|
1
|
Qin Q, Ruan H, Zhang H, Xu Z, Pan W, Yan X, Jiang X. Deubiquitinase MYSM1: An Important Tissue Development and Function Regulator. Int J Mol Sci 2024; 25:13051. [PMID: 39684760 DOI: 10.3390/ijms252313051] [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: 10/18/2024] [Revised: 12/01/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
MYSM1, a deubiquitinating enzyme, plays a pivotal role in diverse biological processes. Both MYSM1 knockout mice and patients with Mysm1 gene mutations exhibit developmental abnormalities across multiple tissues and organs. Serving as a crucial regulator, MYSM1 influences stem cell function, immune responses, and the pathogenesis of diverse diseases. This review comprehensively details MYSM1's deubiquitinating activities in both the nucleus and cytoplasmic compartments, its effects on stem cell proliferation, differentiation, and immune cell function, and its involvement in cancer, aging, and depression. The high sequence homology between murine and human MYSM1, along with similar phenotypes observed in Mysm1-deficient models, provides valuable insights into the etiology of human Mysm1-deficiency syndromes. This review aims to offer a foundation for future comprehensive research on MYSM1.
Collapse
Affiliation(s)
- Qiaozhen Qin
- Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
- Beijing Institute of Basic Medical Sciences, Beijing 100850, China
| | - Huaqiang Ruan
- Beijing Institute of Basic Medical Sciences, Beijing 100850, China
| | - Heyang Zhang
- Beijing Institute of Basic Medical Sciences, Beijing 100850, China
| | - Zhenhua Xu
- Beijing Institute of Basic Medical Sciences, Beijing 100850, China
| | - Wenting Pan
- Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Xinlong Yan
- Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China
| | - Xiaoxia Jiang
- Beijing Institute of Basic Medical Sciences, Beijing 100850, China
| |
Collapse
|
|
2
|
Gharib OA, Fahmy HA, Abdou FY. Role of Olive Leaf Extract, Mesenchymal Stem Cells or Low Radiation Dose in Alleviating Hepatic Injury in Rats. Dose Response 2024; 22:15593258241289301. [PMID: 39483141 PMCID: PMC11526167 DOI: 10.1177/15593258241289301] [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: 06/14/2024] [Accepted: 08/28/2024] [Indexed: 11/03/2024] Open
Abstract
Objectives This study was conducted to determine the efficacy of mesenchymal stem cells (MSCs) or low-dose gamma radiation (LDR) on liver injury compared to the effect of olive leaf extract as a hepatoprotective agent. Methods Rats were allocated into six groups; group I served as the negative control. Group II received 5% dextran sodium sulfate (DSS) in its drinking water for 1 week. Group III was injected with a single dose of 1 × 106 bone marrow-derived mesenchymal stem cells (BM-MSCs) intravenously. Group IV was treated as in group III after 5% DSS treatment. Group V was given 5% DSS, followed by olive leaf extract (OLE) (1000 mg/ kg, oral). Group VI: 5% DSS for 1 week, then was exposed to low-dose gamma radiation (LDR) (0.05 Gy). Results Rats treated with OLE, BM-MSCs, or exposed to LDR exerted significant alleviation in all hepatic biomarkers, significant enhancements in oxidative stress parameters, and improvements in inflammatory biomarkers Interleukin-1 beta (IL-1β) and Interferon gamma (INF-γ) hepatic contents compared with those of the DSS group. Histological pictures emphasized the biochemical findings. Conclusions BM-MSCs might be a valuable therapeutic approach to overcome hepatic injury. Exposure to LDR provided protective mechanisms that allow the body to survive better.
Collapse
Affiliation(s)
- Ola A. Gharib
- Drug Radiation Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Hanan A. Fahmy
- Drug Radiation Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Fatma Y. Abdou
- Drug Radiation Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| |
Collapse
|
|
3
|
Summers BS, Thomas Broome S, Pang TWR, Mundell HD, Koh Belic N, Tom NC, Ng ML, Yap M, Sen MK, Sedaghat S, Weible MW, Castorina A, Lim CK, Lovelace MD, Brew BJ. A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease. Int J Tryptophan Res 2024; 17:11786469241248287. [PMID: 38757094 PMCID: PMC11097742 DOI: 10.1177/11786469241248287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 04/03/2024] [Indexed: 05/18/2024] Open
Abstract
Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body's ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.
Collapse
Affiliation(s)
- Benjamin Sebastian Summers
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Sarah Thomas Broome
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | | | - Hamish D Mundell
- Faculty of Medicine and Health, New South Wales Brain Tissue Resource Centre, School of Medical Sciences, Charles Perkins Centre, University of Sydney, NSW, Australia
| | - Naomi Koh Belic
- School of Life Sciences, University of Technology, Sydney, NSW, Australia
| | - Nicole C Tom
- Formerly of the Department of Physiology, University of Sydney, NSW, Australia
| | - Mei Li Ng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Maylin Yap
- Formerly of the Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Monokesh K Sen
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- School of Medicine, Western Sydney University, NSW, Australia
- Faculty of Medicine and Health, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Sara Sedaghat
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Michael W Weible
- School of Environment and Science, Griffith University, Brisbane, QLD, Australia
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia
| | - Alessandro Castorina
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | - Chai K Lim
- Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
| | - Michael D Lovelace
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Bruce J Brew
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
- Departments of Neurology and Immunology, St. Vincent’s Hospital, Sydney, NSW, Australia
- University of Notre Dame, Darlinghurst, Sydney, NSW, Australia
| |
Collapse
|
|
4
|
Aprile D, Patrone D, Peluso G, Galderisi U. Multipotent/pluripotent stem cell populations in stromal tissues and peripheral blood: exploring diversity, potential, and therapeutic applications. Stem Cell Res Ther 2024; 15:139. [PMID: 38735988 PMCID: PMC11089765 DOI: 10.1186/s13287-024-03752-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 05/02/2024] [Indexed: 05/14/2024] Open
Abstract
The concept of "stemness" incorporates the molecular mechanisms that regulate the unlimited self-regenerative potential typical of undifferentiated primitive cells. These cells possess the unique ability to navigate the cell cycle, transitioning in and out of the quiescent G0 phase, and hold the capacity to generate diverse cell phenotypes. Stem cells, as undifferentiated precursors endow with extraordinary regenerative capabilities, exhibit a heterogeneous and tissue-specific distribution throughout the human body. The identification and characterization of distinct stem cell populations across various tissues have revolutionized our understanding of tissue homeostasis and regeneration. From the hematopoietic to the nervous and musculoskeletal systems, the presence of tissue-specific stem cells underlines the complex adaptability of multicellular organisms. Recent investigations have revealed a diverse cohort of non-hematopoietic stem cells (non-HSC), primarily within bone marrow and other stromal tissue, alongside established hematopoietic stem cells (HSC). Among these non-HSC, a rare subset exhibits pluripotent characteristics. In vitro and in vivo studies have demonstrated the remarkable differentiation potential of these putative stem cells, known by various names including multipotent adult progenitor cells (MAPC), marrow-isolated adult multilineage inducible cells (MIAMI), small blood stem cells (SBSC), very small embryonic-like stem cells (VSELs), and multilineage differentiating stress enduring cells (MUSE). The diverse nomenclatures assigned to these primitive stem cell populations may arise from different origins or varied experimental methodologies. This review aims to present a comprehensive comparison of various subpopulations of multipotent/pluripotent stem cells derived from stromal tissues. By analysing isolation techniques and surface marker expression associated with these populations, we aim to delineate the similarities and distinctions among stromal tissue-derived stem cells. Understanding the nuances of these tissue-specific stem cells is critical for unlocking their therapeutic potential and advancing regenerative medicine. The future of stem cells research should prioritize the standardization of methodologies and collaborative investigations in shared laboratory environments. This approach could mitigate variability in research outcomes and foster scientific partnerships to fully exploit the therapeutic potential of pluripotent stem cells.
Collapse
Affiliation(s)
- Domenico Aprile
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Deanira Patrone
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Gianfranco Peluso
- Faculty of Medicine and Surgery, Saint Camillus International, University of Health Sciences, Rome, Italy
| | - Umberto Galderisi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy.
- Genome and Stem Cell Center (GENKÖK), Erciyes University, Kayseri, Turkey.
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine Temple University, Philadelphia, PA, USA.
| |
Collapse
|
|
5
|
Kim NY, Lee HY, Choi YY, Mo SJ, Jeon S, Ha JH, Park SD, Shim JJ, Lee J, Chung BG. Effect of gut microbiota-derived metabolites and extracellular vesicles on neurodegenerative disease in a gut-brain axis chip. NANO CONVERGENCE 2024; 11:7. [PMID: 38340254 DOI: 10.1186/s40580-024-00413-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 01/21/2024] [Indexed: 02/12/2024]
Abstract
A new perspective suggests that a dynamic bidirectional communication system, often referred to as the microbiome-gut-brain axis, exists among the gut, its microbiome, and the central nervous system (CNS). This system may influence brain health and various brain-related diseases, especially in the realms of neurodevelopmental and neurodegenerative conditions. However, the exact mechanism is not yet understood. Metabolites or extracellular vesicles derived from microbes in the gut have the capacity to traverse the intestinal epithelial barrier or blood-brain barrier, gaining access to the systemic circulation. This phenomenon can initiate the physiological responses that directly or indirectly impact the CNS and its function. However, reliable and controllable tools are required to demonstrate the causal effects of gut microbial-derived substances on neurogenesis and neurodegenerative diseases. The integration of microfluidics enhances scientific research by providing advanced in vitro engineering models. In this study, we investigated the impact of microbe-derived metabolites and exosomes on neurodevelopment and neurodegenerative disorders using human induced pluripotent stem cells (iPSCs)-derived neurons in a gut-brain axis chip. While strain-specific, our findings indicate that both microbial-derived metabolites and exosomes exert the significant effects on neural growth, maturation, and synaptic plasticity. Therefore, our results suggest that metabolites and exosomes derived from microbes hold promise as potential candidates and strategies for addressing neurodevelopmental and neurodegenerative disorders.
Collapse
Affiliation(s)
- Na Yeon Kim
- Department of Biomedical Engineering, Sogang University, Seoul, Korea
| | - Ho Yeon Lee
- Department of Biomedical Engineering, Sogang University, Seoul, Korea
| | - Yoon Young Choi
- Institute of Integrated Biotechnology, Sogang University, Seoul, Korea
| | | | | | - Jang Ho Ha
- Department of Mechanical Engineering, Sogang University, Seoul, Korea
| | | | | | | | - Bong Geun Chung
- Department of Biomedical Engineering, Sogang University, Seoul, Korea.
- Institute of Integrated Biotechnology, Sogang University, Seoul, Korea.
- Department of Mechanical Engineering, Sogang University, Seoul, Korea.
- Institute of Smart Biosensor, Sogang University, Seoul, Korea.
| |
Collapse
|
|
6
|
Qiu Z, Cai W, Liu Q, Liu K, Liu C, Yang H, Huang R, Li P, Zhao Q. Unravelling novel and pleiotropic genes for cannon bone circumference and bone mineral density in Yorkshire pigs. J Anim Sci 2024; 102:skae036. [PMID: 38330300 PMCID: PMC10914368 DOI: 10.1093/jas/skae036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 02/03/2024] [Indexed: 02/10/2024] Open
Abstract
Leg weakness is a prevalent health condition in pig farms. The augmentation of cannon bone circumference and bone mineral density can effectively improve limb strength in pigs and alleviate leg weakness. This study measured forelimb cannon bone circumference (fCBC) and rear limb cannon bone circumference (rCBC) using an inelastic tapeline and rear limb metatarsal area bone mineral density (raBMD) using a dual-energy X-ray absorptiometry bone density scanner. The samples of Yorkshire castrated boars were genotyped using a 50K single-nucleotide polymorphism (SNP) array. The SNP-chip data were imputed to the level of whole-genome sequencing data (iWGS). This study used iWGS data to perform genome-wide association studies and identified novel significant SNPs associated with fCBC on SSC6, SSC12, and SSC13, rCBC on SSC12 and SSC14, and raBMD on SSC7. Based on the high phenotypic and genetic correlations between CBC and raBMD, multi-trait meta-analysis was performed to identify pleiotropic SNPs. A significant potential pleiotropic quantitative trait locus (QTL) regulating both CBC and raBMD was identified on SSC15. Bayes fine mapping was used to establish the confidence intervals for these novel QTLs with the most refined confidence interval narrowed down to 56 kb (15.11 to 15.17 Mb on SSC12 for fCBC). Furthermore, the confidence interval for the potential pleiotropic QTL on SSC15 in the meta-analysis was narrowed down to 7.45 kb (137.55 to137.56 Mb on SSC15). Based on the biological functions of genes, the following genes were identified as novel regulatory candidates for different phenotypes: DDX42, MYSM1, FTSJ3, and MECOM for fCBC; SMURF2, and STC1 for rCBC; RGMA for raBMD. Additionally, RAMP1, which was determined to be located 23.68 kb upstream of the confidence interval of the QTL on SSC15 in the meta-analysis, was identified as a potential pleiotropic candidate gene regulating both CBC and raBMD. These findings offered valuable insights for identifying pathogenic genes and elucidating the genetic mechanisms underlying CBC and BMD.
