F.C.); (A.B.)
- IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy; (E.D.M.); (C.B.); (C.M.)
| | - Elena Della Morte
- IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy; (E.D.M.); (C.B.); (C.M.)
| | - Camilla Baserga
- IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy; (E.D.M.); (C.B.); (C.M.)
| | - Camilla Mazzucato
- IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy; (E.D.M.); (C.B.); (C.M.)
| | - Stefania Niada
- IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy; (E.D.M.); (C.B.); (C.M.)
| | - Alessandro Baj
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20100 Milan, Italy; (F.C.); (A.B.)
- IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy; (E.D.M.); (C.B.); (C.M.)
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Khatibzadeh SM, Dahlgren LA, Caswell CC, Ducker WA, Werre SR, Bogers SH. Equine bone marrow-derived mesenchymal stromal cells reduce established S. aureus and E. coli biofilm matrix in vitro. PLoS One 2024; 19:e0312917. [PMID: 39480794 PMCID: PMC11527187 DOI: 10.1371/journal.pone.0312917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 10/16/2024] [Indexed: 11/02/2024] Open
Abstract
Biofilms reduce antibiotic efficacy and lead to complications and mortality in human and equine patients with orthopedic infections. Equine bone marrow-derived mesenchymal stromal cells (MSC) kill planktonic bacteria and prevent biofilm formation, but their ability to disrupt established orthopedic biofilms is unknown. Our objective was to evaluate the ability of MSC to reduce established S. aureus or E. coli biofilms in vitro. We hypothesized that MSC would reduce biofilm matrix and colony-forming units (CFU) compared to no treatment and that MSC combined with the antibiotic, amikacin sulfate, would reduce these components more than MSC or amikacin alone. MSC were isolated from 5 adult Thoroughbred horses in antibiotic-free medium. 24-hour S. aureus or E. coli biofilms were co-cultured in triplicate for 24 or 48 hours in a transwell plate system: untreated (negative) control, 30 μg/mL amikacin, 1 x 106 passage 3 MSC, and MSC with 30 μg/mL amikacin. Treated biofilms were photographed and biofilm area quantified digitally. Biomass was quantified via crystal violet staining, and CFU quantified following enzymatic digestion. Data were analyzed using mixed model ANOVA with Tukey post-hoc comparisons (p < 0.05). MSC significantly reduced S. aureus biofilms at both timepoints and E. coli biofilm area at 48 hours compared to untreated controls. MSC with amikacin significantly reduced S. aureus biofilms versus amikacin and E. coli biofilms versus MSC at 48 hours. MSC significantly reduced S. aureus biomass at both timepoints and reduced S. aureus CFU at 48 hours versus untreated controls. MSC with amikacin significantly reduced S. aureus biomass versus amikacin at 24 hours and S. aureus and E. coli CFU versus MSC at both timepoints. MSC primarily disrupted the biofilm matrix but performed differently on S. aureus versus E. coli. Evaluation of biofilm-MSC interactions, MSC dose, and treatment time are warranted prior to testing in vivo.
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Affiliation(s)
- Sarah M. Khatibzadeh
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States of America
| | - Linda A. Dahlgren
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States of America
| | - Clayton C. Caswell
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, Virginia, United States of America
| | - William A. Ducker
- Department of Chemical Engineering, College of Engineering, Virginia Tech, Blacksburg, VA, United States of America
| | - Stephen R. Werre
- Laboratory for Study Design and Statistical Analysis, Virginia-Maryland College of Veterinary Medicine, Blacksburg, Virginia, United States of America
| | - Sophie H. Bogers
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States of America
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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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Takegaki J, Sase K, Kono Y, Fujita T, Konishi S, Fujita S. Intramuscular injection of mesenchymal stem cells augments basal muscle protein synthesis after bouts of resistance exercise in male mice. Physiol Rep 2024; 12:e15991. [PMID: 38605421 PMCID: PMC11009371 DOI: 10.14814/phy2.15991] [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: 02/10/2024] [Revised: 03/18/2024] [Accepted: 03/18/2024] [Indexed: 04/13/2024] Open
Abstract
Skeletal muscle mass is critical for activities of daily living. Resistance training maintains or increases muscle mass, and various strategies maximize the training adaptation. Mesenchymal stem cells (MSCs) are multipotent cells with differential potency in skeletal muscle cells and the capacity to secrete growth factors. However, little is known regarding the effect of intramuscular injection of MSCs on basal muscle protein synthesis and catabolic systems after resistance training. Here, we measured changes in basal muscle protein synthesis, the ubiquitin-proteasome system, and autophagy-lysosome system-related factors after bouts of resistance exercise by intramuscular injection of MSCs. Mice performed three bouts of resistance exercise (each consisting of 50 maximal isometric contractions elicited by electrical stimulation) on the right gastrocnemius muscle every 48 h, and immediately after the first bout, mice were intramuscularly injected with either MSCs (2.0 × 106 cells) labeled with green fluorescence protein (GFP) or vehicle only placebo. Seventy-two hours after the third exercise bout, GFP was detected only in the muscle injected with MSCs with concomitant elevation of muscle protein synthesis. The injection of MSCs also increased protein ubiquitination. These results suggest that the intramuscular injection of MSCs augmented muscle protein turnover at the basal state after consecutive resistance exercise.
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Affiliation(s)
- Junya Takegaki
- Research Organization of Science and TechnologyRitsumeikan UniversityKusatsuShigaJapan
- Ritsumeikan Global Innovation Research OrganizationRitsumeikan UniversityKusatsuShigaJapan
- Graduate School of Agricultural ScienceKobe UniversityKobeHyogoJapan
| | - Kohei Sase
- Faculty of Sport and Health ScienceRitsumeikan UniversityKusatsuShigaJapan
| | - Yusuke Kono
- Ritsumeikan Global Innovation Research OrganizationRitsumeikan UniversityKusatsuShigaJapan
- Faculty of Pharmaceutical SciencesKobe Pharmaceutical UniversityKobeHyogoJapan
| | - Takuya Fujita
- College of Pharmaceutical SciencesRitsumeikan UniversityKusatsuShigaJapan
| | - Satoshi Konishi
- Faculty of Science and EngineeringRitsumeikan UniversityKusatsuShigaJapan
| | - Satoshi Fujita
- Faculty of Sport and Health ScienceRitsumeikan UniversityKusatsuShigaJapan
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van Griensven M, Balmayor ER. Extracellular vesicles are key players in mesenchymal stem cells' dual potential to regenerate and modulate the immune system. Adv Drug Deliv Rev 2024; 207:115203. [PMID: 38342242 DOI: 10.1016/j.addr.2024.115203] [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: 06/01/2023] [Revised: 10/15/2023] [Accepted: 02/05/2024] [Indexed: 02/13/2024]
Abstract
MSCs are used for treatment of inflammatory conditions or for regenerative purposes. MSCs are complete cells and allogenic transplantation is in principle possible, but mostly autologous use is preferred. In recent years, it was discovered that cells secrete extracellular vesicles. These are active budded off vesicles that carry a cargo. The cargo can be miRNA, protein, lipids etc. The extracellular vesicles can be transported through the body and fuse with target cells. Thereby, they influence the phenotype and modulate the disease. The extracellular vesicles have, like the MSCs, immunomodulatory or regenerative capacities. This review will focus on those features of extracellular vesicles and discuss their dual role. Besides the immunomodulation, the regeneration will concentrate on bone, cartilage, tendon, vessels and nerves. Current clinical trials with extracellular vesicles for immunomodulation and regeneration that started in the last five years are highlighted as well. In summary, extracellular vesicles have a great potential as disease modulating entity and treatment. Their dual characteristics need to be taken into account and often are both important for having the best effect.
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Affiliation(s)
- Martijn van Griensven
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, 6229 ER Maastricht, the Netherlands; Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA.
| | - Elizabeth R Balmayor
- Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA; Experimental Orthopaedics and Trauma Surgery, Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
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Li XH, Huang P, Cheng HP, Zhou Y, Feng DD, Yue SJ, Han Y, Luo ZQ. NMDAR activation attenuates the protective effect of BM-MSCs on bleomycin-induced ALI via the COX-2/PGE 2 pathway. Heliyon 2024; 10:e23723. [PMID: 38205313 PMCID: PMC10776937 DOI: 10.1016/j.heliyon.2023.e23723] [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: 02/01/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 01/12/2024] Open
Abstract
N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation mediates glutamate (Glu) toxicity and involves bleomycin (BLM)-induced acute lung injury (ALI). We have reported that bone marrow-derived mesenchymal stem cells (BM-MSCs) are NMDAR-regulated target cells, and NMDAR activation inhibits the protective effect of BM-MSCs on BLM-induced pulmonary fibrosis, but its effect on ALI remains unknown. Here, we found that Glu release was significantly elevated in plasma of mice at d 7 after intratracheally injected with BLM. BM-MSCs were pretreated with NMDA (the selective agonist of NMDAR) and transplanted into the recipient mice after the BLM challenge. BM-MSCs administration significantly alleviated the pathological changes, inflammatory response, myeloperoxidase activity, and malondialdehyde content in the damaged lungs, but NMDA-pretreated BM-MSCs did not ameliorate BLM-induced lung injury in vivo. Moreover, NMDA down-regulated prostaglandin E2 (PGE2) secretion and cyclooxygenase (COX)-2 expression instead of COX-1 expression in BM-MSCs in vitro. We also found that NMDAR1 expression was increased and COX-2 expression was decreased, but COX-1 expression was not changed in primary BM-MSCs of BLM-induced ALI mice. Further, the cultured supernatants of lipopolysaccharide (LPS)-pretreated RAW264.7 macrophages were collected to detect inflammatory factors after co-culture with NMDA-pretreated BM-MSCs. The co-culture experiments showed that NMDA precondition inhibited the anti-inflammatory effect of BM-MSCs on LPS-induced macrophage inflammation, and PGE2 could partially alleviate this inhibition. Our findings suggest that NMDAR activation attenuated the protective effect of BM-MSCs on BLM-induced ALI in vivo. NMDAR activation inhibited COX-2 expression and PGE2 secretion in BM-MSCs and weakened the anti-inflammatory effect of BM-MSCs on LPS-induced macrophage inflammation in vitro. In conclusion, NMDAR activation attenuates the protective effect of BM-MSCs on BLM-induced ALI via the COX-2/PGE2 pathway. Keywords: Acute Lung Injury, BM-MSCs, NMDA receptor, COX-1/2, PGE2.
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Affiliation(s)
- Xiao-Hong Li
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Pu Huang
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Health Management Center, Changsha Central Hospital Affiliated to Nanhua University, Changsha, 410018, China
| | - Hai-Peng Cheng
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Yan Zhou
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Dan-Dan Feng
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Shao-Jie Yue
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yang Han
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Zi-Qiang Luo
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, 410078, China
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8
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Yasan GT, Gunel-Ozcan A. Hypoxia and Hypoxia Mimetic Agents As Potential Priming Approaches to Empower Mesenchymal Stem Cells. Curr Stem Cell Res Ther 2024; 19:33-54. [PMID: 36642875 DOI: 10.2174/1574888x18666230113143234] [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: 07/29/2022] [Revised: 10/12/2022] [Accepted: 11/04/2022] [Indexed: 01/17/2023]
Abstract
Mesenchymal stem cells (MSC) exhibit self-renewal capacity and multilineage differentiation potential, making them attractive for research and clinical application. The properties of MSC can vary depending on specific micro-environmental factors. MSC resides in specific niches with low oxygen concentrations, where oxygen functions as a metabolic substrate and a signaling molecule. Conventional physical incubators or chemically hypoxia mimetic agents are applied in cultures to mimic the original low oxygen tension settings where MSC originated. This review aims to focus on the current knowledge of the effects of various physical hypoxic conditions and widely used hypoxia-mimetic agents-PHD inhibitors on mesenchymal stem cells at a cellular and molecular level, including proliferation, stemness, differentiation, viability, apoptosis, senescence, migration, immunomodulation behaviors, as well as epigenetic changes.
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Affiliation(s)
| | - Aysen Gunel-Ozcan
- Department of Stem Cell Sciences, Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
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Taeb S, Rostamzadeh D, Mafi S, Mofatteh M, Zarrabi A, Hushmandi K, Safari A, Khodamoradi E, Najafi M. Update on Mesenchymal Stem Cells: A Crucial Player in Cancer Immunotherapy. Curr Mol Med 2024; 24:98-113. [PMID: 36573062 DOI: 10.2174/1566524023666221226143814] [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: 05/17/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 12/28/2022]
Abstract
The idea of cancer immunotherapy has spread, and it has made tremendous progress with the advancement of new technology. Immunotherapy, which serves to assist the natural defenses of the body in eradicating cancerous cells, is a remarkable achievement that has revolutionized both cancer research and cancer treatments. Currently, the use of stem cells in immunotherapy is widespread and shares a special characteristic, including cancer cell migration, bioactive component release, and immunosuppressive activity. In the context of cancer, mesenchymal stem cells (MSCs) are rapidly being identified as vital stromal regulators of tumor progression. MSCs therapy has been implicated in treating a wide range of diseases, including bone damage, autoimmune diseases, and particularly hematopoietic abnormalities, providing stem cell-based therapy with an extra dimension. Moreover, the implication of MSCs does not have ethical concerns, and the complications known in pluripotent and totipotent stem cells are less common in MSCs. MSCs have a lot of distinctive characteristics that, when coupled, make them excellent for cellular-based immunotherapy and as vehicles for gene and drug delivery in a variety of inflammations and malignancies. MSCs can migrate to the inflammatory site and exert immunomodulatory responses via cell-to-cell contacts with lymphocytes by generating soluble substances. In the current review, we discuss the most recent research on the immunological characteristics of MSCs, their use as immunomodulatory carriers, techniques for approving MSCs to adjust their immunological contour, and their usages as vehicles for delivering therapeutic as well as drugs and genes engineered to destroy tumor cells.
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Affiliation(s)
- Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Davoud Rostamzadeh
- Department of Clinical Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Sahar Mafi
- Department of Clinical Biochemistry, Yasuj University of Medical Sciences, Yasuj, Iran
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mohammad Mofatteh
- Sir William Dunn School of Pathology, Medical Sciences Division, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom
- Lincoln College, University of Oxford, Turl Street, Oxford OX1 3DR, United Kingdom
| | - Ali Zarrabi
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Arash Safari
- Department of Radiology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ehsan Khodamoradi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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10
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Barrett JG, MacDonald ES. Use of Biologics and Stem Cells in the Treatment of Other Inflammatory Diseases in the Horse. Vet Clin North Am Equine Pract 2023; 39:553-563. [PMID: 37607855 DOI: 10.1016/j.cveq.2023.07.004] [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] [Indexed: 08/24/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are powerful immunomodulatory cells that act via multiple mechanisms to coordinate, inhibit, and control the cells of the immune system. MSCs act as rescuers for various damaged or degenerated cells of the body via (1) cytokines, growth factors, and signaling molecules; (2) extracellular vesicle (exosome) signaling; and (3) direct donation of mitochondria. Several studies evaluating the efficacy of MSCs have used MSCs grown using xenogeneic media, which may reduce or eliminate efficacy. Although more research is needed to optimize the anti-inflammatory potential of MSCs, there is ample evidence that MSC therapeutics are worthy of further development.
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Affiliation(s)
- Jennifer G Barrett
- Marion duPont Scott Equine Medical Center, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, USA.
| | - Elizabeth S MacDonald
- Marion duPont Scott Equine Medical Center, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, USA
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11
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Mahjoor M, Fakouri A, Farokhi S, Nazari H, Afkhami H, Heidari F. Regenerative potential of mesenchymal stromal cells in wound healing: unveiling the influence of normoxic and hypoxic environments. Front Cell Dev Biol 2023; 11:1245872. [PMID: 37900276 PMCID: PMC10603205 DOI: 10.3389/fcell.2023.1245872] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 08/11/2023] [Indexed: 10/31/2023] Open
Abstract
The innate and adaptive immune systems rely on the skin for various purposes, serving as the primary defense against harmful environmental elements. However, skin lesions may lead to undesirable consequences such as scarring, accelerated skin aging, functional impairment, and psychological effects over time. The rising popularity of mesenchymal stromal cells (MSCs) for skin wound treatment is due to their potential as a promising therapeutic option. MSCs offer advantages in terms of differentiation capacity, accessibility, low immunogenicity, and their central role in natural wound-healing processes. To accelerate the healing process, MSCs promote cell migration, angiogenesis, epithelialization, and granulation tissue development. Oxygen plays a critical role in the formation and expansion of mammalian cells. The term "normoxia" refers to the usual oxygen levels, defined at 20.21 percent oxygen (160 mm of mercury), while "hypoxia" denotes oxygen levels of 2.91 percent or less. Notably, the ambient O2 content (20%) in the lab significantly differs from the 2%-9% O2 concentration in their natural habitat. Oxygen regulation of hypoxia-inducible factor-1 (HIF-1) mediated expression of multiple genes plays a crucial role in sustaining stem cell destiny concerning proliferation and differentiation. This study aims to elucidate the impact of normoxia and hypoxia on MSC biology and draw comparisons between the two. The findings suggest that expanding MSC-based regenerative treatments in a hypoxic environment can enhance their growth kinetics, genetic stability, and expression of chemokine receptors, ultimately increasing their effectiveness.
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Affiliation(s)
- Mohamad Mahjoor
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Arshia Fakouri
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Simin Farokhi
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hojjatollah Nazari
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Fatemeh Heidari
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Anatomy, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran
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12
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Nguyen QT, Thanh LN, Hoang VT, Phan TTK, Heke M, Hoang DM. Bone Marrow-Derived Mononuclear Cells in the Treatment of Neurological Diseases: Knowns and Unknowns. Cell Mol Neurobiol 2023; 43:3211-3250. [PMID: 37356043 PMCID: PMC11410020 DOI: 10.1007/s10571-023-01377-x] [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: 01/30/2023] [Accepted: 06/14/2023] [Indexed: 06/27/2023]
Abstract
Bone marrow-derived mononuclear cells (BMMNCs) have been used for decades in preclinical and clinical studies to treat various neurological diseases. However, there is still a knowledge gap in the understanding of the underlying mechanisms of BMMNCs in the treatment of neurological diseases. In addition, prerequisite factors for the efficacy of BMMNC administration, such as the optimal route, dose, and number of administrations, remain unclear. In this review, we discuss known and unknown aspects of BMMNCs, including the cell harvesting, administration route and dose; mechanisms of action; and their applications in neurological diseases, including stroke, cerebral palsy, spinal cord injury, traumatic brain injury, amyotrophic lateral sclerosis, autism spectrum disorder, and epilepsy. Furthermore, recommendations on indications for BMMNC administration and the advantages and limitations of BMMNC applications for neurological diseases are discussed. BMMNCs in the treatment of neurological diseases. BMMNCs have been applied in several neurological diseases. Proposed mechanisms for the action of BMMNCs include homing, differentiation and paracrine effects (angiogenesis, neuroprotection, and anti-inflammation). Further studies should be performed to determine the optimal cell dose and administration route, the roles of BMMNC subtypes, and the indications for the use of BMMNCs in neurological conditions with and without genetic abnormalities.
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Affiliation(s)
- Quyen Thi Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam.
- College of Health Science, Vin University, Vinhomes Ocean Park, Gia Lam District, Hanoi, 12400, Vietnam.
- Vinmec International Hospital-Times City, Vinmec Healthcare System, 458 Minh Khai, Hanoi, 11622, Vietnam.
| | - Van T Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
| | - Trang T K Phan
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Duc M Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, 458 Minh Khai, Hai Ba Trung, Hanoi, 11622, Vietnam
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13
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Guarnier LP, Moro LG, Lívero FADR, de Faria CA, Azevedo MF, Roma BP, Albuquerque ER, Malagutti-Ferreira MJ, Rodrigues AGD, da Silva AA, Sekiya EJ, Ribeiro-Paes JT. Regenerative and translational medicine in COPD: hype and hope. Eur Respir Rev 2023; 32:220223. [PMID: 37495247 PMCID: PMC10369169 DOI: 10.1183/16000617.0223-2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 05/23/2023] [Indexed: 07/28/2023] Open
Abstract
COPD is a common, preventable and usually progressive disease associated with an enhanced chronic inflammatory response in the airways and lung, generally caused by exposure to noxious particles and gases. It is a treatable disease characterised by persistent respiratory symptoms and airflow limitation due to abnormalities in the airways and/or alveoli. COPD is currently the third leading cause of death worldwide, representing a serious public health problem and a high social and economic burden. Despite significant advances, effective clinical treatments have not yet been achieved. In this scenario, cell-based therapies have emerged as potentially promising therapeutic approaches. However, there are only a few published studies of cell-based therapies in human patients with COPD and a small number of ongoing clinical trials registered on clinicaltrials.gov Despite the advances and interesting results, numerous doubts and questions remain about efficacy, mechanisms of action, culture conditions, doses, timing, route of administration and conditions related to homing and engraftment of the infused cells. This article presents the state of the art of cell-based therapy in COPD. Clinical trials that have already been completed and with published results are discussed in detail. We also discuss the questions that remain unanswered about cell-based regenerative and translational medicine for COPD.
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Affiliation(s)
- Lucas Pires Guarnier
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | - Lincoln Gozzi Moro
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
- Biomedical Sciences Institute, Butantan Institute, Technological Research Institute, University of São Paulo (USP), São Paulo, Brazil
| | | | | | - Mauricio Fogaça Azevedo
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | - Beatriz Pizoni Roma
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | | | - Maria José Malagutti-Ferreira
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | | | - Adelson Alves da Silva
- São Lucas Research and Education Institute (IEP - São Lucas), TechLife, São Paulo, Brazil
| | - Eliseo Joji Sekiya
- São Lucas Research and Education Institute (IEP - São Lucas), TechLife, São Paulo, Brazil
| | - João Tadeu Ribeiro-Paes
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
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14
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Hori H, Sakai K, Ohashi A, Nakai S. Chitin powder enhances growth factor production and therapeutic effects of mesenchymal stem cells in a chronic kidney disease rat model. J Artif Organs 2023; 26:203-211. [PMID: 35976577 DOI: 10.1007/s10047-022-01346-z] [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: 04/04/2022] [Accepted: 07/06/2022] [Indexed: 10/15/2022]
Abstract
Previously, we fabricated a device with polylactic acid nonwoven filters and mesenchymal stem cells (MSCs), which effectively reduced urinary protein levels in a rat model of chronic kidney disease (CKD) but could not suppress CKD progression. Therefore, to improve the therapeutic effects of MSCs, in this study, we analyzed the ability of rat adipose tissue-derived MSCs (ADSCs) in contact with chitin nonwoven filters or chitin powder to produce growth factors and examined their therapeutic effect in an adriamycin (ADR)-induced CKD rat model. Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) production was significantly enhanced by ADSCs cultured in a medium containing chitin powder (C-ADSCs) compared with that by ADSCs cultured in a standard medium without chitin (N-ADSCs). However, the production of HGF and VEGF by ADSCs on chitin nonwoven filters was not significantly enhanced compared with that by the control. Intravenous C-ADSC injection significantly increased podocin expression and improved proteinuria compared with those in saline-treated CKD rats; however, no such improvements were observed in the N-ADSC-treated group. These results showed that ADSCs cultured in a medium supplemented with chitin powder suppressed proteinuria via enhanced HGF and VEGF production in ADR-induced CKD rats to mitigate podocyte damage, offering a new strategy to reduce the dose of MSC therapy for safe and effective treatment of kidney disease.