Collapse
Affiliation(s)
- Zijian Qiu
- Key Laboratory in Nanjing for Evaluation and Utilization of Pigs Resources, Ministry of Agriculture and Rural Areas of China, Institute of Swine Science, Nanjing Agricultural University, Nanjing 210095, China
| | - Wenwu Cai
- Key Laboratory in Nanjing for Evaluation and Utilization of Pigs Resources, Ministry of Agriculture and Rural Areas of China, Institute of Swine Science, Nanjing Agricultural University, Nanjing 210095, China
| | - Qian Liu
- Key Laboratory in Nanjing for Evaluation and Utilization of Pigs Resources, Ministry of Agriculture and Rural Areas of China, Institute of Swine Science, Nanjing Agricultural University, Nanjing 210095, China
| | - Kaiyue Liu
- Key Laboratory in Nanjing for Evaluation and Utilization of Pigs Resources, Ministry of Agriculture and Rural Areas of China, Institute of Swine Science, Nanjing Agricultural University, Nanjing 210095, China
| | - Chenxi Liu
- Key Laboratory in Nanjing for Evaluation and Utilization of Pigs Resources, Ministry of Agriculture and Rural Areas of China, Institute of Swine Science, Nanjing Agricultural University, Nanjing 210095, China
| | - Huilong Yang
- Key Laboratory in Nanjing for Evaluation and Utilization of Pigs Resources, Ministry of Agriculture and Rural Areas of China, Institute of Swine Science, Nanjing Agricultural University, Nanjing 210095, China
| | - Ruihua Huang
- Key Laboratory in Nanjing for Evaluation and Utilization of Pigs Resources, Ministry of Agriculture and Rural Areas of China, Institute of Swine Science, Nanjing Agricultural University, Nanjing 210095, China
- Huaian Academy, Nanjing Agricultural University, Huaian 223005, China
| | - Pinghua Li
- Key Laboratory in Nanjing for Evaluation and Utilization of Pigs Resources, Ministry of Agriculture and Rural Areas of China, Institute of Swine Science, Nanjing Agricultural University, Nanjing 210095, China
- Huaian Academy, Nanjing Agricultural University, Huaian 223005, China
| | - Qingbo Zhao
- Key Laboratory in Nanjing for Evaluation and Utilization of Pigs Resources, Ministry of Agriculture and Rural Areas of China, Institute of Swine Science, Nanjing Agricultural University, Nanjing 210095, China
| |
Collapse
|
|
7
|
Jankowski M, Farzaneh M, Ghaedrahmati F, Shirvaliloo M, Moalemnia A, Kulus M, Ziemak H, Chwarzyński M, Dzięgiel P, Zabel M, Piotrowska-Kempisty H, Bukowska D, Antosik P, Mozdziak P, Kempisty B. Unveiling Mesenchymal Stem Cells' Regenerative Potential in Clinical Applications: Insights in miRNA and lncRNA Implications. Cells 2023; 12:2559. [PMID: 37947637 PMCID: PMC10649218 DOI: 10.3390/cells12212559] [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: 09/05/2023] [Revised: 10/20/2023] [Accepted: 10/28/2023] [Indexed: 11/12/2023] Open
Abstract
It is now widely recognized that mesenchymal stem cells (MSCs) possess the capacity to differentiate into a wide array of cell types. Numerous studies have identified the role of lncRNA in the regulation of MSC differentiation. It is important to elucidate the role and interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of signalling pathways that govern MSC function. Furthermore, miRNAs and lncRNAs are important clinical for innovative strategies aimed at addressing a wide spectrum of existing and emerging disease. Hence it is important to consider their impact on MSC function and differentiation. Examining the data available in public databases, we have collected the literature containing the latest discoveries pertaining to human stem cells and their potential in both fundamental research and clinical applications. Furthermore, we have compiled completed clinical studies that revolve around the application of MSCs, shedding light on the opportunities presented by harnessing the regulatory potential of miRNAs and lncRNAs. This exploration of the therapeutic possibilities offered by miRNAs and lncRNAs within MSCs unveils exciting prospects for the development of precision therapies and personalized treatment approaches. Ultimately, these advancements promise to augment the efficacy of regenerative strategies and produce positive outcomes for patients. As research in this field continues to evolve, it is imperative to explore and exploit the vast potential of miRNAs and lncRNAs as therapeutic agents. The findings provide a solid basis for ongoing investigations, fuelling the quest to fully unlock the regenerative potential of MSCs.
Collapse
Affiliation(s)
- Maurycy Jankowski
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, 60-812 Poznan, Poland;
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Farhoodeh Ghaedrahmati
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Milad Shirvaliloo
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Future Science Group, Unitec House, 2 Albert Place, London N3 1QB, UK
| | - Arash Moalemnia
- Faculty of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Hanna Ziemak
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Mikołaj Chwarzyński
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Physiotherapy, Wroclaw University School of Physical Education, 50-038 Wroclaw, Poland
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Division of Anatomy and Histology, University of Zielona Góra, 65-046 Zielona Góra, Poland
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27607, USA
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27613, USA
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27613, USA
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 602 00 Brno, Czech Republic
| |
Collapse
|
|
8
|
Smolinska A, Bzinkowska A, Rybkowska P, Chodkowska M, Sarnowska A. Promising Markers in the Context of Mesenchymal Stem/Stromal Cells Subpopulations with Unique Properties. Stem Cells Int 2023; 2023:1842958. [PMID: 37771549 PMCID: PMC10533301 DOI: 10.1155/2023/1842958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/11/2023] [Accepted: 08/25/2023] [Indexed: 09/30/2023] Open
Abstract
The heterogeneity of the mesenchymal stem/stromal cells (MSCs) population poses a challenge to researchers and clinicians, especially those observed at the population level. What is more, the lack of precise evidences regarding MSCs developmental origin even further complicate this issue. As the available evidences indicate several possible pathways of MSCs formation, this diverse origin may be reflected in the unique subsets of cells found within the MSCs population. Such populations differ in specialization degree, proliferation, and immunomodulatory properties or exhibit other additional properties such as increased angiogenesis capacity. In this review article, we attempted to identify such outstanding populations according to the specific surface antigens or intracellular markers. Described groups were characterized depending on their specialization and potential therapeutic application. The reports presented here cover a wide variety of properties found in the recent literature, which is quite scarce for many candidates mentioned in this article. Even though the collected information would allow for better targeting of specific subpopulations in regenerative medicine to increase the effectiveness of MSC-based therapies.
Collapse
Affiliation(s)
- Agnieszka Smolinska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Aleksandra Bzinkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Paulina Rybkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Magdalena Chodkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Anna Sarnowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| |
Collapse
|
|
9
|
Salari Sedigh H, Saffarpour A, Jamshidi S, Ashouri M, Nassiri SM, Dehghan MM, Ranjbar E, Shafieian R. In vitro investigation of canine periodontal ligament-derived mesenchymal stem cells: A possibility of promising tool for periodontal regeneration. J Oral Biol Craniofac Res 2023; 13:403-411. [PMID: 37113531 PMCID: PMC10127137 DOI: 10.1016/j.jobcr.2023.03.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 02/09/2023] [Accepted: 03/15/2023] [Indexed: 04/29/2023] Open
Abstract
Objectives Recent investigations indicate that canine periodontal ligament-derived stem cells (cPDLSCs) may reveal a reliable strategy for repair of periodontal tissues via cell-based tissue engineering approaches. Due to limited research, this study aimed to demonstrate the phenotypic characterization of cPDLSc in comparison with canine bone marrow-derived mesenchymal stem cells (cBMSCs) in vitro. Methods Mesenchymal stem cells (MSCs) were obtained from PDL and BM of five male adult Mongrel dogs. In vitro isolation and expansion as well as biologic characterization including colony unit formation (CFU), osteogenic and adipogenic differentiation, flow cytometric analysis of CD34 and CD44, and RT-PCR of alkaline phosphatase (ALP), osteocalcin (OCN), periostin (POSTN) and S100A4 were performed. Furthermore, electron microscopy analysis was done to complement the comparative research. Results CFU assay revealed that colonies of cPDLSCs presented 70% confluency with a more finite lifespan than BM-MSCs, showing a significant increase in cPDLSCs. Both types of MSCs showed osteogenic and adipogenic phenotypic characterized with clusters of mineralized depositions and lipid vacuoles, respectively. Both types of MSCs expressed CD44 with limited expression of CD34. RT-PCR of cPDLSCs revealed that expression of ALP, POSTN, OCN and S100A4 genes were significantly higher than those of BMSCs. In addition, comparison of SEM and revealed that cPDLSCs expressed more extracellular collagen fibers. Conclusions The current study indicated that cPDLSCs show potency as a novel cellular therapy for periodontal regeneration a large animal model.
Collapse
Affiliation(s)
- Hamideh Salari Sedigh
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Anna Saffarpour
- Department of Periodontology, Tehran University of Medical Sciences, International Campus, Tehran, Iran
| | - Shahram Jamshidi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mahdi Ashouri
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Shahed University of Medical Sciences, Tehran, Iran
| | - Seyed Mahdi Nassiri
- Department of Clinical Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mohammad Mehdi Dehghan
- Department of Surgery & Radiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Esmail Ranjbar
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reyhaneh Shafieian
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Stem Cell and Regenerative Medicine Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
10
|
Wang S, Ying L, Yu SY, Bai J, Hao C. Can precancerous stem cells be risk markers for malignant transformation in the oral mucosa? Cell Mol Biol Lett 2023; 28:30. [PMID: 37029348 PMCID: PMC10080963 DOI: 10.1186/s11658-023-00441-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 03/20/2023] [Indexed: 04/09/2023] Open
Abstract
Accurate assessment of the carcinogenic potential of oral mucosal diseases can significantly reduce the prevalence of oral cancer. We speculate that precancerous stem cells (pCSCs) arise during the evolution of carcinomas based on long-term experimental findings, published literature, and the cancer stem cell (CSC) theory, wherein pCSCs exist in precancerous lesions and have characteristics of both CSCs and normal stem cells. This apparently contradictory feature may be the foundation of the reversible transformation of precancerous lesions. Predicting malignant transformation in potentially malignant oral illnesses would allow for focused treatment, prognosis, and secondary prevention. Currently available clinical assays for chromosomal instability and DNA aneuploidy have several deficiencies. We hope that our study will increase attention to pCSC research and lead to the development of novel strategies for the prevention and treatment of oral cancer by identifying pCSC markers.
Collapse
Affiliation(s)
- Shan Wang
- Department of Oral Pathology, School of Stomatology, Hainan Medical University, Haikou, 571199, People's Republic of China.