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Affiliation(s)
- Hideo Hori
- Faculty of Medical Technology, School of Medical Sciences, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
| | - Kazuyoshi Sakai
- Faculty of Clinical Engineering, School of Medical Sciences, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Atsushi Ohashi
- Faculty of Clinical Engineering, School of Medical Sciences, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Shigeru Nakai
- Faculty of Clinical Engineering, School of Medical Sciences, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
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15
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Jammes M, Contentin R, Audigié F, Cassé F, Galéra P. Effect of pro-inflammatory cytokine priming and storage temperature of the mesenchymal stromal cell (MSC) secretome on equine articular chondrocytes. Front Bioeng Biotechnol 2023; 11:1204737. [PMID: 37720315 PMCID: PMC10502223 DOI: 10.3389/fbioe.2023.1204737] [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: 04/12/2023] [Accepted: 08/21/2023] [Indexed: 09/19/2023] Open
Abstract
Context: Osteoarthritis (OA) is an invalidating articular disease characterized by cartilage degradation and inflammatory events. In horses, OA is associated with up to 60% of lameness and leads to reduced animal welfare along with extensive economic losses; currently, there are no curative therapies to treat OA. The mesenchymal stromal cell (MSC) secretome exhibits anti-inflammatory properties, making it an attractive candidate for improving the management of OA. In this study, we determined the best storage conditions for conditioned media (CMs) and tested whether priming MSCs with cytokines can enhance the properties of the MSC secretome. Methods: First, properties of CMs collected from bone-marrow MSC cultures and stored at -80°C, -20°C, 4°C, 20°C or 37°C were assessed on 3D cultures of equine articular chondrocytes (eACs). Second, we primed MSCs with IL-1β, TNF-α or IFN-γ, and evaluated the MSC transcript levels of immunomodulatory effectors and growth factors. The primed CMs were also harvested for subsequent treatment of eACs, either cultured in monolayers or as 3D cell cultures. Finally, we evaluated the effect of CMs on the proliferation and the phenotype of eACs and the quality of the extracellular matrix of the neosynthesized cartilage. Results: CM storage at -80°C, -20°C, and 4°C improved collagen protein accumulation, cell proliferation and the downregulation of inflammation. The three cytokines chosen for the MSC priming influenced MSC immunomodulator gene expression, although each cytokine led to a different pattern of MSC immunomodulation. The cytokine-primed CM had no major effect on eAC proliferation, with IL-1β and TNF-α slightly increasing collagen (types IIB and I) accumulation in eAC 3D cultures (particularly with the CM derived from MSCs primed with IL-1β), and IFN-γ leading to a marked decrease. IL-1β-primed CMs resulted in increased eAC transcript levels of MMP1, MMP13 and HTRA1, whereas IFNγ-primed CMs decreased the levels of HTRA1 and MMP13. Conclusion: Although the three cytokines differentially affected the expression of immunomodulatory molecules, primed CMs induced a distinct effect on eACs according to the cytokine used for MSC priming. Different mechanisms seemed to be triggered by each priming cytokine, highlighting the need for further investigation. Nevertheless, this study demonstrates the potential of MSC-CMs for improving equine OA management.
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Affiliation(s)
- Manon Jammes
- Normandie University, UNICAEN, BIOTARGEN, Caen, France
| | | | - Fabrice Audigié
- Unit Under Contract 957 Equine Biomechanics and Locomotor Disorders (USC 957 BPLC), Center of Imaging and Research on Locomotor Affections on Equines (CIRALE), French National Research Institute for Agriculture Food and Environment (INRAE), École Nationale Vétérinaire d’Alfort, Maisons-Alfort, France
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16
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Gasparella M, Cenzi C, Piccione M, Madia VN, Di Santo R, Tudino V, Artico M, Taurone S, De Ponte C, Costi R, Di Liddo R. Effects of Modified Glucosamine on the Chondrogenic Potential of Circulating Stem Cells under Experimental Inflammation. Int J Mol Sci 2023; 24:10397. [PMID: 37373540 DOI: 10.3390/ijms241210397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 06/05/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Glucosamine (GlcN) is a glycosaminoglycan (GAGs) constituent in connective tissues. It is naturally produced by our body or consumed from diets. In the last decade, in vitro and in vivo trials have demonstrated that the administration of GlcN or its derivates has a protective effect on cartilage when the balance between catabolic and anabolic processes is disrupted and cells are no longer able to fully compensate for the loss of collagen and proteoglycans. To date, these benefits are still controversial because the mechanism of action of GlcN is not yet well clarified. In this study, we have characterized the biological activities of an amino acid (AA) derivate of GlcN, called DCF001, in the growth and chondrogenic induction of circulating multipotent stem cells (CMCs) after priming with tumor necrosis factor-alpha (TNFα), a pleiotropic cytokine commonly expressed in chronic inflammatory joint diseases. In the present work, stem cells were isolated from the human peripheral blood of healthy donors. After priming with TNFα (10 ng/mL) for 3 h, cultures were treated for 24 h with DCF001 (1 μg/mL) dissolved in a proliferative (PM) or chondrogenic (CM) medium. Cell proliferation was analyzed using a Corning® Cell Counter and trypan blue exclusion technique. To evaluate the potentialities of DCF001 in counteracting the inflammatory response to TNFα, we measured the amount of extracellular ATP (eATP) and the expression of adenosine-generating enzymes CD39/CD73, TNFα receptors, and NF-κB inhibitor IκBα using flow cytometry. Finally, total RNA was extracted to perform a gene expression study of some chondrogenic differentiation markers (COL2A1, RUNX2, and MMP13). Our analysis has shed light on the ability of DCF001 to (a) regulate the expression of CD39, CD73, and TNF receptors; (b) modulate eATP under differentiative induction; (c) enhance the inhibitory activity of IκBα, reducing its phosphorylation after TNFα stimulation; and (d) preserve the chondrogenic potentialities of stem cells. Although preliminary, these results suggest that DCF001 could be a valuable supplement for ameliorating the outcome of cartilage repair interventions, enhancing the efficacy of endogenous stem cells under inflammatory stimuli.
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Affiliation(s)
- Marco Gasparella
- Local Health Unit Treviso, Department of Pediatric Surgery, 31100 Treviso, Italy
| | - Carola Cenzi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
| | - Monica Piccione
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
| | - Valentina Noemi Madia
- Department of Drug Chemistry and Technology, University of Rome "La Sapienza", 00185 Rome, Italy
| | - Roberto Di Santo
- Department of Drug Chemistry and Technology, University of Rome "La Sapienza", 00185 Rome, Italy
| | - Valeria Tudino
- Department of Drug Chemistry and Technology, University of Rome "La Sapienza", 00185 Rome, Italy
| | - Marco Artico
- Department of Sensory Organs, University of Rome "La Sapienza", 00185 Rome, Italy
| | - Samanta Taurone
- Department of Movement, Human and Health Sciences-Division of Health Sciences, University of Rome "Foro Italico", 00185 Rome, Italy
| | - Chiara De Ponte
- Department of Sensory Organs, University of Rome "La Sapienza", 00185 Rome, Italy
| | - Roberta Costi
- Department of Drug Chemistry and Technology, University of Rome "La Sapienza", 00185 Rome, Italy
| | - Rosa Di Liddo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
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17
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Miceli V, Zito G, Bulati M, Gallo A, Busà R, Iannolo G, Conaldi PG. Different priming strategies improve distinct therapeutic capabilities of mesenchymal stromal/stem cells: Potential implications for their clinical use. World J Stem Cells 2023; 15:400-420. [PMID: 37342218 PMCID: PMC10277962 DOI: 10.4252/wjsc.v15.i5.400] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/07/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have shown significant therapeutic potential, and have therefore been extensively investigated in preclinical studies of regenerative medicine. However, while MSCs have been shown to be safe as a cellular treatment, they have usually been therapeutically ineffective in human diseases. In fact, in many clinical trials it has been shown that MSCs have moderate or poor efficacy. This inefficacy appears to be ascribable primarily to the heterogeneity of MSCs. Recently, specific priming strategies have been used to improve the therapeutic properties of MSCs. In this review, we explore the literature on the principal priming approaches used to enhance the preclinical inefficacy of MSCs. We found that different priming strategies have been used to direct the therapeutic effects of MSCs toward specific pathological processes. Particularly, while hypoxic priming can be used primarily for the treatment of acute diseases, inflammatory cytokines can be used mainly to prime MSCs in order to treat chronic immune-related disorders. The shift in approach from regeneration to inflammation implies, in MSCs, a shift in the production of functional factors that stimulate regenerative or anti-inflammatory pathways. The opportunity to fine-tune the therapeutic properties of MSCs through different priming strategies could conceivably pave the way for optimizing their therapeutic potential.
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Affiliation(s)
- Vitale Miceli
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy.
| | - Giovanni Zito
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Matteo Bulati
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Rosalia Busà
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Gioacchin Iannolo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Pier Giulio Conaldi
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
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18
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Kushioka J, Chow SKH, Toya M, Tsubosaka M, Shen H, Gao Q, Li X, Zhang N, Goodman SB. Bone regeneration in inflammation with aging and cell-based immunomodulatory therapy. Inflamm Regen 2023; 43:29. [PMID: 37231450 DOI: 10.1186/s41232-023-00279-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/09/2023] [Indexed: 05/27/2023] Open
Abstract
Aging of the global population increases the incidence of osteoporosis and associated fragility fractures, significantly impacting patient quality of life and healthcare costs. The acute inflammatory reaction is essential to initiate healing after injury. However, aging is associated with "inflammaging", referring to the presence of systemic low-level chronic inflammation. Chronic inflammation impairs the initiation of bone regeneration in elderly patients. This review examines current knowledge of the bone regeneration process and potential immunomodulatory therapies to facilitate bone healing in inflammaging.Aged macrophages show increased sensitivity and responsiveness to inflammatory signals. While M1 macrophages are activated during the acute inflammatory response, proper resolution of the inflammatory phase involves repolarizing pro-inflammatory M1 macrophages to an anti-inflammatory M2 phenotype associated with tissue regeneration. In aging, persistent chronic inflammation resulting from the failure of M1 to M2 repolarization leads to increased osteoclast activation and decreased osteoblast formation, thus increasing bone resorption and decreasing bone formation during healing.Inflammaging can impair the ability of stem cells to support bone regeneration and contributes to the decline in bone mass and strength that occurs with aging. Therefore, modulating inflammaging is a promising approach for improving bone health in the aging population. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that may benefit bone regeneration in inflammation. Preconditioning MSCs with pro-inflammatory cytokines affects MSCs' secretory profile and osteogenic ability. MSCs cultured under hypoxic conditions show increased proliferation rates and secretion of growth factors. Resolution of inflammation via local delivery of anti-inflammatory cytokines is also a potential therapy for bone regeneration in inflammaging. Scaffolds containing anti-inflammatory cytokines, unaltered MSCs, and genetically modified MSCs can also have therapeutic potential. MSC exosomes can increase the migration of MSCs to the fracture site and enhance osteogenic differentiation and angiogenesis.In conclusion, inflammaging can impair the proper initiation of bone regeneration in the elderly. Modulating inflammaging is a promising approach for improving compromised bone healing in the aging population.
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Affiliation(s)
- Junichi Kushioka
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
| | - Simon Kwoon-Ho Chow
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Masakazu Toya
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Masanori Tsubosaka
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Huaishuang Shen
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Qi Gao
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Xueping Li
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Ning Zhang
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
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19
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Phyo H, Aburza A, Mellanby K, Esteves CL. Characterization of canine adipose- and endometrium-derived Mesenchymal Stem/Stromal Cells and response to lipopolysaccharide. Front Vet Sci 2023; 10:1180760. [PMID: 37275605 PMCID: PMC10237321 DOI: 10.3389/fvets.2023.1180760] [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: 03/06/2023] [Accepted: 05/02/2023] [Indexed: 06/07/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are used for regenerative therapy in companion animals. Their potential was initially attributed to multipotency, but subsequent studies in rodents, humans and veterinary species evidenced that MSCs produce factors that are key mediators of immune, anti-infective and angiogenic responses, which are essential in tissue repair. MSCs preparations have been classically obtained from bone marrow and adipose tissue (AT) in live animals, what requires the use of surgical procedures. In contrast, the uterus, which is naturally exposed to external insult and infection, can be accessed nonsurgically to obtain samples, or tissues can be taken after neutering. In this study, we explored the endometrium (EM) as an alternative source of MSCs, which we compared with AT obtained from canine paired samples. Canine AT- and EM-MSCs, formed CFUs when seeded at low density, underwent tri-lineage differentiation into adipocytes, osteocytes and chondrocytes, and expressed the CD markers CD73, CD90 and CD105, at equivalent levels. The immune genes IL8, CCL2 and CCL5 were equally expressed at basal levels by both cell types. However, in the presence of the inflammatory stimulus lipopolysaccharide (LPS), expression of IL8 was higher in EM- than in AT-MSCs (p < 0.04) while the other genes were equally elevated in both cell types (p < 0.03). This contrasted with the results for CD markers, where the expression was unaltered by exposing the MSCs to LPS. Overall, the results indicate that canine EM-MSCs could serve as an alternative cell source to AT-MSCs in therapeutic applications.