- Department of Stomatology, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570216, People's Republic of China.
| | - Liu Ying
- College of Pharmacy, Hainan Medical University, Haikou, 571199, People's Republic of China
| | - Shu-Yi Yu
- Pharmacy Department, First Affiliated Hospital of Jiamusi University, Jiamusi, 154003, People's Republic of China
| | - Jie Bai
- Department of Ophthalmology, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, People's Republic of China.
| | - Chunbo Hao
- Department of Stomatology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, 570100, People's Republic of China.
| |
Collapse
|
|
11
|
Quesenberry PJ, Wen S, Goldberg LR, Dooner MS. The universal stem cell. Leukemia 2022; 36:2784-2792. [PMID: 36307485 PMCID: PMC9712109 DOI: 10.1038/s41375-022-01715-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/26/2022] [Accepted: 09/22/2022] [Indexed: 11/08/2022]
Abstract
Current dogma is that there exists a hematopoietic pluripotent stem cell, resident in the marrow, which is quiescent, but with tremendous proliferative and differentiative potential. Furthermore, the hematopoietic system is essentially hierarchical with progressive differentiation from the pluripotent stem cells to different classes of hematopoietic cells. However, results summarized here indicate that the marrow pluripotent hematopoietic stem cell is actively cycling and thus continually changing phenotype. As it progresses through cell cycle differentiation potential changes as illustrated by sequential changes in surface expression of B220 and GR-1 epitopes. Further data indicated that the potential of purified hematopoietic stem cells extends to multiple other non-hematopoietic cells. It appears that marrow stem cells will give rise to epithelial pulmonary cells at certain points in cell cycle. Thus, it appears that the marrow "hematopoietic" stem cell is also a stem cell for other non-hematopoietic tissues. These observations give rise to the concept of a universal stem cell. The marrow stem cell is not limited to hematopoiesis and its differentiation potential continually changes as it transits cell cycle. Thus, there is a universal stem cell in the marrow which alters its differentiation potential as it progresses through cell cycle. This potential is expressed when it resides in tissues compatible with its differentiation potential, at a particular point in cell cycle transit, or when it interacts with vesicles from that tissue.
Collapse
Affiliation(s)
- Peter J Quesenberry
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA.
| | - Sicheng Wen
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
| | - Laura R Goldberg
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
- Division of Hematology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Mark S Dooner
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
| |
Collapse
|
|
12
|
Deng Z, Luo F, Lin Y, Luo J, Ke D, Song C, Xu J. Research trends of mesenchymal stem cells application in orthopedics: A bibliometric analysis of the past 2 decades. Front Public Health 2022; 10:1021818. [PMID: 36225768 PMCID: PMC9548591 DOI: 10.3389/fpubh.2022.1021818] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 09/07/2022] [Indexed: 01/28/2023] Open
Abstract
Background Bibliometric analysis and visualization tools were used to determine the development trend of mesenchymal stem cells (MSCs) in orthopedics in the past 20 years, so as to guide researchers to explore new directions and hotspots in the field in the future. Methods In the Web of Science Core Collection, all articles about the application of MSCs in orthopedics from 2002 to 2021 were searched. The qualitative and quantitative analysis was performed based on Web of Science and CiteSpace software. Results A total of 2,207 articles were retrieved. After excluding non-article articles such as review and letter and non-English language articles, 1,489 articles were finally included. Over the past 2 decades, the number of publications on the application of MSCs in orthopedic diseases increased. Among them, the United States, China, Japan and the United Kingdom have made significant contributions in this field. The most productive institution was Shanghai Jiao Tong University. Journal of Orthopedic Research published the largest number of publications. The journal with the highest citation frequency was Experimental Hematology. The authors with the highest output and the highest citation frequency on average were Rochy S. Tuan and Scott A. Rodeo, respectively. "Mesenchymal stem cell", "in vitro" and "Differentiation" were the top three keywords that appeared. From the keyword analysis, the current research trend indicates that the primary research hotspots of MSCs in orthopedics are the source of MSCs, in vitro experiments and the differentiation of MSCs into bone and cartilage. The frontiers of this field are the combination of MSCs and platelet-rich plasma (PRP), the treatment of knee diseases such as osteoarthritis, osteogenic differentiation, and the application of biological scaffolds combined with MSCs. Conclusion Over the past 2 decades, the application of MSCs in orthopedic diseases has received increasing attention. Our bibliometric analysis results provide valuable information and research trends for researchers in the field to understand the basic knowledge of the field, identify current research hotspots, potential collaborators, and future research frontiers.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Jie Xu
- Department of Orthopedics, Fujian Clinical Research Center for Spinal Nerve and Joint Diseases, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| |
Collapse
|
|
13
|
Effects of Intra-Articular Autologous Adipose Micrograft for the Treatment of Osteoarthritis in Dogs: A Prospective, Randomized, Controlled Study. Animals (Basel) 2022; 12:ani12141844. [PMID: 35883392 PMCID: PMC9311928 DOI: 10.3390/ani12141844] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/14/2022] [Indexed: 12/12/2022] Open
Abstract
The purpose of this study was to estimate the safety, feasibility, and efficacy of the intra-articular treatment of autologous microfragmented adipose tissue in dogs with spontaneous osteoarthritis (OA) in comparison with hyaluronic acid (HA), the standard intra-articular treatment. Specifically, it clinically evaluated pain and lameness, the radiographic progression of osteoarthritis, and synovial fluid inflammation. This was a prospective, single-center, parallel-group, randomized, controlled, in vivo clinical study. Participants (n = 40) received either a single intra-articular injection of microfragmented adipose tissue or a single intra-articular injection of HA (1:1). Clinical outcomes were determined using a specialistic clinician assessment obtained by the completion of a specific clinical form based on the Vesseur modified lameness classification system, a pain evaluation using the Visual Analogue Scale (VAS), the measurement of the range of motion (ROM) of the affected joint, limb circumference, and the owners' score evaluation using the Canine Brief Pain Inventory (CBPI) for up to 6 months after the time of injection. Patients underwent a radiographic examination to establish the degree of OA in the affected joint, and synovial fluid samples were collected to assess the biochemical environment of the joint and evaluate and quantify the cellular population and the presence of three specific inflammation biomarkers for up to 60 days. The results of this study suggest that microfragmented autologous adipose tissue is safe and can effectively relieve pain and improve function in dogs with spontaneous articular OA. This one-step procedure is simple, timesaving, cost-effective, minimally invasive, and eliminates the need for complex and time-intensive cell culture processing. Furthermore, the clinical evidence and cytological results suggest better long-term pain control, resulting in an improvement in joint function, compared to HA treatment. The canine spontaneous OA model could play a key role in developing successful treatments for human medicine.
Collapse
|
|
14
|
Du S, Li Y, Geng Z, Zhang Q, Buhler LH, Gonelle-Gispert C, Wang Y. Engineering Islets From Stem Cells: The Optimal Solution for the Treatment of Diabetes? Front Immunol 2022; 13:869514. [PMID: 35572568 PMCID: PMC9092457 DOI: 10.3389/fimmu.2022.869514] [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: 02/04/2022] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetes is a metabolic disease characterized by insulin deficiency. Bioengineering of stem cells with the aim to restore insulin production and glucose regulation has the potential to cure diabetic patients. In this review, we focus on the recent developments for bioengineering of induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and pancreatic progenitor cells in view of generating insulin producing and glucose regulating cells for β-cell replacement therapies. Recent clinical trials using islet cells derived from stem cells have been initiated for the transplantation into diabetic patients, with crucial bottlenecks of tumorigenesis, post-transplant survival, genetic instability, and immunogenicity that should be further optimized. As a new approach given high expectations, bioengineered islets from stem cells occupies considerable potential for the future clinical application and addressing the treatment dilemma of diabetes.
Collapse
Affiliation(s)
- Suya Du
- Department of Clinical Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanjiao Li
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhen Geng
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China.,Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Qi Zhang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Leo H Buhler
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China.,Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | | | - Yi Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China.,Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, China
| |
Collapse
|
|
15
|
Purwaningrum M, Jamilah NS, Purbantoro SD, Sawangmake C, Nantavisai S. Comparative characteristic study from bone marrow-derived mesenchymal stem cells. J Vet Sci 2021; 22:e74. [PMID: 34697921 PMCID: PMC8636658 DOI: 10.4142/jvs.2021.22.e74] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 11/29/2022] Open
Abstract
Tissue engineering has been extensively investigated and proffered to be a potential platform for novel tissue regeneration. The utilization of mesenchymal stem cells (MSCs) from various sources has been widely explored and compared. In this regard, MSCs derived from bone marrow have been proposed and described as a promising cell resource due to their high yield of isolated cells with colony-forming potential, self-renewal capacity, MSC surface marker expression, and multi-lineage differentiation capacities in vitro. However, there is evidence for bone marrow MSCs (BM-MSCs) both in vitro and in vivo from different species presenting identical and distinct potential stemness characteristics. In this review, the fundamental knowledge of the growth kinetics and stemness properties of BM-MSCs in different animal species and humans are compared and summarized. Finally, to provide a full perspective, this review will procure results of current information studies focusing on the use of BM-MSCs in clinical practice.
Collapse
Affiliation(s)
- Medania Purwaningrum
- Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Veterinary Pharmacology and Stem Cell Research Laboratory, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand.,Department of Biochemistry, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Nabila Syarifah Jamilah
- Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Veterinary Pharmacology and Stem Cell Research Laboratory, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Steven Dwi Purbantoro
- Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Veterinary Pharmacology and Stem Cell Research Laboratory, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Chenphop Sawangmake
- Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Veterinary Pharmacology and Stem Cell Research Laboratory, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand.,Veterinary Stem Cell and Bioengineering Research Unit, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand.,Department of Pharmacology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Sirirat Nantavisai
- Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Veterinary Pharmacology and Stem Cell Research Laboratory, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand.,Veterinary Stem Cell and Bioengineering Research Unit, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand.
| |
Collapse
|
|
16
|
The Efficacy of Schwann-Like Differentiated Muscle-Derived Stem Cells in Treating Rodent Upper Extremity Peripheral Nerve Injury. Plast Reconstr Surg 2021; 148:787-798. [PMID: 34550935 DOI: 10.1097/prs.0000000000008383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND There is a pressing need to identify alternative mesenchymal stem cell sources for Schwann cell cellular replacement therapy, to improve peripheral nerve regeneration. This study assessed the efficacy of Schwann cell-like cells (induced muscle-derived stem cells) differentiated from muscle-derived stem cells (MDSCs) in augmenting nerve regeneration and improving muscle function after nerve trauma. METHODS The Schwann cell-like nature of induced MDSCs was characterized in vitro using immunofluorescence, flow cytometry, microarray, and reverse-transcription polymerase chain reaction. In vivo, four groups (n = 5 per group) of rats with median nerve injuries were examined: group 1 animals were treated with intraneural phosphate-buffered saline after cold and crush axonotmesis (negative control); group 2 animals were no-injury controls; group 3 animals were treated with intraneural green fluorescent protein-positive MDSCs; and group 4 animals were treated with green fluorescent protein-positive induced MDSCs. All animals underwent weekly upper extremity functional testing. Rats were euthanized 5 weeks after treatment. The median nerve and extrinsic finger flexors were harvested for nerve histomorphometry, myelination, muscle weight, and atrophy analyses. RESULTS In vitro, induced MDSCs recapitulated native Schwann cell gene expression patterns and up-regulated pathways involved in neuronal growth/signaling. In vivo, green fluorescent protein-positive induced MDSCs remained stably transformed 5 weeks after injection. Induced MDSC therapy decreased muscle atrophy after median nerve injury (p = 0.0143). Induced MDSC- and MDSC-treated animals demonstrated greater functional muscle recovery when compared to untreated controls (hand grip after induced MDSC treatment: group 1, 0.91 N; group 4, 3.38 N); p < 0.0001) at 5 weeks after treatment. This may demonstrate the potential beneficial effects of MDSC therapy, regardless of differentiation stage. CONCLUSION Both MDSCs and induced MDSCs decrease denervation muscle atrophy and improve subsequent functional outcomes after upper extremity nerve trauma in rodents.
Collapse
|
|
17
|
Ejma M, Madetko N, Brzecka A, Alster P, Budrewicz S, Koszewicz M, Misiuk-Hojło M, Tomilova IK, Somasundaram SG, Kirkland CE, Aliev G. The Role of Stem Cells in the Therapy of Stroke. Curr Neuropharmacol 2021; 20:630-647. [PMID: 34365923 PMCID: PMC9608230 DOI: 10.2174/1570159x19666210806163352] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/19/2021] [Accepted: 06/03/2021] [Indexed: 11/22/2022] Open
Abstract
Background: Stroke is a major challenge in neurology due to its multifactorial genesis and irreversible consequences. Processes of endogenous post-stroke neurogenesis, although insufficient, may indicate possible direction of future therapy. Multiple research considers stem-cell-based approaches in order to maximize neuroregeneration and minimize post-stroke deficits. Objective: Aim of this study is to review current literature considering post-stroke stem-cell-based therapy and possibilities of inducing neuroregeneration after brain vascular damage. Methods: Papers included in this article were obtained from PubMed and MEDLINE databases. The following medical subject headings (MeSH) were used: “stem cell therapy”, “post-stroke neurogenesis”, “stem-cells stroke”, “stroke neurogenesis”, “stroke stem cells”, “stroke”, “cell therapy”, “neuroregeneration”, “neurogenesis”, “stem-cell human”, “cell therapy in human”. Ultimate inclusion was made after manual review of the obtained reference list. Results: Attempts of stimulating neuroregeneration after stroke found in current literature include supporting endogenous neurogenesis, different routes of exogenous stem cells supplying and extracellular vesicles used as a method of particle transport. Conclusion: Although further research in this field is required, post stroke brain recovery supported by exogenous stem cells seems to be promising future therapy revolutionizing modern neurology.
Collapse
Affiliation(s)
- Maria Ejma
- Department of Neurology, Wroclaw Medical University, 50-556 Wrocław, Borowska 213. Poland
| | - Natalia Madetko
- Department of Neurology, Medical University of Warsaw, Kondratowicza 8, 03-242 Warszawa. Poland
| | - Anna Brzecka
- Department of Pulmonology and Lung Oncology, Wroclaw Medical University, Grabiszynska 105, 53-439 Wroclaw. Poland
| | - Piotr Alster
- Department of Neurology, Medical University of Warsaw, Kondratowicza 8, 03-242 Warszawa. Poland
| | - Sławomir Budrewicz
- Department of Neurology, Wroclaw Medical University, 50-556 Wrocław, Borowska 213. Poland
| | - Magdalena Koszewicz
- Department of Neurology, Wroclaw Medical University, 50-556 Wrocław, Borowska 213. Poland
| | - Marta Misiuk-Hojło
- Department of Ophthalmology, Wroclaw Medical University, 50-556 Wroclaw, Borowska 213. Poland
| | - Irina K Tomilova
- Department of Biochemistry, Ivanovo State Medical Academy, Avenue Sheremetyevsky 8, Ivanovo, 153012. Russian Federation
| | - Siva G Somasundaram
- Department of Biological Sciences, Salem University, Salem, WV, 26426. United States
| | - Cecil E Kirkland
- Department of Biological Sciences, Salem University, Salem, WV, 26426. United States
| | - Gjumrakch Aliev
- Wroclaw Medical University, Department of Pulmonology and Lung Oncology, Wroclaw. Poland
| |
Collapse
|
|
18
|
Latifi-Navid H, Soheili ZS, Samiei S, Sadeghi M, Taghizadeh S, Pirmardan ER, Ahmadieh H. Network analysis and the impact of Aflibercept on specific mediators of angiogenesis in HUVEC cells. J Cell Mol Med 2021; 25:8285-8299. [PMID: 34250732 PMCID: PMC8419159 DOI: 10.1111/jcmm.16778] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/25/2021] [Accepted: 06/11/2021] [Indexed: 12/31/2022] Open
Abstract
Angiogenesis, inflammation and endothelial cells’ migration and proliferation exert fundamental roles in different diseases. However, more studies are needed to identify key proteins and pathways involved in these processes. Aflibercept has received the approval of the US Food and Drug Administration (FDA) for the treatment of wet AMD and colorectal cancer. Moreover, the effect of Aflibercept on VEGFR2 downstream signalling pathways has not been investigated yet. Here, we integrated text mining data, protein‐protein interaction networks and multi‐experiment microarray data to specify candidate genes that are involved in VEGFA/VEGFR2 signalling pathways. Network analysis of candidate genes determined the importance of the nominated genes via different centrality parameters. Thereupon, several genes—with the highest centrality indexes—were recruited to investigate the impact of Aflibercept on their expression pattern in HUVEC cells. Real‐time PCR was performed, and relative expression of the specific genes revealed that Aflibercept modulated angiogenic process by VEGF/PI3KA/AKT/mTOR axis, invasion by MMP14/MMP9 axis and inflammation‐related angiogenesis by IL‐6‐STAT3 axis. Data showed Aflibercept simultaneously affected these processes and determined the nominated axes that had been affected by the drug. Furthermore, integrating the results of Aflibercept on expression of candidate genes with the current network analysis suggested that resistance against the Aflibercept effect is a plausible process in HUVEC cells.
Collapse
Affiliation(s)
- Hamid Latifi-Navid
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Zahra-Soheila Soheili
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Shahram Samiei
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Mehdi Sadeghi
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran.,School of Biological Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
| | - Sepideh Taghizadeh
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Ehsan Ranaei Pirmardan
- Ocular Tissue Engineering Research Center, Molecular Biomarkers Nano-Imaging Laboratory, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Department of Radiology, Harvard Medical School, Boston, Massachusetts, USA
| | - Hamid Ahmadieh
- Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
19
|
Garcia-Contreras M, Thakor AS. Human adipose tissue-derived mesenchymal stem cells and their extracellular vesicles modulate lipopolysaccharide activated human microglia. Cell Death Discov 2021; 7:98. [PMID: 33972507 PMCID: PMC8110535 DOI: 10.1038/s41420-021-00471-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/05/2021] [Accepted: 04/07/2021] [Indexed: 12/16/2022] Open
Abstract
Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), are driven by neuroinflammation triggered by activated microglial cells; hence, the phenotypic regulation of these cells is an appealing target for intervention. Human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) may be a potential therapeutic candidate to treat NDs given their immunomodulatory properties. Evidence suggests that the mechanism of action of hAD-MSCs is through their secretome, which includes secreted factors such as cytokines, chemokines, or growth factors as well as extracellular vesicles (EVs). Recently, EVs have emerged as important mediators in cell communication given, they can transfer proteins, lipids, and RNA species (i.e., miRNA, mRNA, and tRNAs) to modulate recipient cells. However, the therapeutic potential of hAD-MSCs and their secreted EVs has not been fully elucidated with respect to human microglia. In this study, we determined the therapeutic potential of different hAD-MSCs doses (200,000, 100,000, and 50,000 cells) or their secreted EVs (50, 20, or 10 µg/ml), on human microglial cells (HMC3) that were activated by lipopolysaccharides (LPS). Upregulation of inducible nitric oxide synthase (iNOS), an activation marker of HMC3 cells, was prevented when they were cocultured with hAD-MSCs and EVs. Moreover, hAD-MSCs inhibited the secretion of proinflammatory factors, such as IL-6, IL-8, and MCP-1, while their secreted EVs promoted the expression of anti-inflammatory mediators such as IL-10 or TIMP-1 in activated microglia. The present data therefore support a role for hAD-MSCs and their secreted EVs, as potential therapeutic candidates for the treatment of NDs.
Collapse
Affiliation(s)
- Marta Garcia-Contreras
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA, 94304, USA
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA, 94304, USA.
| |
Collapse
|
|
20
|
Abstract
PURPOSE OF REVIEW Liver transplantation is the gold standard for the treatment of end-stage liver disease. However, a shortage of donor organs, high cost, and surgical complications limit the use of this treatment. Cellular therapies using hepatocytes, hematopoietic stem cells, bone marrow mononuclear cells, and mesenchymal stem cells (MSCs) are being investigated as alternative treatments to liver transplantation. The purpose of this review is to describe studies using MSC transplantation for liver diseases based on the reported literature and to discuss prospective research designed to improve the efficacy of MSC therapy. RECENT FINDINGS MSCs have several properties that show potential to regenerate injured tissues or organs, such as homing, transdifferentiation, immunosuppression, and cellular protective capacity. Additionally, MSCs can be noninvasively isolated from various tissues and expanded ex vivo in sufficient numbers for clinical evaluation. SUMMARY Currently, there is no approved MSC therapy for the treatment of liver disease. However, MSC therapy is considered a promising alternative treatment for end-stage liver diseases and is reported to improve liver function safely with no side effects. Further robust preclinical and clinical studies will be needed to improve the therapeutic efficacy of MSC transplantation.
Collapse
|
|
21
|
Maeta N, Tamura K, Ezuka F, Takemitsu H. Comparative analysis of canine mesenchymal stem cells and bone marrow-derived mononuclear cells. Vet World 2021; 14:1028-1037. [PMID: 34083956 PMCID: PMC8167527 DOI: 10.14202/vetworld.2021.1028-1037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 03/16/2021] [Indexed: 12/16/2022] Open
Abstract
Background and aim: Mesenchymal stem cells (MSCs), which have multi-lineage differentiation potentials, are a promising source for regenerative medicine. However, the focus of study of MSCs is shifting from the characterization of the differentiation potential to their secretion potential for cell transplantation. Tissue regeneration and the attenuation of immune responses are thought to be affected by the secretion of multiple growth factors and cytokines by MSCs. However, the secretion potential of MSCs profiling remains incompletely characterized. In this study, we focused on the secretion ability related and protein mRNA expression of dog adipose tissue-derived MSCs (AT-MSC), bone marrow (BM)-derived MSCs, and BM-derived mononuclear cells (BM-MNC). Materials and Methods: Real-time polymerase chain reaction analyses revealed mRNA expression of nine growth factors and seven interleukins in these types of cells and three growth factors protein expression were determined using Enzyme-linked immunosorbent assay. Results: For the BM-MNC growth factors, the mRNA expression of transforming growth factor-β (TGF-β) was the highest. For the BM-derived MSC (BM-MSC) and AT-MSC growth factors, the mRNA expression of vascular endothelial growth factor (VEGF) was highest. BM-MSCs and AT-MSCs showed similar expression profiles. In contrast, BM-MNCs showed unique expression profiles for hepatocyte growth factor and epidermal growth factor. The three types of cells showed a similar expression of TGF-β. Conclusion: We conclude that expression of cytokine proteins and mRNAs suggests involvement in tissue repair and protection.
Collapse
Affiliation(s)
- Noritaka Maeta
- Aikouishida Animal Hospital, Isehara, 1195-4 Takamori, Isehara, Kanagawa, 259-1114, Japan.,Faculty of Veterinary Medicine, Okayama University of Science, 1-3 Ikoinooka, Imabari, Ehime, 794-8555, Japan
| | - Katsutoshi Tamura
- Aikouishida Animal Hospital, Isehara, 1195-4 Takamori, Isehara, Kanagawa, 259-1114, Japan
| | - Fuuna Ezuka
- Science and Humanities Master's Programme, Graduate School of Science and the Humanities, Kurashiki University of Science and The Arts, 2640 Nishinoura Tsurajima Kurashiki Okayama, 712-8505, Japan
| | - Hiroshi Takemitsu
- Science and Humanities Master's Programme, Graduate School of Science and the Humanities, Kurashiki University of Science and The Arts, 2640 Nishinoura Tsurajima Kurashiki Okayama, 712-8505, Japan.,Department of Comparative Animal Science, College of Life Science, Kurashiki University of Science and The Arts, 2640 Nishinoura Tsurajima Kurashiki Okayama, 712-8505, Japan
| |
Collapse
|
|
22
|
Yamashita T, Kushida Y, Abe K, Dezawa M. Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases. Cells 2021; 10:cells10040961. [PMID: 33924240 PMCID: PMC8074773 DOI: 10.3390/cells10040961] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/15/2021] [Accepted: 04/17/2021] [Indexed: 02/06/2023] Open
Abstract
Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.
Collapse
Affiliation(s)
- Toru Yamashita
- Department of Neurology, School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan; (T.Y.); (K.A.)
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, School of Medicine, Tohoku University, Sendai 980-8575, Japan;
| | - Koji Abe
- Department of Neurology, School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan; (T.Y.); (K.A.)
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, School of Medicine, Tohoku University, Sendai 980-8575, Japan;
- Correspondence: ; Tel.: +81-22-717-8025; Fax: +81-22-717-8030
| |
Collapse
|
|
23
|
Postnatal Pluripotent Cells: Quarter of a Century of Research. Bull Exp Biol Med 2021; 170:515-521. [PMID: 33713237 DOI: 10.1007/s10517-021-05099-2] [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: 10/09/2020] [Indexed: 10/21/2022]
Abstract
Almost quarter of a century long studies aimed at identification, isolation, culturing, and use of postnatal pluripotent cells for the development of cell-based technologies have not met with success and failed to provide reliable and reproducible protocols of cell isolation, identification, and culturing. At the same time, experimental data in this field suggest that postnatal pluripotent cells are not the copies of embryonic cells and, therefore, the tests routinely used for identification of embryonic pluripotent cells are not fully adequate for characterization of their postnatal analogues. Therefore, cell lineage tracing methods showing the differentiation routes of the studied cells in human or animal body after birth should be developed and used.