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Feng L, Yang Z, Hou N, Wang M, Lu X, Li Y, Wang H, Wang Y, Bai S, Zhang X, Lin Y, Yan X, Lin S, Tortorella MD, Li G. Long Non-Coding RNA Malat1 Increases the Rescuing Effect of Quercetin on TNFα-Impaired Bone Marrow Stem Cell Osteogenesis and Ovariectomy-Induced Osteoporosis. Int J Mol Sci 2023; 24:5965. [PMID: 36983039 PMCID: PMC10059267 DOI: 10.3390/ijms24065965] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/09/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Osteoporosis, a common systematic bone homeostasis disorder related disease, still urgently needs innovative treatment methods. Several natural small molecules were found to be effective therapeutics in osteoporosis. In the present study, quercetin was screened out from a library of natural small molecular compounds by a dual luciferase reporter system. Quercetin was found to upregulate Wnt/β-catenin while inhibiting NF-κB signaling activities, and thereby rescuing osteoporosis-induced tumor necrosis factor alpha (TNFα) impaired BMSCs osteogenesis. Furthermore, a putative functional lncRNA, Malat1, was shown to be a key mediator in quercetin regulated signaling activities and TNFα-impaired BMSCs osteogenesis, as mentioned above. In an ovariectomy (OVX)-induced osteoporosis mouse model, quercetin administration could significantly rescue OVX-induced bone loss and structure deterioration. Serum levels of Malat1 were also obviously rescued in the OVX model after quercetin treatment. In conclusion, our study demonstrated that quercetin could rescue TNFα-impaired BMSCs osteogenesis in vitro and osteoporosis-induced bone loss in vivo, in a Malat1-dependent manner, suggesting that quercetin may serve as a therapeutic candidate for osteoporosis treatment.
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Affiliation(s)
- Lu Feng
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Zhengmeng Yang
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Nan Hou
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Ming Wang
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Xuan Lu
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Yucong Li
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Haixing Wang
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Yaofeng Wang
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
| | - Shanshan Bai
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Xiaoting Zhang
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Yuejun Lin
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Xu Yan
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Sien Lin
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Micky D. Tortorella
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
| | - Gang Li
- Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen 518000, China
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21
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Valiulienė G, Zentelytė A, Beržanskytė E, Navakauskienė R. Effect of 3D Spheroid Culturing on NF-κB Signaling Pathway and Neurogenic Potential in Human Amniotic Fluid Stem Cells. Int J Mol Sci 2023; 24:ijms24043584. [PMID: 36834995 PMCID: PMC9963588 DOI: 10.3390/ijms24043584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/05/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Human amniotic fluid stem cells (hAFSCs) are known for their advantageous properties when compared to somatic stem cells from other sources. Recently hAFSCs have gained attention for their neurogenic potential and secretory profile. However, hAFSCs in three-dimensional (3D) cultures remain poorly investigated. Therefore, we aimed to evaluate cellular properties, neural differentiation, and gene and protein expression in 3D spheroid cultures of hAFSCs in comparison to traditional two-dimensional (2D) monolayer cultures. For this purpose, hAFSCs were obtained from amniotic fluid of healthy pregnancies and cultivated in vitro, either in 2D, or 3D under untreated or neuro-differentiated conditions. We observed upregulated expression of pluripotency genes OCT4, NANOG, and MSI1 as well as augmentation in gene expression of NF-κB-TNFα pathway genes (NFKB2, RELA and TNFR2), associated miRNAs (miR103a-5p, miR199a-3p and miR223-3p), and NF-κB p65 protein levels in untreated hAFSC 3D cultures. Additionally, MS analysis of the 3D hAFSCs secretome revealed protein upregulation of IGFs signaling the cascade and downregulation of extracellular matrix proteins, whereas neural differentiation of hAFSC spheroids increased the expression of SOX2, miR223-3p, and MSI1. Summarizing, our study provides novel insights into how 3D culture affects neurogenic potential and signaling pathways of hAFSCs, especially NF-κB, although further studies are needed to elucidate the benefits of 3D cultures more thoroughly.
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22
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Isaković J, Šerer K, Barišić B, Mitrečić D. Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force? Front Bioeng Biotechnol 2023; 11:1139359. [PMID: 36926687 PMCID: PMC10011535 DOI: 10.3389/fbioe.2023.1139359] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Neurological disorders are recognized as major causes of death and disability worldwide. Because of this, they represent one of the largest public health challenges. With awareness of the massive burden associated with these disorders, came the recognition that treatment options were disproportionately scarce and, oftentimes, ineffective. To address these problems, modern research is increasingly looking into novel, more effective methods to treat neurological patients; one of which is cell-based therapies. In this review, we present a critical analysis of the features, challenges, and prospects of one of the stem cell types that can be employed to treat numerous neurological disorders-mesenchymal stem cells (MSCs). Despite the fact that several studies have already established the safety of MSC-based treatment approaches, there are still some reservations within the field regarding their immunocompatibility, heterogeneity, stemness stability, and a range of adverse effects-one of which is their tumor-promoting ability. We additionally examine MSCs' mechanisms of action with respect to in vitro and in vivo research as well as detail the findings of past and ongoing clinical trials for Parkinson's and Alzheimer's disease, ischemic stroke, glioblastoma multiforme, and multiple sclerosis. Finally, this review discusses prospects for MSC-based therapeutics in the form of biomaterials, as well as the use of electromagnetic fields to enhance MSCs' proliferation and differentiation into neuronal cells.
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Affiliation(s)
- Jasmina Isaković
- Omnion Research International, Zagreb, Croatia.,Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Klara Šerer
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Barbara Barišić
- University of Zagreb School of Dental Medicine, Zagreb, Croatia
| | - Dinko Mitrečić
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia.,Laboratory for Stem Cells, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
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23
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Shanbhag S, Rana N, Suliman S, Idris SB, Mustafa K, Stavropoulos A. Influence of Bone Substitutes on Mesenchymal Stromal Cells in an Inflammatory Microenvironment. Int J Mol Sci 2022; 24:ijms24010438. [PMID: 36613880 PMCID: PMC9820717 DOI: 10.3390/ijms24010438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
Bone regeneration is driven by mesenchymal stromal cells (MSCs) via their interactions with immune cells, such as macrophages (MPs). Bone substitutes, e.g., bi-calcium phosphates (BCPs), are commonly used to treat bone defects. However, little research has focused on MSC responses to BCPs in the context of inflammation. The objective of this study was to investigate whether BCPs influence MSC responses and MSC-MP interactions, at the gene and protein levels, in an inflammatory microenvironment. In setup A, human bone marrow MSCs combined with two different BCP granules (BCP 60/40 or BCP 20/80) were cultured with or without cytokine stimulation (IL1β + TNFα) to mimic acute inflammation. In setup B, U937 cell-line-derived MPs were introduced via transwell cocultures to setup A. Monolayer MSCs with and without cytokine stimulation served as controls. After 72 h, the expressions of genes related to osteogenesis, healing, inflammation and remodeling were assessed in the MSCs via quantitative polymerase chain reactions. Additionally, MSC-secreted cytokines related to healing, inflammation and chemotaxis were assessed via multiplex immunoassays. Overall, the results indicate that, under both inflammatory and non-inflammatory conditions, the BCP granules significantly regulated the MSC gene expressions towards a pro-healing genotype but had relatively little effect on the MSC secretory profiles. In the presence of the MPs (coculture), the BCPs positively regulated both the gene expression and cytokine secretion of the MSCs. Overall, similar trends in MSC responses were observed with BCP 60/40 and BCP 20/80. In summary, within the limits of in vitro models, these findings suggest that the presence of BCP granules at a surgical site may not necessarily have a detrimental effect on MSC-mediated wound healing, even in the event of inflammation.
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Affiliation(s)
- Siddharth Shanbhag
- Center for Translational Oral Research (TOR), Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, 5009 Bergen, Norway
- Department of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen, Norway
| | - Neha Rana
- Center for Translational Oral Research (TOR), Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, 5009 Bergen, Norway
| | - Salwa Suliman
- Center for Translational Oral Research (TOR), Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, 5009 Bergen, Norway
| | | | - Kamal Mustafa
- Center for Translational Oral Research (TOR), Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, 5009 Bergen, Norway
| | - Andreas Stavropoulos
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria
- Department of Periodontology, Faculty of Odontology, Malmö University, 205 06 Malmö, Sweden
- Correspondence: ; Tel.: +46-040-6658066
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24
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Wang D, Xie Y, Peng HQ, Wen ZM, Ying ZY, Geng C, Wu J, Lv HY, Xu B. LPS preconditioning of MSC-CM improves protection against hypoxia/reoxygenation-induced damage in H9c2 cells partly via HMGB1/Bach1 signalling. Clin Exp Pharmacol Physiol 2022; 49:1319-1333. [PMID: 36052438 DOI: 10.1111/1440-1681.13714] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 08/14/2022] [Accepted: 08/28/2022] [Indexed: 01/31/2023]
Abstract
Mesenchymal stem cell-derived conditioned medium (MSC-CM) improves cardiac function after myocardial infarction; however, this cardioprotective effect is moderate and transient. Lipopolysaccharide (LPS) pretreatment partially improves MSC-CM-mediated cardioprotective effects owing to the presence of paracrine factors. However, the mechanism underlying these improved effects remains unknown. To study the effect of LPS-pretreated MSC-CM on hypoxia/reoxygenation (H/R)-induced injury, MSCs were treated with or without LPS (400 ng/mL) for 48 h, and the supernatant was collected (MSC-CM). Subsequently, H9c2 cells were co-cultured with Nor-CM (CM derived from LPS-untreated MSCs) and LPS-CM (CM derived from LPS-pretreated MSCs) for 24 h and subjected to H/R. MSC-CM inhibited the progression of H/R-induced injury in H9c2 cells, and this protective effect was enhanced via LPS pretreatment as evidenced by the improved apoptosis assessment index (i.e. caspase-3 and B-cell lymphoma-2 [Bcl-2] expression) and decreased levels of lactic dehydrogenase (LDH) and cardiac troponin (cTn). In addition, the results of haematoxylin-eosin staining (H&E), transmission electron microscopy (TEM) and TdT-mediated dUTP nick-end labelling (TUNEL) validated that MSC-CM inhibited H/R-induced injury in H9c2 cardiomyocytes. LPS pretreatment downregulated the expression of high mobility group box-1 (HMGB1) and BTB and CNC homology-1 (Bach1) proteins in MSCs but upregulated the expression of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and insulin-like growth factor (IGF). HMGB1 knockdown (MSC/siHMGB1-CM) significantly decreased the expression of Bach1 and increased the expression of VEGF, HGF and IGF. Bach1 knockdown (MSC/siBach1-CM) did not alter the production of HMGB1 but increased the expression of VEGF and IGF. LPS pretreatment did not alter the expression of the paracrine factors VEGF and HGF in the MSC/siHMGB1 group but increased their expression in the MSC/siBach1 group. The myocyte anti-apoptotic effects of MSCs/siBach1-CM were similar to those of untreated MSCs, which were not enhanced by LPS. LPS-pretreated MSC-CM protects H9c2 cells against H/R-induced injury partly through the HMGB1/Bach1 signalling pathway.
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Affiliation(s)
- Dan Wang
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.,Department of Pharmacy, Ordos Central Hospital, Ordos, China
| | - Yu Xie
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hui-Qian Peng
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhi-Min Wen
- Department of Clinical Laboratory, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zi-Yue Ying
- Department of Clinical Laboratory, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Cong Geng
- Department of Clinical Laboratory, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jun Wu
- Department of Echocardiography, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hui-Yi Lv
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bing Xu
- Department of Clinical Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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25
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Liu C, Lu Y, Du P, Yang F, Guo P, Tang X, Diao L, Lu G. Mesenchymal stem cells pretreated with proinflammatory cytokines accelerate skin wound healing by promoting macrophages migration and M2 polarization. Regen Ther 2022; 21:192-200. [PMID: 35983499 PMCID: PMC9356027 DOI: 10.1016/j.reth.2022.06.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 04/22/2022] [Accepted: 06/23/2022] [Indexed: 11/26/2022] Open
Abstract
Introduction Methods Results Conclusions
We found that S-IT MSCs were better at promoting macrophage migration and activation than S-MSCs in vitro. Next, we reconfirmed that S-IT MSCs were more effective than S-MSCs in accelerating wound closure by promoting macrophage migration and activation. High levels of CCL2 and IL-6 in S-IT MSCs may play a key role in improving macrophage function.
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26
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Huang Y, Zhu M, Liu Z, Hu R, Li F, Song Y, Geng Y, Ma W, Song K, Zhang M. Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects. Front Immunol 2022; 13:997808. [PMID: 36389844 PMCID: PMC9646528 DOI: 10.3389/fimmu.2022.997808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/17/2022] [Indexed: 12/31/2022] Open
Abstract
Premature ovarian failure (POF) is a common female reproductive disorder and characterized by menopause, increased gonadotropin levels and estrogen deficiency before the age of 40 years old. The etiologies and pathogenesis of POF are not fully clear. At present, hormone replacement therapy (HRT) is the main treatment options for POF. It helps to ameliorate perimenopausal symptoms and related health risks, but can't restore ovarian function and fertility fundamentally. With the development of regenerative medicine, bone marrow mesenchymal stem cells (BMSCs) have shown great potential for the recovery of ovarian function and fertility based on the advantages of abundant sources, high capacity for self-renewal and differentiation, low immunogenicity and less ethical considerations. This systematic review aims to summarize the possible therapeutic mechanisms of BMSCs for POF. A detailed search strategy of preclinical studies and clinical trials on BMSCs and POF was performed on PubMed, MEDLINE, Web of Science and Embase database. A total of 21 studies were included in this review. Although the standardization of BMSCs need more explorations, there is no doubt that BMSCs transplantation may represent a prospective therapy for POF. It is hope to provide a theoretical basis for further research and treatment for POF.