Collapse
|
|
24
|
Hénon P, Lahlil R. CD34+ Stem Cells and Regenerative Medicine. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
25
|
Kang J, Zhang C, Zhi Z, Wang Y, Liu J, Wu F, Xu G. Stem-like cells of various origins showed therapeutic effect to improve the recovery of spinal cord injury. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2020; 48:627-638. [PMID: 32054316 DOI: 10.1080/21691401.2020.1725031] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
We aimed to evaluate the therapeutic effects of exosomes, which were collected from human neuroepithelial stem cells (HNESCs) treated by miR-29b mimics, on the treatment of spinal cord injury (SCI). Computational analysis, real-time PCR, Western blot analysis and TUNEL assay, a BBB score system, the Nissl staining and IHC assay were conducted to explore the molecular signalling pathway underlying the function of exosomes in SCI. Exosomes isolated from cells treated with HNESC exhibited the strongest inhibitory effect on cell apoptosis while exhibiting the highest level of miR-29b expression and the lowest levels of PTEN and caspase-3 expression. Moreover, PTEN and caspase-3 were identified as the direct target genes of miR-29b. The exosomes isolated from the groups of HNESC and HNESC + miR-29b mimics exhibited in vivo therapeutic effects by restoring the BBB score and apoptosis index of post-SCI neuron cells to those of normal neuron cells, with the exosomes collected from the group of HNESC + miR-29b mimics showing the strongest effect. We suggested that the exosomes derived from the group of HNESC + miR-29b mimics exerted therapeutic effects on SCI by down-regulating the expression of PTEN/caspase-3 and subsequently suppressing the apoptosis of neuron cells.
Collapse
Affiliation(s)
- Jian Kang
- Department of Orthopedics, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Chenglin Zhang
- Department of Orthopedics, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Zhongzheng Zhi
- Department of Orthopedics, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Yingjie Wang
- Department of Orthopedics, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Jingdong Liu
- Department of Orthopedics, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Furong Wu
- Shanghai Clinical Research Center for Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Guanghui Xu
- Department of Orthopedics, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| |
Collapse
|
|
26
|
Weng L, Funderburgh JL, Khandaker I, Geary ML, Yang T, Basu R, Funderburgh ML, Du Y, Yam GHF. The anti-scarring effect of corneal stromal stem cell therapy is mediated by transforming growth factor β3. EYE AND VISION 2020; 7:52. [PMID: 33292650 PMCID: PMC7607765 DOI: 10.1186/s40662-020-00217-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023]
Abstract
Background Corneal stromal stem cells (CSSC) reduce corneal inflammation, prevent fibrotic scarring, and regenerate transparent stromal tissue in injured corneas. These effects rely on factors produced by CSSC to block the fibrotic gene expression. This study investigated the mechanism of the scar-free regeneration effect. Methods Primary human CSSC (hCSSC) from donor corneal rims were cultivated to passage 3 and co-cultured with mouse macrophage RAW264.7 cells induced to M1 pro-inflammatory phenotype by treatment with interferon-γ and lipopolysaccharides, or to M2 anti-inflammatory phenotype by interleukin-4, in a Transwell system. The time-course expression of human transforming growth factor β3 (hTGFβ3) and hTGFβ1 were examined by immunofluorescence and qPCR. TGFβ3 knockdown for > 70% in hCSSC [hCSSC-TGFβ3(si)] was achieved by small interfering RNA transfection. Naïve CSSC and hCSSC-TGFβ3(si) were transplanted in a fibrin gel to mouse corneas, respectively, after wounding by stromal ablation. Corneal clarity and the expression of mouse inflammatory and fibrosis genes were examined. Results hTGFβ3 was upregulated by hCSSC when co-cultured with RAW cells under M1 condition. Transplantation of hCSSC to wounded mouse corneas showed significant upregulation of hTGFβ3 at days 1 and 3 post-injury, along with the reduced expression of mouse inflammatory genes (CD80, C-X-C motif chemokine ligand 5, lipocalin 2, plasminogen activator urokinase receptor, pro-platelet basic protein, and secreted phosphoprotein 1). By day 14, hCSSC treatment significantly reduced the expression of fibrotic and scar tissue genes (fibronectin, hyaluronan synthase 2, Secreted protein acidic and cysteine rich, tenascin C, collagen 3a1 and α-smooth muscle actin), and the injured corneas remained clear. However, hCSSC-TGFβ3(si) lost these anti-inflammatory and anti-scarring functions, and the wounded corneas showed intense scarring. Conclusion This study has demonstrated that the corneal regenerative effect of hCSSC is mediated by TGFβ3, inducing a scar-free tissue response.
Collapse
Affiliation(s)
- Lin Weng
- Department of Ophthalmology, University of Pittsburgh School of medicine, 203 Lothrop Street, Pittsburgh, PA, 15213, USA.,Shanghai Lanhe Optometry and Ophthalmology Clinic, Shanghai, 200032, People's Republic of China
| | - James L Funderburgh
- Department of Ophthalmology, University of Pittsburgh School of medicine, 203 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - Irona Khandaker
- Department of Ophthalmology, University of Pittsburgh School of medicine, 203 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - Moira L Geary
- Department of Ophthalmology, University of Pittsburgh School of medicine, 203 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - Tianbing Yang
- Department of Ophthalmology, University of Pittsburgh School of medicine, 203 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - Rohan Basu
- Department of Ophthalmology, University of Pittsburgh School of medicine, 203 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - Martha L Funderburgh
- Department of Ophthalmology, University of Pittsburgh School of medicine, 203 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - Yiqin Du
- Department of Ophthalmology, University of Pittsburgh School of medicine, 203 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - Gary Hin-Fai Yam
- Department of Ophthalmology, University of Pittsburgh School of medicine, 203 Lothrop Street, Pittsburgh, PA, 15213, USA.
| |
Collapse
|
|
27
|
Yianni V, Sharpe PT. Transcriptomic Profiling of Dental Pulp Pericytes: An RNAseq Approach. FRONTIERS IN DENTAL MEDICINE 2020. [DOI: 10.3389/fdmed.2020.00006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
|
|
28
|
Santos GC, Silva DN, Fortuna V, Silveira BM, Orge ID, de Santana TA, Sampaio GL, Paredes BD, Ribeiro-Dos-Santos R, Soares MBP. Leukemia Inhibitory Factor (LIF) Overexpression Increases the Angiogenic Potential of Bone Marrow Mesenchymal Stem/Stromal Cells. Front Cell Dev Biol 2020; 8:778. [PMID: 32923442 PMCID: PMC7456813 DOI: 10.3389/fcell.2020.00778] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 07/24/2020] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have the ability to secrete bioactive molecules, exerting multiple biological effects, such as tissue regeneration, reduction of inflammation, and neovascularization. The therapeutic potential of MSCs can be increased by genetic modification to overexpress cytokines and growth factors. Here we produced mouse MSCs overexpressing human leukemia inhibitory factor (LIF) to assess their proangiogenic potential in vitro and in vivo. Mouse bone marrow-derived MSCs were transduced by using a second-generation lentiviral system to express human LIF. Leukemia inhibitory factor expression was confirmed by RT-qPCR and by ELISA, allowing the quantification of the transcript and secreted protein, respectively. Flow cytometry analysis and trilineage differentiation assay showed that the MSC_LIF cell line maintained the immunophenotype and a multipotency characteristic of MSCs. The immunosuppressive activity of MSC_LIF was confirmed using a lymphoproliferation assay. Moreover, gene expression analysis demonstrated upregulation of genes coding for strategic factors in the neovascularization process, such as angiogenin, IL-8, MCP-1, and VEGF, and for the perivascular cell markers αSMA, Col4a1, SM22, and NG2. To evaluate the pro-angiogenic potential of MSC_LIF, we first tested its effects on endothelial cells obtained from umbilical vein in a scratch wound healing assay. Conditioned medium (CM) from MSC_LIF promoted a significant increase in cell migration compared to CM from control MSC. Additionally, in vitro tube formation of endothelial cells was increased by the presence of MSC_LIF, as shown in microvessel sprouting in aortic ring cultures. Finally, an in vivo Matrigel plug assay was performed, showing that MSC_LIF were more potent in promoting in vivo angiogenesis and tissue vascularization than control MSCs. In conclusion, LIF overexpression is a promising strategy to increase the proangiogenic potential of MSCs and sets precedents for future investigations of their potential applications for the treatment of ischemic diseases and tissue repair.
Collapse
Affiliation(s)
- Girlaine Café Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil.,Health Institute of Technology, SENAI-CIMATEC, Salvador, Brazil
| | - Daniela Nascimento Silva
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil.,Health Institute of Technology, SENAI-CIMATEC, Salvador, Brazil
| | - Vitor Fortuna
- Health Sciences Institute, Federal University of Bahia, Salvador, Brazil
| | | | - Iasmim Diniz Orge
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil.,Health Institute of Technology, SENAI-CIMATEC, Salvador, Brazil
| | - Thaís Alves de Santana
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil.,Health Institute of Technology, SENAI-CIMATEC, Salvador, Brazil
| | | | | | - Ricardo Ribeiro-Dos-Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil.,Health Institute of Technology, SENAI-CIMATEC, Salvador, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Milena Botelho Pereira Soares
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil.,Health Institute of Technology, SENAI-CIMATEC, Salvador, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| |
Collapse
|
|
29
|
Ahangar P, Mills SJ, Smith LE, Strudwick XL, Ting AE, Vaes B, Cowin AJ. Human multipotent adult progenitor cell-conditioned medium improves wound healing through modulating inflammation and angiogenesis in mice. Stem Cell Res Ther 2020; 11:299. [PMID: 32680566 PMCID: PMC7368692 DOI: 10.1186/s13287-020-01819-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/15/2020] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Stem cell therapies have been widely investigated for their healing effects. However, the translation of these therapies has been hampered by the requirement to deliver live allogeneic or autologous cells directly to the wound in a clinical setting. Multipotent adult progenitor cells (MAPC® cells) are a subpopulation of bone marrow-derived adherent stem cells that secrete a wide range of factors known to accelerate the wound healing process. The aim of this study was to determine the impact of MAPC cells secretome on healing outcomes without the presence of MAPC cells. METHODS The effect of MAPC-conditioned medium (MAPC-CM) on the capacity of keratinocytes, fibroblasts and endothelial cells to migrate and proliferate was determined in vitro using scratch wound closure and WST1 assay, respectively. The effect of MAPC-CM on collagen deposition and angiogenesis was also assessed using in vitro methods. Additionally, two excisional wounds were created on the dorsal surface of mice (n = 8/group) and 100 μL of 20× MAPC-CM were intradermally injected to the wound margins. Wound tissues were collected at 3, 7 and 14 days post-wounding and stained with H&E for microscopic analysis. Immunohistochemistry was performed to investigate inflammation, angiogenesis and collagen deposition in the wounds. RESULTS Skin fibroblasts, keratinocytes and endothelial cells treated with MAPC-CM all showed improved rates of scratch closure and increased cellular proliferation. Moreover, fibroblasts treated with MAPC-CM deposited more collagens I and III and endothelial cells treated with MAPC-CM showed increased capillary tube formation. Murine excisional wounds intradermally injected with MAPC-CM showed a significant reduction in the wound area and an increase in the rate of reepithelialisation. The results also showed that inflammatory cell infiltration was decreased while an increase in angiogenesis, as well as collagens I and III expressions, was observed. CONCLUSION These findings suggest that factors produced by MAPC cells can have an important effect on cutaneous wound healing by affecting skin cell proliferation and migration, balancing inflammation and improving the formation of extracellular matrix and angiogenesis. Development of stem cell-free therapy for the treatment of wounds may be a more clinically translatable approach for improving healing outcomes.
Collapse
Affiliation(s)
- Parinaz Ahangar
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia
| | - Stuart J Mills
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia
| | - Louise E Smith
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia
| | - Xanthe L Strudwick
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia
| | | | - Bart Vaes
- ReGenesys BVBA, Bio-Incubator Leuven, Gaston Geenslaan 1, 3001, Heverlee, Belgium
| | - Allison J Cowin
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia. .,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia.
| |
Collapse
|
|
30
|
Liu D, Cheng F, Pan S, Liu Z. Stem cells: a potential treatment option for kidney diseases. Stem Cell Res Ther 2020; 11:249. [PMID: 32586408 PMCID: PMC7318741 DOI: 10.1186/s13287-020-01751-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 05/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
The prevalence of kidney diseases is emerging as a public health problem. Stem cells (SCs), currently considered as a promising tool for therapeutic application, have aroused considerable interest and expectations. With self-renewal capabilities and great potential for proliferation and differentiation, stem cell therapy opens new avenues for the development of renal function and structural repair in kidney diseases. Mounting evidence suggests that stem cells exert a therapeutic effect mainly by replacing damaged tissues and paracrine pathways. The benefits of various types of SCs in acute kidney disease and chronic kidney disease have been demonstrated in preclinical studies, and preliminary results of clinical trials present its safety and tolerability. This review will focus on the stem cell-based therapy approaches for the treatment of kidney diseases, including various cell sources used, possible mechanisms involved, and outcomes that are generated so far, along with prospects and challenges in clinical application.
Collapse
Affiliation(s)
- Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Fei Cheng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Shaokang Pan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China.
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China.
| |
Collapse
|
|
31
|
Eom YW, Kang SH, Kim MY, Lee JI, Baik SK. Mesenchymal stem cells to treat liver diseases. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:563. [PMID: 32775364 PMCID: PMC7347787 DOI: 10.21037/atm.2020.02.163] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) are being developed for stem cell therapy and can be efficiently used in regenerative medicine. To date, more than 1,000 clinical trials have used MSCs; of these, more than 80 clinical trials have targeted liver disease. MSCs migrate to damaged liver tissues, differentiate into hepatocytes, reduce liver inflammatory responses, reduce liver fibrosis, and act as antioxidants. According to the reported literature, MSCs are safe, have no side effects, and improve liver function; however, their regenerative therapeutic effects are unsatisfactory. Here, we explain, in detail, the basic therapeutic effects and recent clinical advances of MSCs. Furthermore, we discuss future research directions for improving the regenerative therapeutic effects of MSCs.
Collapse
Affiliation(s)
- Young Woo Eom
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Seong Hee Kang
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jong In Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| |
Collapse
|
|
32
|
Pawar AS, Eirin A, Tang H, Zhu XY, Lerman A, Lerman LO. Upregulated tumor necrosis factor-α transcriptome and proteome in adipose tissue-derived mesenchymal stem cells from pigs with metabolic syndrome. Cytokine 2020; 130:155080. [PMID: 32240922 PMCID: PMC7529712 DOI: 10.1016/j.cyto.2020.155080] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 03/04/2020] [Accepted: 03/21/2020] [Indexed: 01/02/2023]
Abstract
INTRODUCTION Mesenchymal stem cells (MSCs) have endogenous reparative properties, and may constitute an exogenous therapeutic intervention in patients with chronic kidney disease. The microenvironment of metabolic syndrome (MetS) induces fat inflammation, with abundant expression of tumor necrosis factor (TNF)-α. MetS may also alter the content of adipose tissue-derived MSCs, and we hypothesized that the inflammatory profile of MetS manifests via upregulating MSC mRNAs and proteins of the TNF-α pathway. METHODS Domestic pigs were fed a 16-week Lean or MetS diet (n = 4 each). MSCs were harvested from abdominal subcutaneous fat, and their extracellular vesicles (EVs) isolated. Expression profiles of mRNAs and proteins in MSCs and EVs were obtained by high-throughput sequencing and proteomics. Nuclear translocation of the pro-inflammatory transcription factor (NF)-kB was evaluated in MSC and in pig renal tubular cells (TEC) co-incubated with EVs. RESULTS We found 13 mRNAs and 4 proteins in the TNF-α pathway upregulated in MetS- vs. Lean-MSCs (fold-change > 1.4, p < 0.05), mostly via TNF-α receptor-1 (TNF-R1) signaling. Three mRNAs were upregulated in MetS-EVs. MetS-MSCs, as well as TECs co-incubated with MetS-EVs, showed increased nuclear translocation of NF-kB. Using qPCR, JUNB, MAP2K7 and TRAF2 genes followed the same direction of RNA-sequencing findings. CONCLUSIONS MetS upregulates the TNF-α transcriptome and proteome in swine adipose tissue-derived MSCs, which are partly transmitted to their EV progeny, and are associated with activation of NF-kB in target cells. Hence, the MetS milieu may affect the profile of endogenous MSCs and their paracrine vectors and limit their use as an exogenous regenerative therapy. Anti-inflammatory strategies targeting the TNF-α pathway might be a novel strategy to restore MSC phenotype, and in turn function.
Collapse
Affiliation(s)
- Aditya S Pawar
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States; Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States.
| |
Collapse
|
|
33
|
Chen K, Huang Y, Singh R, Wang ZZ. Arrhythmogenic risks of stem cell replacement therapy for cardiovascular diseases. J Cell Physiol 2020; 235:6257-6267. [PMID: 31994198 DOI: 10.1002/jcp.29554] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 12/17/2019] [Indexed: 12/22/2022]
Abstract
Ischemic heart disease and congestive heart failure are major contributors to high morbidity and mortality. Approximately 1.5 million cases of myocardial infarction occur annually in the United States; the yearly incidence rate is approximately 600 cases per 100,000 people. Although significant progress to improve the survival rate has been made by medications and implantable medical devices, damaged cardiomyocytes are unable to be recovered by current treatment strategies. After almost two decades of research, stem cell therapy has become a very promising approach to generate new cardiomyocytes and enhance the function of the heart. Along with clinical trials with stem cells conducted in cardiac regeneration, concerns regarding safety and potential risks have emerged. One of the contentious issues is the electrical dysfunctions of cardiomyocytes and cardiac arrhythmia after stem cell therapy. In this review, we focus on the cell sources currently used for stem cell therapy and discuss related arrhythmogenic risk.
Collapse
Affiliation(s)
- Kang Chen
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuting Huang
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, Maryland
| | - Radhika Singh
- Center for Biotechnology Education, Johns Hopkins University, Baltimore, Maryland
| | - Zack Z Wang
- Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
34
|
Kim OH, Hong HE, Seo H, Kwak BJ, Choi HJ, Kim KH, Ahn J, Lee SC, Kim SJ. Generation of induced secretome from adipose-derived stem cells specialized for disease-specific treatment: An experimental mouse model. World J Stem Cells 2020; 12:70-86. [PMID: 32110276 PMCID: PMC7031761 DOI: 10.4252/wjsc.v12.i1.70] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 08/16/2019] [Accepted: 09/26/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recently, the exclusive use of mesenchymal stem cell (MSC)-secreted molecules, named as the secretome, have been evaluated for overcoming the limitations of cell-based therapy while maintaining its advantages. AIM To improve cell-free therapy by adding disease-specificity through stimulation of MSCs using disease-causing materials. METHODS We collected the secretory materials (named as inducers) released from AML12 hepatocytes that had been pretreated with thioacetamide (TAA) and generated the TAA-induced secretome (TAA-isecretome) after stimulating adipose-derived stem cells with the inducers. The TAA-isecretome was intravenously administered to mice with TAA-induced hepatic failure and those with partial hepatectomy. RESULTS TAA-isecretome infusion showed higher therapeutic potential in terms of (1) restoring disorganized hepatic tissue to normal tissue; (2) inhibiting proinflammatory cytokines (interleukin-6 and tumor necrosis factor-α); and (3) reducing abnormally elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase) compared to the naïve secretome infusion in mice with TAA-induced hepatic failure. However, the TAA-isecretome showed inferior therapeutic potential for restoring hepatic function in partially hepatectomized mice. Proteomic analysis of TAA-isecretome identified that antioxidant processes were the most predominant enriched biological networks of the proteins exclusively identified in the TAA-isecretome. In addition, peroxiredoxin-1, a potent antioxidant protein, was found to be one of representative components of TAA-isecretome and played a central role in the protection of TAA-induced hepatic injury. CONCLUSION Appropriate stimulation of adipose-derived stem cells with TAA led to the production of a secretome enriched with proteins, especially peroxiredoxin-1, with higher antioxidant activity. Our results suggest that appropriate stimulation of MSCs with pathogenic agents can lead to the production of a secretome specialized for protecting against the pathogen. This approach is expected to open a new way of developing various specific therapeutics based on the high plasticity and responsiveness of MSCs.
Collapse
Affiliation(s)
- Ok-Hee Kim
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Division of Hepato-biliary Pancreatic Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Ha-Eun Hong
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Division of Hepato-biliary Pancreatic Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Haeyeon Seo
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Division of Hepato-biliary Pancreatic Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Bong Jun Kwak
- Department of Surgery, Division of Hepato-biliary Pancreatic Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Ho Joong Choi
- Department of Surgery, Division of Hepato-biliary Pancreatic Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Kee-Hwan Kim
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul 11765, South Korea
| | - Joseph Ahn
- Department of Surgery, Division of Hepato-biliary Pancreatic Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Sang Chul Lee
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 34943, South Korea
| | - Say-June Kim
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Division of Hepato-biliary Pancreatic Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea.
| |
Collapse
|
|
35
|
de Miguel-Gómez L, Ferrero H, López-Martínez S, Campo H, López-Pérez N, Faus A, Hervás D, Santamaría X, Pellicer A, Cervelló I. Stem cell paracrine actions in tissue regeneration and potential therapeutic effect in human endometrium: a retrospective study. BJOG 2020; 127:551-560. [PMID: 31876085 DOI: 10.1111/1471-0528.16078] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2019] [Indexed: 01/07/2023]
Abstract
OBJECTIVE Determining genetic and paracrine mechanisms behind endometrial regeneration in Asherman's syndrome and endometrial atrophy (AS/EA) patients after autologous CD133+ bone marrow-derived stem cell (CD133+ BMDSC) transplantation. DESIGN Retrospective study using human endometrial biopsies and mouse models. SETTING Fundación-IVI, IIS-La Fe, Valencia, Spain. SAMPLES Endometrial biopsies collected before and after CD133+ BMDSC therapy, from eight women with AS/EA (NCT02144987) from the uterus of five mice with only left horns receiving CD133+ BMDSC therapy. METHODS In human samples, haematoxylin and eosin (H&E) staining, RNA arrays, PCR validation, and neutrophil elastase (NE) immunohistochemistry (IHQ). In mouse samples, PCR validation and protein immunoarrays. MAIN OUTCOME MEASURES H&E microscopic evaluation, RNA expression levels, PCR, and growth/angiogenic factors quantification, NE IHQ signal. RESULTS Treatment improved endometrial morphology and thickness for all patients. In human samples, Jun, Serpine1, and Il4 were up-regulated whereas Ccnd1 and Cxcl8 were down-regulated after treatment. The significant decrease of NE signal corroborated Cxcl8 expression. Animal model analysis confirmed human results and revealed a higher expression of pro-angiogenic cytokines (IL18, HGF, MCP-1, MIP2) in treated uterine horns. CONCLUSIONS CD133+ BMDSC seems to activate several factors through a paracrine mechanism to help tissue regeneration, modifying endometrial behaviour through an immunomodulatory milieu that precedes proliferation and angiogenic processes. Insight into these processes could bring us one step closer to a non-invasive treatment for AS/EA patients. TWEETABLE ABSTRACT CD133+ BMDSC therapy regenerates endometrium, modifying the immunological milieu that precedes proliferation and angiogenesis.