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Affiliation(s)
- Yanjing Huang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengdi Zhu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhuo Liu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Runan Hu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fan Li
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yufan Song
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuli Geng
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenwen Ma
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kunkun Song
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Mingmin Zhang, ; Kunkun Song,
| | - Mingmin Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Mingmin Zhang, ; Kunkun Song,
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27
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Colombini A, Libonati F, Cangelosi D, Lopa S, De Luca P, Coviello DA, Moretti M, de Girolamo L. Inflammatory priming with IL-1β promotes the immunomodulatory behavior of adipose derived stem cells. Front Bioeng Biotechnol 2022; 10:1000879. [PMID: 36338130 PMCID: PMC9632288 DOI: 10.3389/fbioe.2022.1000879] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 10/05/2022] [Indexed: 11/15/2023] Open
Abstract
Inflammatory processes contribute to osteoarthritis (OA) severity and progression. Mesenchymal stem cells, particularly those derived from adipose tissue (ASCs), are able to sense and control the inflammatory environment. This immunomodulatory potential can be boosted by different priming strategies based on inflammatory stimulation. The aim of the present study is to investigate the transcriptional modulation of a huge panel of genes and functionally verify the predicted immunomodulatory ability of ASCs after interleukin one beta (IL-1β) priming. ASCs were isolated from adipose tissue obtained from three donors and expanded. After stimulation with 1 ng/ml of IL-1β for 48 h, cells were collected for gene array and functional tests. Pooled cells from three donors were used for RNA extraction and gene array analysis. Gene Ontology (GO) enrichment analysis and Gene Set Enrichment Analysis (GSEA) were performed to assess the involvement of the modulated genes after priming in specific biological processes and pathways. Functional co-culture tests of ASCs with T cells and macrophages were performed to assess the ability of primed ASCs to modulate immune cell phenotype. Among the overall genes analyzed in the gene array, about the 18% were up- or down-regulated in ASCs after IL-1β priming. GO enrichment analysis of up- or down-regulated genes in ASCs after IL-1β priming allowed identifying specific pathways involved in the modulation of inflammation and extracellular matrix remodeling. The main processes enriched according to the GSEA are related to the inflammatory response and cell proliferative processes. Functional tests on immune cells showed that primed and non-primed ASCs induced a decrease in the CD3+ T lymphocytes survival rate and an anti-inflammatory macrophage polarization. In conclusion, IL-1β priming represents a tailored strategy to enhance the ability of ASCs to direct macrophages towards an anti-inflammatory phenotype and, consequently, improve the efficacy of ASCs in counteracting the OA inflammatory component.
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Affiliation(s)
| | - Francesca Libonati
- Orthopaedic Biotechnology Lab, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Davide Cangelosi
- Unità di Bioinformatica Clinica, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Silvia Lopa
- Cell and Tissue Engineering Laboratory, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Paola De Luca
- Orthopaedic Biotechnology Lab, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | | | - Matteo Moretti
- Cell and Tissue Engineering Laboratory, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Regenerative Medicine Technologies Lab, Ente Ospedaliero Cantonale, Laboratories for Translational Research (LRT), Bellinzona, Switzerland
- Department of Surgery, Ente Ospedaliero Cantonale, Service of Orthopaedics and Traumatology, Lugano, Switzerland
- Faculty of Biomedical Sciences, Euler Institute, Lugano, Switzerland
| | - Laura de Girolamo
- Orthopaedic Biotechnology Lab, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
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28
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Hoang VT, Nguyen HP, Nguyen VN, Hoang DM, Nguyen TST, Nguyen Thanh L. “Adipose-derived mesenchymal stem cell therapy for the management of female sexual dysfunction: Literature reviews and study design of a clinical trial”. Front Cell Dev Biol 2022; 10:956274. [PMID: 36247008 PMCID: PMC9554747 DOI: 10.3389/fcell.2022.956274] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/29/2022] [Indexed: 11/25/2022] Open
Abstract
Hormone imbalance and female sexual dysfunction immensely affect perimenopausal female health and quality of life. Hormone therapy can improve female hormone deficiency, but long-term use increases the risk of cardiovascular diseases and cancer. Therefore, it is necessary to develop a novel effective treatment to achieve long-term improvement in female general and sexual health. This study reviewed factors affecting syndromes of female sexual dysfunction and its current therapy options. Next, the authors introduced research data on mesenchymal stromal cell/mesenchymal stem cell (MSC) therapy to treat female reproductive diseases, including Asherman’s syndrome, premature ovarian failure/primary ovarian insufficiency, and vaginal atrophy. Among adult tissue-derived MSCs, adipose tissue-derived stem cells (ASCs) have emerged as the most potent therapeutic cell therapy due to their abundant presence in the stromal vascular fraction of fat, high proliferation capacity, superior immunomodulation, and strong secretion profile of regenerative factors. Potential mechanisms and side effects of ASCs for the treatment of female sexual dysfunction will be discussed. Our phase I clinical trial has demonstrated the safety of autologous ASC therapy for women and men with sexual hormone deficiency. We designed the first randomized controlled crossover phase II trial to investigate the safety and efficacy of autologous ASCs to treat female sexual dysfunction in perimenopausal women. Here, we introduce the rationale, trial design, and methodology of this clinical study. Because aging and metabolic diseases negatively impact the bioactivity of adult-derived MSCs, this study will use ASCs cultured in physiological oxygen tension (5%) to cope with these challenges. A total of 130 perimenopausal women with sexual dysfunction will receive two intravenous infusions of autologous ASCs in a crossover design. The aims of the proposed study are to evaluate 1) the safety of cell infusion based on the frequency and severity of adverse events/serious adverse events during infusion and follow-up and 2) improvements in female sexual function assessed by the Female Sexual Function Index (FSFI), the Utian Quality of Life Scale (UQOL), and the levels of follicle-stimulating hormone (FSH) and estradiol. In addition, cellular aging biomarkers, including plasminogen activator inhibitor-1 (PAI-1), p16 and p21 expression in T cells and the inflammatory cytokine profile, will also be characterized. Overall, this study will provide essential insights into the effects and potential mechanisms of ASC therapy for perimenopausal women with sexual dysfunction. It also suggests direction and design strategies for future research.
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Affiliation(s)
- Van T. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Hoang-Phuong Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Viet Nhan Nguyen
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
- College of Health Science, Vin University, Vinhomes Ocean Park, Hanoi, Vietnam
| | - Duc M. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Tan-Sinh Thi Nguyen
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
- College of Health Science, Vin University, Vinhomes Ocean Park, Hanoi, Vietnam
- *Correspondence: Liem Nguyen Thanh,
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Aru B, Gürel G, Yanikkaya Demirel G. Mesenchymal Stem Cells: History, Characteristics and an Overview of Their Therapeutic Administration. TURKISH JOURNAL OF IMMUNOLOGY 2022. [DOI: 10.4274/tji.galenos.2022.18209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Liu C, Xu Y, Lu Y, Du P, Li X, Wang C, Guo P, Diao L, Lu G. Mesenchymal stromal cells pretreated with proinflammatory cytokines enhance skin wound healing via IL-6-dependent M2 polarization. Stem Cell Res Ther 2022; 13:414. [PMID: 35964139 PMCID: PMC9375394 DOI: 10.1186/s13287-022-02934-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/23/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Numerous studies have shown that mesenchymal stromal cells (MSCs) promote cutaneous wound healing via paracrine signaling. Our previous study found that the secretome of MSCs was significantly amplified by treatment with IFN-γ and TNF-α (IT). It has been known that macrophages are involved in the initiation and termination of inflammation, secretion of growth factors, phagocytosis, cell proliferation, and collagen deposition in wound, which is the key factor during wound healing. In this study, we aim to test whether the supernatant of MSCs pretreated with IT (S-IT MSCs) possesses a more pronounced effect on improving wound healing and describe the interplay between S-IT MSCs and macrophages as well as the potential mechanism in skin wound healing. METHODS In the present study, we used a unique supernatant of MSCs from human umbilical cord-derived MSCs (UC-MSCs) pretreated with IT, designated S-IT MSCs, subcutaneously injected into a mice total skin excision. We evaluated the effect of S-IT MSCs on the speed and quality of wound repair via IT MSCs-derived IL-6-dependent M2 polarization in vivo by hematoxylin-eosin staining (H&E), immunohistochemistry (IHC), immunofluorescence (IF), Masson's trichrome staining, Sirius red staining, quantitative real-time PCR (qPCR). In addition, the effect of S-IT MSCs on the polarization of macrophages toward M2 phenotype and the potential mechanism of it were also investigated in vitro by flow cytometry (FCM), enzyme-linked immunosorbent assay (ELISA), tube formation assay, and western blot analysis. RESULTS Compared with control supernatant (S-MSCs), our H&E and IF results showed that S-IT MSCs were more effectively in promoting macrophages convert to the M2 phenotype and enhancing phagocytosis of M2 macrophages. Meanwhile, the results of tube formation assay, IHC, Masson's trichrome staining, Sirius red staining showed that the abilities of M2 phenotype to promote vascularization and collagen deposition were significantly enhanced by S-IT MSCs-treated, thereby accelerating higher quality wound healing. Further, our ELISA, FCM, qPCR and western blot results showed that IL-6 was highly enriched in S-IT MSCs and acted as a key regulator to induce macrophages convert to the M2 phenotype through IL-6-dependent signaling pathways, ultimately achieving the above function of promoting wound repair. CONCLUSIONS These findings provide the first evidence that the S-IT MSCs is more capable of eliciting M2 polarization of macrophages via IL-6-dependent signaling pathways and accelerating wound healing, which may represent a new strategy for optimizing the therapeutic effect of MSCs on wound healing.
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Affiliation(s)
- Chenyang Liu
- Nanjng University of Traditional Chinese Medcine, Nanjng, Jiangsu, China.,Engineering Research Center of the Ministry of Education for Wound Repair Technology, Jiangnan University, The Affiliated Hospital of Jiangnan University, Jiangsu, China
| | - Yan Xu
- Nanjng University of Traditional Chinese Medcine, Nanjng, Jiangsu, China.,Engineering Research Center of the Ministry of Education for Wound Repair Technology, Jiangnan University, The Affiliated Hospital of Jiangnan University, Jiangsu, China
| | - Yichi Lu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Pan Du
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Xiaoxiao Li
- Nanjng University of Traditional Chinese Medcine, Nanjng, Jiangsu, China
| | - Chengchun Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Peng Guo
- Nantong University, Nantong, Jiangsu, China
| | - Ling Diao
- Engineering Research Center of the Ministry of Education for Wound Repair Technology, Jiangnan University, The Affiliated Hospital of Jiangnan University, Jiangsu, China.
| | - Guozhong Lu
- Nanjng University of Traditional Chinese Medcine, Nanjng, Jiangsu, China. .,Engineering Research Center of the Ministry of Education for Wound Repair Technology, Jiangnan University, The Affiliated Hospital of Jiangnan University, Jiangsu, China.
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The secretome obtained under hypoxic preconditioning from human adipose-derived stem cells exerts promoted anti-apoptotic potentials through upregulated autophagic process. Mol Biol Rep 2022; 49:8859-8870. [PMID: 35941418 DOI: 10.1007/s11033-022-07736-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 06/14/2022] [Accepted: 06/22/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Hypoxic preconditioning (HP) is a stem cell preconditioning modality designed to augment the therapeutic effects of mesenchymal stem cells (MSCs). Although autophagy is expected to play a role in HP, very little is known regarding the relationship between HP and autophagy. METHODS AND RESULTS The adipose-derived stem cell (ASC)-secretome obtained under normoxia (NCM) and ASC-secretome obtained under HP (HCM) were obtained by culturing ASCs for 24 h under normoxic (21% partial pressure of O2) and hypoxic (1% partial pressure of O2) conditions, respectively. Subsequently, to determine the in vivo effects of HCM, each secretome was injected into 70% partially hepatectomized mice, and liver specimens were obtained. HCM significantly reduced the apoptosis of thioacetamide-treated AML12 hepatocytes and promoted the autophagic processes of the cells (P < 0.05). Autophagy blockage by either bafilomycin A1 or ATG5 siRNA significantly abrogated the anti-apoptotic effect of HCM (P < 0.05), demonstrating that HCM exerts its anti-apoptotic effect by promoting autophagy. The effect of HCM - reduction of cell apoptosis and promotion of autophagic process - was also demonstrated in a mouse model. CONCLUSIONS HP appears to induce ASCs to release a secretome with enhanced anti-apoptotic effects by promoting the autophagic process of ASCs.