Collapse
Affiliation(s)
- L de Miguel-Gómez
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - H Ferrero
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - S López-Martínez
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - H Campo
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - N López-Pérez
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - A Faus
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - D Hervás
- Data Science, Biostatistics and Bioinformatics, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - X Santamaría
- Igenomix Academy, Valencia, Spain.,IVIRMA, Barcelona, Barcelona, Spain
| | - A Pellicer
- IVIRMA Valencia, Valencia, Spain.,Reproductive Medicine Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - I Cervelló
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| |
Collapse
|
|
36
|
Potential Therapies Using Myogenic Stem Cells Combined with Bio-Engineering Approaches for Treatment of Muscular Dystrophies. Cells 2019; 8:cells8091066. [PMID: 31514443 PMCID: PMC6769835 DOI: 10.3390/cells8091066] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/06/2019] [Accepted: 09/10/2019] [Indexed: 12/31/2022] Open
Abstract
Muscular dystrophies (MDs) are a group of heterogeneous genetic disorders caused by mutations in the genes encoding the structural components of myofibres. The current state-of-the-art treatment is oligonucleotide-based gene therapy that restores disease-related protein. However, this therapeutic approach has limited efficacy and is unlikely to be curative. While the number of studies focused on cell transplantation therapy has increased in the recent years, this approach remains challenging due to multiple issues related to the efficacy of engrafted cells, source of myogenic cells, and systemic injections. Technical innovation has contributed to overcoming cell source challenges, and in recent studies, a combination of muscle resident stem cells and gene editing has shown promise as a novel approach. Furthermore, improvement of the muscular environment both in cultured donor cells and in recipient MD muscles may potentially facilitate cell engraftment. Artificial skeletal muscle generated by myogenic cells and muscle resident cells is an alternate approach that may enable the replacement of damaged tissues. Here, we review the current status of myogenic stem cell transplantation therapy, describe recent advances, and discuss the remaining obstacles that exist in the search for a cure for MD patients.
Collapse
|
|
37
|
Khan RS, Newsome PN. A Comparison of Phenotypic and Functional Properties of Mesenchymal Stromal Cells and Multipotent Adult Progenitor Cells. Front Immunol 2019; 10:1952. [PMID: 31555259 PMCID: PMC6724467 DOI: 10.3389/fimmu.2019.01952] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 08/02/2019] [Indexed: 12/15/2022] Open
Abstract
Both Multipotent Adult Progenitor Cells and Mesenchymal Stromal Cells are bone-marrow derived, non-haematopoietic adherent cells, that are well-known for having immunomodulatory and pro-angiogenic properties, whilst being relatively non-immunogenic. However, they are phenotypically and functionally distinct cell types, which has implications for their efficacy in different settings. In this review we compare the phenotypic and functional properties of these two cell types, to help in determining which would be the superior cell type for different applications.
Collapse
Affiliation(s)
- Reenam S Khan
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Philip N Newsome
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| |
Collapse
|
|
38
|
Eliyasi Dashtaki M, Hemadi M, Saki G, Mohammadiasl J, Khodadadi A. Spermatogenesis Recovery Potentials after Transplantation of Adipose Tissue-Derived Mesenchymal Stem Cells Cultured with Growth Factors in Experimental Azoospermic Mouse Models. CELL JOURNAL 2019; 21:401-409. [PMID: 31376321 PMCID: PMC6722443 DOI: 10.22074/cellj.2020.6055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 11/17/2018] [Indexed: 12/26/2022]
Abstract
Objective Approximately 1% of the male population suffers from obstructive or non-obstructive azoospermia. Previous
in vitro studies have successfully differentiated mesenchymal stem cells (MSCs) into germ cells. Because of immune-
modulating features, safety, and simple isolation, adipose tissue-derived MSCs (AT-MSCs) are good candidates for
such studies. However, low availability is the main limitation in using these cells. Different growth factors have been
investigated to overcome this issue. In the present study, we aimed to comparatively assess the performance of
AT-MSCs cultured under the presence or absence of three different growth factors, epidermal growth factor (EGF),
leukemia inhibitory factor (LIF) and glial cell line-derived neurotrophic factor (GDNF), following transplantation in
testicular torsion-detorsion mice
Materials and Methods This was an experimental study in which AT-MSCs were first isolated from male Naval
Medical Research Institute (NMRI) mice. Then, the mice underwent testicular torsion-detorsion surgery and received
bromodeoxyuridine (BrdU)-labeled AT-MSCs into the lumen of seminiferous tubules. The transplanted cells had been
cultured in different conditioned media, containing the three growth factors and without them. The expression of germ
cell-specific markers was evaluated with real-time polymerase chain reaction (PCR) and western-blot. Moreover,
immunohistochemical staining was used to trace the labeled cells.
Results The number of transplanted AT-MSCs resided in the basement membrane of seminiferous tubules significantly
increased after 8 weeks. The expression levels of Gcnf and Mvh genes in the transplanted testicles by AT-MSCs
cultured in the growth factors-supplemented medium was greater than those in the control group (P<0.001 and P<0.05,
respectively). The expression levels of the c-Kit and Scp3 genes did not significantly differ from the control group.
Conclusion Our findings showed that the use of EGF, LIF and GDNF to culture AT-MSCs can be very helpful in terms of
MSC survival and localization.
Collapse
Affiliation(s)
- Masoumeh Eliyasi Dashtaki
- Cellular and Molecular Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Masoud Hemadi
- Cellular and Molecular Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ghasem Saki
- Physiology Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Electronic Address:
| | - Javad Mohammadiasl
- Department of Medical Genetics, School of Medicine, Ahvaz University of Medical Sciences, Ahvaz, Iran
| | - Ali Khodadadi
- Cancer, Environmental and Petroleum Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| |
Collapse
|
|
39
|
The Combination of TGF-β3 and BMP-6 Synergistically Promotes the Chondrogenic Differentiation of Equine Bone Marrow-Derived Mesenchymal Stem Cells. Int J Pept Res Ther 2019. [DOI: 10.1007/s10989-019-09880-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
|
|
40
|
Guo Y, Zhang Z, Xu X, Xu Z, Wang S, Huang D, Li Y, Mou X, Liu F, Xiang C. Menstrual Blood-Derived Stem Cells as Delivery Vehicles for Oncolytic Adenovirus Virotherapy for Colorectal Cancer. Stem Cells Dev 2019; 28:882-896. [PMID: 30991894 DOI: 10.1089/scd.2018.0222] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Oncolytic adenoviruses (Ads) have potential applications in cancer therapy due to their ability to replicate and induce tumor cell death. However, their clinical application has been limited by the lack of efficient cell-based delivery systems that can provide protection from immune attack and prevent virus clearance by neutralizing antibodies. We previously demonstrated that menstrual blood-derived mesenchymal stem cells (MenSCs) can specifically target tumor cells and serve as a novel drug delivery platform. We engineered CRAd5/F11 chimeric oncolytic Ads that can infect MenSCs and preserve their tumor targeting ability in vitro. MenSCs loaded with these Ads were transplanted in a mouse tumor model. We found that a large number of the CRAd5/F11 viruses were accumulated in tumor site and mediated marked inhibitory effects against colorectal cancer (CRC). Thus, we concluded that MenSC-cloaked oncolytic Ads hold great potential as a novel virus-delivery platform for the therapy of various cancers, including CRC.
Collapse
Affiliation(s)
- Yang Guo
- 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhenzhen Zhang
- 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaogang Xu
- 2 Zhejiang Hospital and Zhejiang Provincial Key Lab of Geriatrics, Hangzhou, China
| | - Zhenyu Xu
- 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shibing Wang
- 3 Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,4 Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China
| | - Dongsheng Huang
- 3 Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,4 Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China
| | - Yifei Li
- 5 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaozhou Mou
- 3 Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,4 Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China
| | - Fanlong Liu
- 6 Department of Colorectal and Anal Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Charlie Xiang
- 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou, China.,5 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
41
|
Farzaneh M, Rahimi F, Alishahi M, Khoshnam SE. Paracrine Mechanisms Involved in Mesenchymal Stem Cell Differentiation into Cardiomyocytes. Curr Stem Cell Res Ther 2019; 14:9-13. [PMID: 30152289 DOI: 10.2174/1574888x13666180821160421] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 08/01/2018] [Accepted: 08/16/2018] [Indexed: 12/27/2022]
Abstract
Cardiovascular Disease (CVD) is one of the world-wide healthcare problem that involves the heart or blood vessels. CVD includes myocardial infarction and coronary artery diseases (CAD). Dysfunctional myocardial cells are leading causes of low cardiac output or ventricular dysfunction after cardiac arrest and may contribute to the progression of CVD which could not generate new cardiomyocytes in human adult heart. The mesenchymal stem cells (MSCs) which are present in adult marrow can self-renew and have the capacity of differentiation into multiple types of cells including cardiomyocytes. Recent biochemical analyses greatly revealed that several regulators of MSCs, such as HGF, PDGF, Wnt, and Notch-1 signaling pathways have been shown to be involved in the proliferation and differentiation into cardiomyocytes. Preclinical studies are paving the way for further applications of MSCs in the repair of myocardial infarction. In this study, we discuss and summarize the paracrine mechanisms involved in MSCs differentiation into cardiomyocytes.
Collapse
Affiliation(s)
- Maryam Farzaneh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fatemeh Rahimi
- Department of Biology, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Masoumeh Alishahi
- Department of Biology, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Seyed E Khoshnam
- Physiology Research Center, Department of Physiology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| |
Collapse
|
|
42
|
Tao SC, Guo SC. Extracellular vesicles in bone: "dogrobbers" in the "eternal battle field". Cell Commun Signal 2019; 17:6. [PMID: 30658653 PMCID: PMC6339294 DOI: 10.1186/s12964-019-0319-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/06/2019] [Indexed: 02/07/2023] Open
Abstract
Throughout human life, bone is constantly in a delicate dynamic equilibrium of synthesis and resorption, hosting finely-tuned bone mineral metabolic processes for bone homeostasis by collaboration or symphony among several cell types including osteoclasts (OCs), osteoblasts (OBs), osteocytes (OYs), vascular endothelial cells (ECs) and their precursors. Beyond these connections, a substantial level of communication seems to occur between bone and other tissues, and together, they form an organic unit linked to human health and disease. However, the current hypothesis, which includes growth factors, hormones and specific protein secretion, incompletely explains the close connections among bone cells or between bone and other tissues. Extracellular vesicles (EVs) are widely-distributed membrane structures consisting of lipid bilayers, membrane proteins and intravesicular cargo (including proteins and nucleic acids), ranging from 30 nm to 1000 nm in diameter, and their characters have been highly conserved throughout evolution. EVs have targeting abilities and the potential to transmit multidimensional, abundant and complicated information, as powerful and substantial "dogrobbers" mediating intercellular communications. As research has progressed, EVs have gradually become thought of as "dogrobbers" in bone tissue-the "eternal battle field" -in a delicate dynamic balance of destruction and reconstruction. In the current review, we give a brief description of the major constituent cells in bone tissues and explore the progress of current research on bone-derived EVs. In addition, this review also discusses in depth not only potential directions for future research to breakthrough in this area but also problems existing in current research that need to be solved for a better understanding of bone tissues.
Collapse
Affiliation(s)
- Shi-Cong Tao
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
| | - Shang-Chun Guo
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
| |
Collapse
|
|
43
|
Suman S, Domingues A, Ratajczak J, Ratajczak MZ. Potential Clinical Applications of Stem Cells in Regenerative Medicine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1201:1-22. [PMID: 31898779 DOI: 10.1007/978-3-030-31206-0_1] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The field of regenerative medicine is looking for a pluripotent/multipotent stem cell able to differentiate across germ layers and be safely employed in therapy. Unfortunately, with the exception of hematopoietic stem/progenitor cells (HSPCs) for hematological applications, the current clinical results with stem cells are somewhat disappointing. The potential clinical applications of the more primitive embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have so far been discouraging, as both have exhibited several problems, including genomic instability, a risk of teratoma formation, and the possibility of rejection. Therefore, the only safe stem cells that have so far been employed in regenerative medicine are monopotent stem cells, such as the abovementioned HSPCs or mesenchymal stem cells (MSCs) isolated from postnatal tissues. However, their monopotency, and therefore limited differentiation potential, is a barrier to their broader application in the clinic. Interestingly, results have accumulated indicating that adult tissues contain rare, early-development stem cells known as very small embryonic-like stem cells (VSELs), which can differentiate into cells from more than one germ layer. This chapter addresses different sources of stem cells for potential clinical application and their advantages and problems to be solved.
Collapse
Affiliation(s)
- Suman Suman
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Alison Domingues
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Janina Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Warsaw Medical University, Warsaw, Poland.
| |
Collapse
|
|
44
|
Musavi L, Brandacher G, Hoke A, Darrach H, Lee WPA, Kumar A, Lopez J. Muscle-derived stem cells: important players in peripheral nerve repair. Expert Opin Ther Targets 2018; 22:1009-1016. [PMID: 30347175 DOI: 10.1080/14728222.2018.1539706] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Stem cell therapy for peripheral nerve repair is a rapidly evolving field in regenerative medicine. Although most studies to date have investigated stem cells originating from bone marrow or adipose, skeletal muscle has recently been recognized as an abundant and easily accessible source of stem cells. Muscle-derived stem cells (MDSCs) are a diverse population of multipotent cells with pronounced antioxidant and regenerative capacity. Areas covered: The current literature on the various roles MDSCs serve within the micro- and macro-environment of nerve injury. Furthermore, the exciting new research that is establishing MDSC-cellular therapy as an important therapeutic modality to improve peripheral nerve regeneration. Expert opinion: MDSCs are a promising therapeutic agent for the repair of peripheral nerves; MDSCs not only undergo gliogenesis and angiogenesis, but they also orchestrate larger pro-regenerative host responses. However, the isolation, transformation, and in-vivo behavior of MDSCs require further evaluation prior to clinical application.
Collapse
Affiliation(s)
- Leila Musavi
- a Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory , Johns Hopkins Hospital , Baltimore , Maryland
| | - Gerald Brandacher
- a Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory , Johns Hopkins Hospital , Baltimore , Maryland
| | - Ahmet Hoke
- b The Solomon H Snyder Department of Neuroscience , Johns Hopkins University , Baltimore , Maryland
| | - Halley Darrach
- a Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory , Johns Hopkins Hospital , Baltimore , Maryland
| | - W P Andrew Lee
- a Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory , Johns Hopkins Hospital , Baltimore , Maryland
| | - Anand Kumar
- c Department of Plastic & Reconstructive Surgery , Case Western Reserve University, Rainbow Babies Children's Hospital , Cleveland , OH , USA
| | - Joseph Lopez
- a Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory , Johns Hopkins Hospital , Baltimore , Maryland
| |
Collapse
|
|
45
|
Synaptic Plasticity of Human Umbilical Cord Mesenchymal Stem Cell Differentiating into Neuron-like Cells In Vitro Induced by Edaravone. Stem Cells Int 2018; 2018:5304279. [PMID: 30510585 PMCID: PMC6230402 DOI: 10.1155/2018/5304279] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 08/02/2018] [Accepted: 08/14/2018] [Indexed: 12/12/2022] Open
Abstract
Objective The human umbilical cord mesenchymal stem cells (hUMSCs) are characterized with the potential ability to differentiate to several types of cells. Edaravone has been demonstrated to prevent the hUMSCs from the oxidative damage, especially its ability in antioxidative stress. We hypothesized that Edaravone induces the hUMSCs into the neuron-like cells. Methods The hUMSCs were obtained from the human umbilical cord tissue. The differentiation of hUMSCs was induced by Edaravone with three different doses: 0.65 mg/ml, 1.31 mg/ml, and 2.62 mg/ml. Flow cytometry was used to detect the cell markers. Protein and mRNA levels of nestin, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP) were detected by Western blot and RT-PCR. The expression of synaptophysin (SYN), growth-associated protein 43 (GAP43), and postsynaptic density 95 (PSD95) was detected by Real-Time PCR. Results As long as the prolongation of the culture, the hUMSCs displayed with the long strips or long fusiform to fat and then characterized with the radial helix growth. By using flow cytometry, the cultured hUMSCs at the 3rd, 5th, and 10th passages were expressed with CD73, CD90, and CD105 but not CD11b, CD19, CD34, CD45, and HLA-DR. Most of the hUMSCs cultured with Edaravone exhibited typical nerve-immediately characters including the cell body contraction, increased refraction, and protruding one or more elongated protrusions, which were not found in the control group without addition of Edaravone. NSE, nestin, and GFAP were positive in these neuron-like cells. Edaravone dose-dependently increased expression levels of NSE, nestin, and GFAP. After replacement of maintenance fluid, neuron-like cells continued to be cultured for five days. These neuron-like cells were positive for SYN, PSD95, and GAP43. Conclusion Edaravone can dose-dependently induce hUMSCs to differentiate into neuron-like cells that expressed the neuronal markers including NSE, nestin, and GFAP and synaptic makers such as SYN, PSD95, and GAP43.
Collapse
|
|
46
|
Seyhoun I, Hajighasemlou S, Muhammadnejad S, Ai J, Nikbakht M, Alizadeh AA, Hosseinzadeh F, Mirmoghtadaei M, Seyhoun SM, Verdi J. Combination therapy of sorafenib with mesenchymal stem cells as a novel cancer treatment regimen in xenograft models of hepatocellular carcinoma. J Cell Physiol 2018; 234:9495-9503. [PMID: 30362607 DOI: 10.1002/jcp.27637] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 10/02/2018] [Indexed: 12/12/2022]
Abstract
AIM Hepatocellular carcinoma (HCC) is the most common liver malignancy and the second leading cause of cancer-related deaths in the world. Sorafenib is the first-line treatment of HCC. Although sorafenib has positive effects on the survival of patients, novel therapeutic strategies are needed to extend survival and improve the efficacy of sorafenib. This study combines sorafenib with mesenchymal stem cells (MSCs) as a new approach to enhance the efficacy of sorafenib. MATERIAL AND METHODS A subcutaneous xenograft model of HCC, established by human HepG2 cell lines, was implanted into the flank of nude mice and was used to evaluate tumor growth after treatment with sorafenib alone or in combination with MSCs. The aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels were measured for safety assessment. Histopathological studies were performed using hematoxylin and eosin staining, and immunohistochemistry tests were performed to evaluate proliferation (Ki67) and angiogenesis (CD34). The TUNEL assay was used to detect apoptosis and measure the expression of major inflammatory cytokines (IL-1a, IL-10, and TNF-α) with real-time polymerase chain reaction. RESULT Sorafenib, in combination with MSCs, strongly inhibited tumor growth in the xenograft model. Furthermore, the combination therapy significantly inhibited HCC cell proliferation, decreased tumor angiogenesis, and induced apoptosis and maintained antitumor-associated anti-inflammatory effects of MSCs. CONCLUSION This combination therapy strategy could be used as a new therapeutic approach to the treatment of HCC that significantly improves upon the results achieved using sorafenib as monotherapy.
Collapse
Affiliation(s)
- Iman Seyhoun
- Tissue Engineering & Applied Cell Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Saieh Hajighasemlou
- Tissue Engineering & Applied Cell Sciences, Tehran University of Medical Sciences, Tehran, Iran.,Food and Drug Control Laboratory (FDCL), Iran Ministry of Health and Medical Education, Tehran, Iran
| | - Samad Muhammadnejad
- Cell-Based Therapies Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Jafar Ai
- Tissue Engineering & Applied Cell Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Nikbakht
- Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Alizadeh
- Tissue Engineering & Applied Cell Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Faezeh Hosseinzadeh
- Tissue Engineering & Applied Cell Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Milad Mirmoghtadaei
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | | | - Javad Verdi
- Tissue Engineering & Applied Cell Sciences, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
47
|
Abstract
PURPOSE OF REVIEW The purpose of this article is to provide a review of state-of-the-art cellular therapy in cerebrovascular diseases by discussing published and ongoing clinical trials. RECENT FINDINGS In spite of the challenge in translating the success of cellular therapy in acute strokes from preclinical models to clinical trials, early phase clinical trial have recently shown promise in overcoming these challenges. Various stem cell types and doses are being studied, different routes of administration are under investigation, as well as defining the optimal time window to intervene. In addition, experimental methods to enhance cellular therapy, such as ischemic preconditioning, are evolving. After the failure of neuroprotectants in cerebrovascular diseases, researchers have been keen to provide a way of replacement of damaged brain tissue and to promote recovery in order to achieve better outcomes. The field has progressed from intravenous delivery in the 24- to 36-h time window to later intracerebral administration in chronic stroke in clinical trials. New optimism in acute stroke care fostered by the success of mechanical thrombectomy will hopefully extend into cell therapy to promote recovery.
Collapse
Affiliation(s)
- Michael I Nahhas
- Department of Neurology, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - David C Hess
- Department of Neurology, Medical College of Georgia at Augusta University, Augusta, GA, USA.
| |
Collapse
|
|
48
|
New Approaches to Treat Osteoarthritis with Mesenchymal Stem Cells. Stem Cells Int 2018; 2018:5373294. [PMID: 30305819 PMCID: PMC6165608 DOI: 10.1155/2018/5373294] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 07/21/2018] [Accepted: 07/29/2018] [Indexed: 12/15/2022] Open
Abstract
Osteoarthritis is one of the most common chronic health problems in the world that causes disability and chronic pain with reduced mobility and is a progressive degenerative disease in weight-bearing joints such as the knee. The pathology of the joint resulting from OA includes loss of cartilage volume and cartilage lesions leading to inflammation of the articular joint structures; its incidence and progression are associated with a variety of risk factors. Most of the current treatments focus on symptom management such as physical and occupational therapies, pharmacological intervention for pain management, and surgical intervention with limited success and do not address nor halt the progression of the disease. In this review, we will describe the current treatment options for OA and the exciting new translational medical research currently underway utilising mesenchymal stem cells for OA therapy.
Collapse
|
|
49
|
Al-Jaibaji O, Swioklo S, Gijbels K, Vaes B, Figueiredo FC, Connon CJ. Alginate encapsulated multipotent adult progenitor cells promote corneal stromal cell activation via release of soluble factors. PLoS One 2018; 13:e0202118. [PMID: 30192833 PMCID: PMC6128465 DOI: 10.1371/journal.pone.0202118] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 07/28/2018] [Indexed: 01/26/2023] Open
Abstract
To reduce the increasing need for corneal transplantation, attempts are currently aiming to restore corneal clarity, one potent source of cells are multipotent adult progenitor cells (MAPC®). These cells release a powerful cocktail of paracrine factors that can guide wound healing and tissue regeneration. However, their role in corneal regeneration has been overlooked. Thus, we sought to explore the potential of combining the cytoprotective storage feature of alginate, with MAPC to generate a storable cell-laden gel for corneal wound healing. 72 hours following hypothermic storage, alginate encapsulation was shown to maintain MAPC viability at either 4 or 15°C. Encapsulated MAPC (2 x106 cells/mL) stored at 15°C presented the optimum temperature that allowed for cell recovery. These cells had the ability to reattach to tissue culture plastic whilst exhibiting normal phenotype and this was maintained in serum-free and xenobiotic-free medium. Furthermore, corneal stromal cells presented a significant decrease in scratch-wounds in the presence of alginate encapsulated MAPC compared to a no-cell control (p = 0.018). This study shows that immobilization of MAPC within an alginate hydrogel does not hinder their ability to affect a secondary cell population via soluble factors and that these effects are successfully retained following hypothermic storage.
Collapse
Affiliation(s)
- Olla Al-Jaibaji
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Stephen Swioklo
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | | | | | - Che J. Connon
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
- * E-mail:
| |
Collapse
|
|
50
|
Abstract
Objective: Gliomas are the most common neoplasm of the central nervous system (CNS); however, traditional imaging techniques do not show the boundaries of tumors well. Some researchers have found a new therapeutic mode to combine nanoparticles, which are nanosized particles with various properties for specific therapeutic purposes, and stem cells for tracing gliomas. This review provides an introduction of the basic understanding and clinical applications of the combination of stem cells and nanoparticles as a contrast agent for glioma imaging. Data Sources: Studies published in English up to and including 2017 were extracted from the PubMed database with the selected key words of “stem cell,” “glioma,” “nanoparticles,” “MRI,” “nuclear imaging,” and “Fluorescence imaging.” Study Selection: The selection of studies focused on both preclinical studies and basic studies of tracking glioma with nanoparticle-labeled stem cells. Results: Studies have demonstrated successful labeling of stem cells with multiple types of nanoparticles. These labeled stem cells efficiently migrated to gliomas of varies models and produced signals sensitively captured by different imaging modalities. Conclusion: The use of nanoparticle-labeled stem cells is a promising imaging platform for the tracking and treatment of gliomas.
Collapse
Affiliation(s)
- Shuang-Lin Deng
- Department of Neurosurgical Oncology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yun-Qian Li
- Department of Neurosurgical Oncology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Gang Zhao
- Department of Neurosurgical Oncology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| |
Collapse
|