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Ramuta TŽ, Kreft ME. Mesenchymal Stem/Stromal Cells May Decrease Success of Cancer Treatment by Inducing Resistance to Chemotherapy in Cancer Cells. Cancers (Basel) 2022; 14:cancers14153761. [PMID: 35954425 PMCID: PMC9367361 DOI: 10.3390/cancers14153761] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Tumours consist of different cell types and an extracellular matrix, all of which together form a complex microenvironment. The tumour microenvironment plays a critical role in various aspects of tumour development and progression. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells that have a tri-lineage differentiation capacity and are one of the key stromal cells in the tumour microenvironment. Following the interaction with cancer cells, they are transformed from naïve MSCs to tumour-associated MSCs, which substantially affect tumour growth and progression as well as the development of chemoresistance in cancer cells. The aim of this review article is to provide an overview of studies that have investigated how MSCs affect the susceptibility of cancer cells to chemotherapeutics. Their results show that MSCs protect cancer cells from chemotherapeutics by influencing several signalling pathways. This knowledge is crucial for the development of new treatment approaches that will lead to improved treatment outcomes. Abstract The tumour microenvironment, which is comprised of various cell types and the extracellular matrix, substantially impacts tumour initiation, progression, and metastasis. Mesenchymal stem/stromal cells (MSCs) are one of the key stromal cells in the tumour microenvironment, and their interaction with cancer cells results in the transformation of naïve MSCs to tumour-associated MSCs. The latter has an important impact on tumour growth and progression. Recently, it has been shown that they can also contribute to the development of chemoresistance in cancer cells. This review provides an overview of 42 studies published between 1 January 2001 and 1 January 2022 that examined the effect of MSCs on the susceptibility of cancer cells to chemotherapeutics. The studies showed that MSCs affect various signalling pathways in cancer cells, leading to protection against chemotherapy-induced damage. Promising results emerged from the use of inhibitors of various signalling pathways that are affected in cancer cells due to interactions with MSCs in the tumour microenvironment. These studies present a good starting point for the investigation of novel treatment approaches and demonstrate the importance of targeting the stroma in the tumour microenvironment to improve treatment outcomes.
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Wang D, Cao H, Hua W, Gao L, Yuan Y, Zhou X, Zeng Z. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Bone Defect Repair. MEMBRANES 2022; 12:716. [PMID: 35877919 PMCID: PMC9315966 DOI: 10.3390/membranes12070716] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 12/12/2022]
Abstract
The repair of critical bone defects is a hotspot of orthopedic research. With the development of bone tissue engineering (BTE), there is increasing evidence showing that the combined application of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) (MSC-EVs), especially exosomes, with hydrogels, scaffolds, and other bioactive materials has made great progress, exhibiting a good potential for bone regeneration. Recent studies have found that miRNAs, proteins, and other cargo loaded in EVs are key factors in promoting osteogenesis and angiogenesis. In BTE, the expression profile of the intrinsic cargo of EVs can be changed by modifying the gene expression of MSCs to obtain EVs with enhanced osteogenic activity and ultimately enhance the osteoinductive ability of bone graft materials. However, the current research on MSC-EVs for repairing bone defects is still in its infancy, and the underlying mechanism remains unclear. Therefore, in this review, the effect of bioactive materials such as hydrogels and scaffolds combined with MSC-EVs in repairing bone defects is summarized, and the mechanism of MSC-EVs promoting bone defect repair by delivering active molecules such as internal miRNAs is further elucidated, which provides a theoretical basis and reference for the clinical application of MSC-EVs in repairing bone defects.
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Affiliation(s)
- Dongxue Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Hong Cao
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Weizhong Hua
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Lu Gao
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Yu Yuan
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Xuchang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Zhipeng Zeng
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
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Wang Z, Yu T, Hou Y, Zhou W, Ding Y, Nie H. Mesenchymal Stem Cell Therapy for ALI/ARDS: Therapeutic Potential and Challenges. Curr Pharm Des 2022; 28:2234-2240. [PMID: 35796453 DOI: 10.2174/1381612828666220707104356] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 05/24/2022] [Indexed: 11/22/2022]
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a serious clinical common disease, which may be caused by a variety of pathological factors and can induce a series of serious complications. There is still no specific and effective method for the treatment of ALI/ARDS. Mesenchymal stem cells (MSCs) have been one of the treatment methods for ALI, which can regulate related signal pathways such as PI3K/AKT, Wnt, and NF-κB to reduce inflammation. MSCs exist in a variety of tissues and have the ability of self-renewal and differentiation, which can be activated by specific substances or environments and home to the site of tissue damage, where they differentiate into new tissue cells and repair the damage. Both exosomes and cytokines involving the paracrine mechanism of MSCs have benefits on the treatment of ALI. Lung organoids produced by 3D culture technology can simulate the characteristics of the lung and help to research the pathophysiological process of ALI. This review summarizes the mechanisms by which MSCs treat ALI/ARDS and expects to use 3D models for future challenges in this field.
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Affiliation(s)
- Zhenxing Wang
- Department of Hematology and Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Tong Yu
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yapeng Hou
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Wei Zhou
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yan Ding
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Hongguang Nie
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
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35
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Hamid OIA, Domouky AM, El-Fakharany YM. Molecular evidence of the amelioration of toluene induced encephalopathy by human breast milk mesenchymal stem cells. Sci Rep 2022; 12:9194. [PMID: 35654991 PMCID: PMC9163168 DOI: 10.1038/s41598-022-13173-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/18/2022] [Indexed: 11/09/2022] Open
Abstract
Toluene was widely used volatile organic compound that accumulates in tissues with high lipid content. Stem cells have been proposed as an increasingly attractive approach for repair of damaged nervous system, we aimed to evaluate the ability of breast milk mesenchymal stem cells (MSc) to ameliorate toluene-induced encephalopathy. Sixty adult male albino rats were assigned to 3 groups, control, toluene, and toluene/breast milk-MSc. Neurological assessment was evaluated as well as serum levels of glial fibrillary acidic protein (GFAP), tumor necrosis factor-alpha (TNF-α), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), tissue dopamine and oxidative markers. Gene expression of peroxisome Proliferator-Activated Receptor-Gamma (PPAR-ɣ), nuclear factor-kappaB (NF-kB), and interleukin-6 (IL-6) were evaluated. Moreover, histological and immunohistochemical investigation were done. Results revealed that toluene caused cerebral injury, as evidenced by a significant increase in serum GFAP, TNF-α, malondialdehyde (MDA) and nitric oxide (NO), a significant decrease in serum NGF, tissue dopamine and oxidative markers, besides, a non-significant change in VEGF. Toluene also caused changes in normal cerebral structure and cellular degeneration, including a significant decrease in the total number of neurons and thickness of frontal cortex. Meninges showing signs of inflammation with inflammatory cell infiltration and exudation, a significant decrease in MBP immunoreactivity, and increase in the percent of high motility group box protein-1 (HMGB1) positive cells. PPAR- ɣ, NF-kB, and IL-6 gene expression were all considerably elevated by toluene. These changes were greatly improved by breast milk MSc. Therefore, we conclude that breast milk MSc can attenuate toluene-induced encephalopathy.
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Affiliation(s)
- Omaima I Abdel Hamid
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Alsharquiah, 44519, Egypt
| | - Ayat M Domouky
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Alsharquiah, 44519, Egypt.
| | - Yara M El-Fakharany
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Alsharquiah, 44519, Egypt
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36
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Kang M, Huang CC, Gajendrareddy P, Lu Y, Shirazi S, Ravindran S, Cooper LF. Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration. Front Immunol 2022; 13:878194. [PMID: 35585987 PMCID: PMC9108364 DOI: 10.3389/fimmu.2022.878194] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 04/07/2022] [Indexed: 01/08/2023] Open
Abstract
Mesenchymal stem cells show remarkable versatility and respond to extracellular and micro environmental cues by altering their phenotype and behavior. In this regard, the MSC's immunomodulatory properties in tissue repair are well documented. The paracrine effects of MSCs in immunomodulation are, in part, attributable to their secreted extracellular vesicles (EVs). When MSCs migrate to the wound bed, they are exposed to a myriad of inflammatory signals. To understand their response to an inflammatory environment from an EV perspective, we sought to evaluate the effects of the inflammatory cytokine TNFα on MSC EV mediated immunomodulation. Our results indicate that while the physical characteristics of the EVs remain unchanged, the TNFα preconditioned MSC EVs possess enhanced immunomodulatory properties. In vitro experiments using polarized (M1 and M2) primary mouse macrophages indicated that the preconditioned MSC EVs suppressed pro-inflammatory (M1) markers such as IL-1β and iNOS and elevated reparatory (M2) markers such as Arg1 and CD206. When evaluated in vivo in a rat calvarial defect model, the TNFα preconditioned MSC EVs reduced inflammation at 1-, 3- and 7-days post wounding resulting in the subsequent enhanced bone formation at 4- and 8-weeks post wounding possibly by modulation of oncostatin M (OSM) expression. An analysis of EV miRNA composition revealed significant changes to anti-inflammatory miRNAs in the preconditioned MSC EVs hinting at a possible role for EV derived miRNA in the enhanced immunomodulatory activity. Overall, these results indicate that MSC exposure to inflammatory signals influence the MSC EV's immunomodulatory function in the context of tissue repair. The specific function of TNFα preconditioned MSC EV miRNAs in immunomodulatory control of bone regeneration merits further investigation.
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Affiliation(s)
- Miya Kang
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Chun-Chieh Huang
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Praveen Gajendrareddy
- Department of Periodontics, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Yu Lu
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Sajjad Shirazi
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Sriram Ravindran
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Lyndon F. Cooper
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
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Mikłosz A, Nikitiuk BE, Chabowski A. Using adipose-derived mesenchymal stem cells to fight the metabolic complications of obesity: Where do we stand? Obes Rev 2022; 23:e13413. [PMID: 34985174 PMCID: PMC9285813 DOI: 10.1111/obr.13413] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 12/15/2022]
Abstract
Obesity is a critical risk factor for the development of metabolic diseases, and its prevalence is increasing worldwide. Stem cell-based therapies have become a promising tool for therapeutic intervention. Among them are adipose-derived mesenchymal stem cells (ADMSCs), secreting numerous bioactive molecules, like growth factors, cytokines, and chemokines. Their unique features, including immunosuppressive and immunomodulatory properties, make them an ideal candidates for clinical applications. Numerous experimental studies have shown that ADMSCs can improve pancreatic islet cell viability and function, ameliorate hyperglycemia, improve insulin sensitivity, restore liver function, counteract dyslipidemia, lower pro-inflammatory cytokines, and reduce oxidative stress in the animal models. These results prompted scientists to use ADMSCs clinically. However, up to date, there have been few clinical studies or ongoing trails using ADMSCs to treat metabolic disorders such as type 2 diabetes mellitus (T2DM) or liver cirrhosis. Most human studies have implemented autologous ADMSCs with minimal risk of cellular rejection. Because the functionality of ADMSCs is significantly reduced in subjects with obesity and/or metabolic syndrome, their efficacy is questioned. ADMSCs transplantation may offer a potential therapeutic approach for the treatment of metabolic complications of obesity, but randomized controlled trials are required to establish their safety and efficacy in humans prior to routine clinical use.
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Affiliation(s)
- Agnieszka Mikłosz
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | | | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
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Zoehler B, Fracaro L, Boldrini-Leite LM, da Silva JS, Travers PJ, Brofman PRS, Bicalho MDG, Senegaglia AC. HLA-G and CD152 Expression Levels Encourage the Use of Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells as an Alternative for Immunosuppressive Therapy. Cells 2022; 11:cells11081339. [PMID: 35456019 PMCID: PMC9032010 DOI: 10.3390/cells11081339] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/30/2022] [Accepted: 04/11/2022] [Indexed: 12/04/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have been used in immunosuppressive therapy due to their therapeutic effects, with the HLA-G molecule seeming to play a fundamental role. This work evaluated alternative MSC sources to bone marrow (BM), namely, umbilical cord tissue (UC), adipose tissue (AD) and dental pulp tissue (DP), and the influence of interferon-γ (IFN-γ) and hypoxia on the cultivation of these cells for use in immunosuppression therapies. Expression of costimulatory markers CD40, CD80 and CD86 and immunosuppressive molecules CD152 and HLA-G was analyzed. Lymphocyte inhibition assays were also performed. Sequencing of the HLA-G gene from exons 1 to 5 was performed using next-generation sequencing to determine the presence of alleles. UC-derived MSCs (UCMSCs) expressed higher CD152 and HLA-G1 under standard cultivation. UCMSCs and DP-derived MSCs (DPSCs) secreted similar levels of HLA-G5. All MSC sources inhibited the proliferation of peripheral blood mononuclear cells (PBMCs); growth under regular versus hypoxic conditions resulted in similar levels of inhibition. When IFN-γ was added, PBMC growth was inhibited to a lesser extent by UCMSCs. The HLA-G*01:04:01:01 allele appears to generate a more efficient MSC response in inhibiting lymphocyte proliferation. However, the strength of this conclusion was limited by the small sample size. UCMSCs are an excellent alternative to BM in immunosuppressive therapy: they express high concentrations of inhibitory molecules and can be cultivated without stimuli, which minimizes cost.
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Affiliation(s)
- Bernardo Zoehler
- Immunogenetics and Histocompatibility Laboratory, Department of Genetics, Universidade Federal do Paraná (UFPR), Curitiba 81530-001, PR, Brazil; (J.S.d.S.); (M.d.G.B.)
- Correspondence: (B.Z.); (A.C.S.)
| | - Letícia Fracaro
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80910-215, PR, Brazil; (L.F.); (L.M.B.-L.); (P.R.S.B.)
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro 21941-902, RJ, Brazil
| | - Lidiane Maria Boldrini-Leite
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80910-215, PR, Brazil; (L.F.); (L.M.B.-L.); (P.R.S.B.)
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro 21941-902, RJ, Brazil
| | - José Samuel da Silva
- Immunogenetics and Histocompatibility Laboratory, Department of Genetics, Universidade Federal do Paraná (UFPR), Curitiba 81530-001, PR, Brazil; (J.S.d.S.); (M.d.G.B.)
| | - Paul J. Travers
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh EH16 4UU, UK;
| | - Paulo Roberto Slud Brofman
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80910-215, PR, Brazil; (L.F.); (L.M.B.-L.); (P.R.S.B.)
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro 21941-902, RJ, Brazil
| | - Maria da Graça Bicalho
- Immunogenetics and Histocompatibility Laboratory, Department of Genetics, Universidade Federal do Paraná (UFPR), Curitiba 81530-001, PR, Brazil; (J.S.d.S.); (M.d.G.B.)
| | - Alexandra Cristina Senegaglia
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80910-215, PR, Brazil; (L.F.); (L.M.B.-L.); (P.R.S.B.)
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro 21941-902, RJ, Brazil
- Correspondence: (B.Z.); (A.C.S.)
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Liu C, Wang C, Yang F, Lu Y, Du P, Hu K, Yin X, Zhao P, Lu G. The conditioned medium from mesenchymal stromal cells pretreated with proinflammatory cytokines promote fibroblasts migration and activation. PLoS One 2022; 17:e0265049. [PMID: 35404961 PMCID: PMC9000110 DOI: 10.1371/journal.pone.0265049] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 02/22/2022] [Indexed: 11/19/2022] Open
Abstract
Human dermal fibroblasts (HDFs) play important roles in all stages of wound healing. However, in nonhealing wounds, fibroblasts are prone to aging, resulting in insufficient migration, proliferation and secretion functions. Recent studies have suggested that mesenchymal stromal cells (MSCs) are conducive to wound healing and cell growth through paracrine cytokine signaling. In our studies, we found that conditioned medium of MSCs pretreated with IFN-γ and TNF-α (IT MSC-CM) has abundant growth factors associated with wound repair. Our in vitro results showed that the effects of IT MSC-CM on promoting cell migration, proliferation and activation in HDFs were better than those of conditioned medium from mesenchymal stromal cells (MSC-CM). Moreover, we embedded a scaffold material containing IT MSC-CM and reconfirmed that cell migration and activation were superior to that in the presence of MSC-CM in vivo. Generally, PDGF-BB is perceived as a promoter of the migration and proliferation of HDFs. Moreover, a high level of PDGF-BB in IT MSC-CM was detected, according to which we guess that the effect on HDFs may be mediated by the upregulation of PDGF-BB. These studies all showed the potential of IT MSC-CM to promote rapid and effective wound healing.
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Affiliation(s)
- Chenyang Liu
- Nanjng University of Traditional Chinese Medcine, Nanjng, Jiangsu, China
| | - Chengchun Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | | | - Yichi Lu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Pan Du
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Kai Hu
- Nanjng University of Traditional Chinese Medcine, Nanjng, Jiangsu, China
| | - Xinyao Yin
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Peng Zhao
- Engineering Research Center of the Ministry of Education for Wound Repair Technology, Jiangnan University, The Affiliated Hospital of Jiangnan University, Jiangsu, China
- * E-mail: (GL); (PZ)
| | - Guozhong Lu
- Engineering Research Center of the Ministry of Education for Wound Repair Technology, Jiangnan University, The Affiliated Hospital of Jiangnan University, Jiangsu, China
- * E-mail: (GL); (PZ)
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Tan KX, Chang T, Lin XL. Secretomes as an emerging class of bioactive ingredients for enhanced cosmeceutical applications. Exp Dermatol 2022; 31:674-688. [PMID: 35338666 DOI: 10.1111/exd.14570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/23/2022] [Accepted: 03/22/2022] [Indexed: 11/30/2022]
Abstract
Skin aging is predominantly caused by either intrinsic or extrinsic factors, leading to undesirable skin features. Advancements in both molecular and cellular fields have created possibilities in developing novel stem cell-derived active ingredients for cosmeceutical applications and the beauty industry. Mesenchymal stromal cell (MSC)-derived secretomes or conditioned media hold great promise for advancing skin repair and regeneration due to the presence of varying cytokines. These cytokines signal our cells and trigger biological mechanisms associated with anti-inflammatory, antioxidant, anti-aging, proliferative, and immunomodulatory effects. In this review, we discuss the potential of MSC secretomes as novel biomaterials for skincare and rejuvenation by illustrating their mechanism of action related to wound healing, anti-aging, and whitening properties. The advantages and disadvantages of secretomes are compared to both plant-based and animal-derived extracts. In addition, this paper reviews the current safety standards, regulations, market products and research work related to the cosmeceutical applications of secretomes along with strategies to maintain and improve the therapeutic efficacy and production of secretomes. The future outlook of beauty industry is also presented. Lastly, we highlight significant challenges to be addressed for the clinical realization of MSC secretomes-based skin therapies as well as providing perspectives for the future direction of secretomes.
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Affiliation(s)
- Kei-Xian Tan
- Esco Aster, Block 67, Ayer Rajah Crescent, 139950, Singapore
| | - Trixie Chang
- Esco Aster, Block 67, Ayer Rajah Crescent, 139950, Singapore
| | - Xiang-Liang Lin
- Esco Aster, Block 67, Ayer Rajah Crescent, 139950, Singapore
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41
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Xin DQ, Zhao YJ, Li TT, Ke HF, Gai CC, Guo XF, Chen WQ, Liu DX, Wang Z. The delivery of miR-21a-5p by extracellular vesicles induces microglial polarization via the STAT3 pathway following hypoxia-ischemia in neonatal mice. Neural Regen Res 2022; 17:2238-2246. [PMID: 35259844 PMCID: PMC9083169 DOI: 10.4103/1673-5374.336871] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs) have previously been shown to protect against brain injury caused by hypoxia-ischemia (HI). The neuroprotective effects have been found to relate to the anti-inflammatory effects of EVs. However, the underlying mechanisms have not previously been determined. In this study, we induced oxygen-glucose deprivation in BV-2 cells (a microglia cell line), which mimics HI in vitro, and found that treatment with MSCs-EVs increased the cell viability. The treatment was also found to reduce the expression of pro-inflammatory cytokines, induce the polarization of microglia towards the M2 phenotype, and suppress the phosphorylation of selective signal transducer and activator of transcription 3 (STAT3) in the microglia. These results were also obtained in vivo using neonatal mice with induced HI. We investigated the potential role of miR-21a-5p in mediating these effects, as it is the most highly expressed miRNA in MSCs-EVs and interacts with the STAT3 pathway. We found that treatment with MSCs-EVs increased the levels of miR-21a-5p in BV-2 cells, which had been lowered following oxygen-glucose deprivation. When the level of miR-21a-5p in the MSCs-EVs was reduced, the effects on microglial polarization and STAT3 phosphorylation were reduced, for both the in vitro and in vivo HI models. These results indicate that MSCs-EVs attenuate HI brain injury in neonatal mice by shuttling miR-21a-5p, which induces microglial M2 polarization by targeting STAT3.
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Affiliation(s)
- Dan-Qing Xin
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Yi-Jing Zhao
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Ting-Ting Li
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Hong-Fei Ke
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Cheng-Cheng Gai
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Xiao-Fan Guo
- Department of Neurology, Loma Linda University Health, Loma Linda, CA, USA
| | - Wen-Qiang Chen
- Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - De-Xiang Liu
- Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Zhen Wang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
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42
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Alagesan S, Brady J, Byrnes D, Fandiño J, Masterson C, McCarthy S, Laffey J, O’Toole D. Enhancement strategies for mesenchymal stem cells and related therapies. Stem Cell Res Ther 2022; 13:75. [PMID: 35189962 PMCID: PMC8860135 DOI: 10.1186/s13287-022-02747-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/05/2022] [Indexed: 12/14/2022] Open
Abstract
Cell therapy, particularly mesenchymal stem/stromal (MSC) therapy, has been investigated for a wide variety of disease indications, particularly those with inflammatory pathologies. However, recently it has become evident that the MSC is far from a panacea. In this review we will look at current and future strategies that might overcome limitations in efficacy. Many of these take their inspiration from stem cell niche and the mechanism of MSC action in response to the injury microenvironment, or from previous gene therapy work which can now benefit from the added longevity and targeting ability of a live cell vector. We will also explore the nascent field of extracellular vesicle therapy and how we are already seeing enhancement protocols for this exciting new drug. These enhanced MSCs will lead the way in more difficult to treat diseases and restore potency where donors or manufacturing practicalities lead to diminished MSC effect.
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43
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Indriawati R, Risdiana N, Wibowo T. An Increase in TNF-α Levels in Fetus due to Prenatal Ischemic Hypoxia. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.7840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Prenatal ischemic hypoxia can increase mortality and morbidity and affect the immune system. One of the immune responses is tumor necrosis factor-α (TNF-α) levels. However, the cellular mechanism of immune response abnormalities due to prenatal hypoxia remains unclear. An 11–17-day-old fetus is a sensitive period of neural development. Brain ischemia will cause cell dysfunction and can even affect TNF-α levels. Thus, how prenatal ischemic hypoxia increases TNF-α levels in the fetus remains unclear.
AIM: This study aims to examine the effect of the onset and duration of prenatal ischemic hypoxia on TNF-α levels.
METHODOLOGY: An experimental study with a post-test control design was conducted. Thirty Rattus norvegicus were induced with prenatal ischemic hypoxia (embryos aged 7, 12, and 17 days). The independent variable was prenatal ischemic hypoxia, while the dependent variable was TNF-α levels. TNF-α was measured using the ELISA technique and was carried out when the fetus was 19 days old (E19). The TNF-α was analyzed using ANOVA, and the limit of significance was set at p < 0.05.
RESULTS: The TNF-α levels in the prenatal ischemic hypoxia group were statistically higher than in the control group (p < 0.05). The more the onset and the longer the ischemic hypoxia is, the higher the TNF-level (p < 0.05).
CONCLUSION: The prenatal ischemic hypoxia increased TNF-α levels in the fetus.
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Bao H, Li Y, Yu C, Li X, Wang Y, Gao L, Huang J, Zhang Z. DNA-coated gold nanoparticles for tracking hepatocyte growth factor secreted by transplanted mesenchymal stem cells in pulmonary fibrosis therapy. Biomater Sci 2021; 10:368-375. [PMID: 34897301 DOI: 10.1039/d1bm01362a] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The identification of paracrine factors secreted by transplanted mesenchymal stem cells (MSCs) during the treatment of idiopathic pulmonary fibrosis (IPF) is essential for understanding the role of MSCs in therapy. Herein, we report a facile and efficient strategy for in vivo tracking the secretion of hepatocyte growth factor (HGF) in MSCs during IPF therapy. In our strategy, a novel nanoflare tracer consisting of gold nanoparticles (AuNPs), complementary sequences and dye-labeled recognition sequences is developed. Briefly, the AuNPs are functionalized with oligonucleotide complementary sequences hybridized to the organic dye-labeled recognition sequences, where the organic fluorophores are in close proximity to the AuNPs. In the absence of targets, the dye and AuNPs are separated from each other, inducing the quenching of the fluorescence signal. However, in the presence of targets, the recognition sequences gradually fall off from the AuNPs, causing the fluorescence signal to rise. In brief, in vivo monitoring of the dynamic expression of HGF mRNA in transplanted MSCs during IPF therapy in the current work may provide new insight into the paracrine process of the transplanted MSCs, thereby advancing the MSC-based IPF therapy toward clinical applications.
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Affiliation(s)
- Hongying Bao
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.,CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Yuxuan Li
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.,CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Chenggong Yu
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Xiaodi Li
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.,CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Yujie Wang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Li Gao
- School of Life Science, Jiangsu University, Zhenjiang 212013, China
| | - Jie Huang
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.,CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Zhijun Zhang
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.,CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
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Esquivel-Ruiz S, González-Rodríguez P, Lorente JA, Pérez-Vizcaíno F, Herrero R, Moreno L. Extracellular Vesicles and Alveolar Epithelial-Capillary Barrier Disruption in Acute Respiratory Distress Syndrome: Pathophysiological Role and Therapeutic Potential. Front Physiol 2021; 12:752287. [PMID: 34887773 PMCID: PMC8650589 DOI: 10.3389/fphys.2021.752287] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) mediate intercellular communication by transferring genetic material, proteins and organelles between different cells types in both health and disease. Recent evidence suggests that these vesicles, more than simply diagnostic markers, are key mediators of the pathophysiology of acute respiratory distress syndrome (ARDS) and other lung diseases. In this review, we will discuss the contribution of EVs released by pulmonary structural cells (alveolar epithelial and endothelial cells) and immune cells in these diseases, with particular attention to their ability to modulate inflammation and alveolar-capillary barrier disruption, a hallmark of ARDS. EVs also offer a unique opportunity to develop new therapeutics for the treatment of ARDS. Evidences supporting the ability of stem cell-derived EVs to attenuate the lung injury and ongoing strategies to improve their therapeutic potential are also discussed.
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Affiliation(s)
- Sergio Esquivel-Ruiz
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Paloma González-Rodríguez
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain
| | - José A Lorente
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain.,Clinical Section, School of Medicine, European University of Madrid, Madrid, Spain
| | - Francisco Pérez-Vizcaíno
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Raquel Herrero
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain
| | - Laura Moreno
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
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46
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Farrokhi S, Sotoodehnejadnematalahi F, Fathollahi A, Haji Molla Hoseini M, Hashemi SM, Yeganeh F. The immunomodulatory potential of murine adipose-derived mesenchymal stem cells is enhanced following culture on chitosan film. Tissue Cell 2021; 74:101709. [PMID: 34920235 DOI: 10.1016/j.tice.2021.101709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 12/04/2021] [Accepted: 12/07/2021] [Indexed: 10/25/2022]
Abstract
INTRODUCTION Recent studies show that the paracrine immunomodulatory effects of mesenchymal stem cells (MSCs) are mediated by the secretion of interleukin-10 (IL-10), transforming growth factor-beta (TGF β), and nitric oxide (NO). The preconditioning of MSCs improves their immunomodulatory characteristics. Chitosan is a biopolymer with low toxicity and biodegradability, used as a membrane for MSCs three-dimensional culture. The present study aimed to evaluate the levels of immunomodulatory mediators of mesenchymal cells cultured on the chitosan film. MATERIALS & METHODS MSCs were isolated from abdominal adipose tissue of BALB/c mice. Flow cytometry and differential culture medium were used to confirm the identity of isolated mesenchymal stem cells. The MSCs were divided into three groups; The first group was treated with 10 ng/mL LPS. The second group was seeded in the flasks coated with the chitosan film (3% w/v). The last group was cultured in the flasks without any preconditioning. After 72 h, IL-10, TGF-β, and NO concentrations were measured in the conditioned media. In addition, the arginase activity in mesenchymal stem cells was measured using a colorimetric method. RESULTS The proliferative spindle-shaped MSCs formed several three-dimensional spheroids on the chitosan film. It was shown that the level of TGF-β and IL-10 were increased significantly after treatment with LPS (P = 0.02) and spheroid formation (P = 0.01). In addition, the arginase activity was enormously augmented in spheroids compared to controls (7.13-fold increase; 1.71 ± 0.08 and 0.24 ± 0.01 respectively; P = 0.021). On the other hand, the LPS treatment but not the culture on chitosan film increased the NO level significantly (P = 0.02 and P = 0.14, respectively). CONCLUSION Using chitosan film as a three-dimensional culture strategy significantly affects the production of immunosuppressive factors by MSCs in vitro through increased secretion of TGF-β and IL-10 and arginase activity.
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Affiliation(s)
- Sheida Farrokhi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Anwar Fathollahi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mostafa Haji Molla Hoseini
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshid Yeganeh
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Li H, Wang W, Chang J. Calcium silicate enhances immunosuppressive function of MSCs to indirectly modulate the polarization of macrophages. Regen Biomater 2021; 8:rbab056. [PMID: 34804588 PMCID: PMC8597971 DOI: 10.1093/rb/rbab056] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/13/2021] [Accepted: 09/27/2021] [Indexed: 12/23/2022] Open
Abstract
Bioactive silicate ceramics (BSCs) have been widely reported to be able to induce bone tissue regeneration, but the underlying mechanisms have not been fully elucidated. Previous studies have reported that ionic products of BSCs can promote bone regeneration by directly simulating osteogenic differentiation of mesenchymal stem cells (MSCs) and modulating the polarization of macrophages to create a favorable inflammation microenvironment for initiating bone regeneration cascades. However, the immunomodulatory ability of MSCs also plays a critical role in bone regeneration but the effects of BSCs on the immunomodulatory ability of MSCs have been rarely investigated. This study aims to investigate the effects of ionic products of BSCs on the immunoregulatory ability of MSCs to further understand the mechanism of BSCs enhancing bone regeneration. Results showed that ionic products of calcium silicate (CS), one of the representative BSCs, could enhance the immunosuppressive function of human bone marrow mesenchymal stem cells (HBMSCs) by up-regulating the expression of immunosuppressive factors in HBMSCs via NF-κB pathway. In addition, CS-activated HBMSCs showed stronger stimulatory effects on M2 polarization of macrophages than CS ionic products. Furthermore, the macrophages educated by CS-activated HBMSCs showed stronger stimulatory effects on the early osteogenic differentiation of HBMSCs than the ones regulated by CS ionic products. These results not only provide further understanding on the mechanism of BSCs enhancing bone regeneration but also suggest that it is critical to consider the effects of biomaterials on the immunomodulatory function of the tissue forming cells when the immunomodulatory function of biomaterials is investigated.
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Affiliation(s)
- Haiyan Li
- School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China.,Chemical and Environment Engineering Department, School of Engineering, RMIT University, 124 La Trobe Street, Melbourne, VIC 3001, Australia
| | - Wenrui Wang
- School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
| | - Jiang Chang
- State Key Laboratory of Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai 200050, China
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Takegaki J, Sase K, Kono Y, Nakano D, Fujita T, Konishi S, Fujita S. Intramuscular injection of mesenchymal stem cells activates anabolic and catabolic systems in mouse skeletal muscle. Sci Rep 2021; 11:21224. [PMID: 34707171 PMCID: PMC8551189 DOI: 10.1038/s41598-021-00627-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 10/01/2021] [Indexed: 01/06/2023] Open
Abstract
Skeletal muscle mass is critical for good quality of life. Mesenchymal stem cells (MSCs) are multipotent stem cells distributed across various tissues. They are characterized by the capacity to secrete growth factors and differentiate into skeletal muscle cells. These capabilities suggest that MSCs might be beneficial for muscle growth. Nevertheless, little is known regarding the effects on muscle protein anabolic and catabolic systems of intramuscular injection of MSCs into skeletal muscle. Therefore, in the present study, we measured changes in mechanistic target of rapamycin complex 1 (mTORC1) signaling, the ubiquitin–proteasome system, and autophagy-lysosome system-related factors after a single intramuscular injection of MSCs with green fluorescence protein (GFP) into mouse muscles. The intramuscularly-injected MSCs were retained in the gastrocnemius muscle for 7 days after the injection, indicated by detection of GFP and expression of platelet-derived growth factor receptor-alpha. The injection of MSCs increased the expression of satellite cell-related genes, activated mTORC1 signaling and muscle protein synthesis, and increased protein ubiquitination and autophagosome formation (indicated by the expression of microtubule-associated protein 1 light chain 3-II). These results suggest that the intramuscular injection of MSCs activated muscle anabolic and catabolic systems and accelerated muscle protein turnover.
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Affiliation(s)
- Junya Takegaki
- Research Organization of Science and Technology, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan.,Ritsumeikan Global Innovation Research Organization, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Kohei Sase
- Faculty of Sport and Health Science, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Yusuke Kono
- Ritsumeikan Global Innovation Research Organization, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Daiki Nakano
- Ritsumeikan Global Innovation Research Organization, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Takuya Fujita
- College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Satoshi Konishi
- Faculty of Science and Engineering, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Satoshi Fujita
- Faculty of Sport and Health Science, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan.
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Yu Q, Liao M, Sun C, Zhang Q, Deng W, Cao X, Wang Q, Omari-Siaw E, Bi S, Zhang Z, Yu J, Xu X. LBO-EMSC Hydrogel Serves a Dual Function in Spinal Cord Injury Restoration via the PI3K-Akt-mTOR Pathway. ACS APPLIED MATERIALS & INTERFACES 2021; 13:48365-48377. [PMID: 34633177 DOI: 10.1021/acsami.1c12013] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
It is critical to obtain an anti-inflammatory microenvironment when curing spinal cord injury (SCI). On the basis of this, we prepared Lycium barbarum oligosaccharide (LBO)-nasal mucosa-derived mesenchymal stem cells (EMSCs) fibronectin hydrogel for SCI restoration via inflammatory license effect and M2 polarization of microglias. LBO exhibited remarkable M2 polarization potential for microglia. However, EMSCs primed by LBO generated enhanced paracrine effects through the inflammatory license-like process. The observed dual function is likely based on the TNFR2 pathway. In addition, LBO-EMSC hydrogel possesses a synergistic effect on M2 polarization of microglia through the PI3K-Akt-mTOR signaling pathway. The obtained findings provide a simple approach for MSC-based therapies for SCI and shed more light on the role of TNFR2 on bidirectional regulation in tissue regeneration.
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Affiliation(s)
| | | | | | | | | | - Xia Cao
- Jiangsu University, 212013 Zhenjiang, China
| | | | | | - Shiqi Bi
- Affiliated Hospital of Jiangsu University, 212001 Zhenjiang, China
| | | | | | - Ximing Xu
- Jiangsu University, 212013 Zhenjiang, China
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50
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Hayes CA, Valcarcel-Ares MN, Ashpole NM. Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke. J Cereb Blood Flow Metab 2021; 41:2475-2491. [PMID: 33757314 PMCID: PMC8504958 DOI: 10.1177/0271678x211000894] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Ischemic strokes are highly prevalent in the elderly population and are a leading cause of mortality and morbidity worldwide. The risk of ischemic stroke increases in advanced age, corresponding with a noted decrease in circulating insulin growth factor-1 (IGF-1). IGF-1 is a known neuroprotectant involved in embryonic development, neurogenesis, neurotransmission, cognition, and lifespan. Clinically, several studies have shown that reduced levels of IGF-1 correlate with increased mortality rate, poorer functional outcomes, and increased morbidities following an ischemic stroke. In animal models of ischemia, administering exogenous IGF-1 using various routes of administration (intranasal, intravenous, subcutaneous, or topical) at various time points prior to and following insult attenuates neurological damage and accompanying behavioral changes caused by ischemia. However, there are some contrasting findings in select clinical and preclinical studies. This review discusses the role of IGF-1 as a determinant factor of ischemic stroke outcomes, both within the clinical settings and preclinical animal models. Furthermore, the review provides insight on the role of IGF-1 in mechanisms and cellular processes that contribute to stroke damage.
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Affiliation(s)
- Cellas A Hayes
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Mississippi, USA
| | - M Noa Valcarcel-Ares
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Mississippi, USA
| | - Nicole M Ashpole
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Mississippi, USA.,Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA
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