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Li Z, Stachon T, Zimmermann J, Trusen S, Fries FN, Berger M, Suiwal S, Chai N, Seitz B, Shi L, Amini M, Szentmáry N. Expression of PAX6 and Keratocyte-Characteristic Markers in Human Limbal Stromal Cells of Congenital Aniridia and Healthy Subjects, In Vitro. Curr Eye Res 2025; 50:362-372. [PMID: 39791356 DOI: 10.1080/02713683.2025.2449915] [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: 03/19/2024] [Revised: 11/17/2024] [Accepted: 12/24/2024] [Indexed: 01/12/2025]
Abstract
PURPOSE Our aim was to examine the expression of PAX6 and keratocyte-specific markers in human limbal stromal cells (LSCs) in congenital aniridia (AN) and in healthy corneas, in vitro. METHODS Primary human LSCs were extracted from individuals with aniridia (AN-LSCs) (n = 8) and from healthy corneas (LSCs) (n = 8). The cells were cultured in either normal-glucose serum-containing cell culture medium (NGSC-medium) or low-glucose serum-free cell culture medium (LGSF-medium). Analysis of PAX6 and keratocyte-specific markers was conducted using qPCR and Western blotting. The keratocyte-specific markers included Collagen I (COL1A1), Collagen III (COL3A1), Collagen V (COL5A1), α-smooth muscle actin (ACTA2), Aldehyde Dehydrogenase 3 Family, Member A1 (ALDH3A1), Keratocan (KER), Lumican (LUM), and CD34. RESULTS PAX6 mRNA expression exhibited a significant decrease in AN-LSCs compared to LSCs in both NGSC- and LGSF-medium (p = 0.04; p = 0.014). There was a marked reduction in COL5A1 mRNA expression (p = 0.011), accompanied by notably higher ALDH3A1 and KER mRNA levels (p = 0.007; p = 0.013) in AN-LSCs compared to LSCs when using NGSC-medium. In LGSF-medium, AN-LSCs showed a significant increase in COL1A1 and COL5A1 mRNA expression compared to LSCs (p = 0.048; p = 0.002). Moreover, COL1A1 and α-SMA protein expression were significantly elevated in AN-LSCs compared to LSCs in LGSF-medium (p = 0.048, p = 0.008). CONCLUSIONS Our investigation affirms the altered expression of PAX6 and keratocyte-specific markers in AN-LSCs relative to healthy controls. Both NGSC- and LGSF-medium exerted distinct effects on both LSCs and AN-LSCs. The observed variations in PAX6 and keratocyte-specific marker expression in AN-LSCs may play a pivotal role in the development and progression of aniridia-associated keratopathy.
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Affiliation(s)
- Zhen Li
- Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research, Saarland University, Saar, Germany
| | - Tanja Stachon
- Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research, Saarland University, Saar, Germany
| | - Julia Zimmermann
- Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research, Saarland University, Saar, Germany
| | - Simon Trusen
- Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research, Saarland University, Saar, Germany
| | - Fabian N Fries
- Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research, Saarland University, Saar, Germany
- Department of Ophthalmology, Saarland University Medical Center, Saar, Germany
| | - Maximilian Berger
- Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research, Saarland University, Saar, Germany
| | - Shweta Suiwal
- Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research, Saarland University, Saar, Germany
| | - Ning Chai
- Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research, Saarland University, Saar, Germany
| | - Berthold Seitz
- Department of Ophthalmology, Saarland University Medical Center, Saar, Germany
| | - Lei Shi
- Department of Ophthalmology, Anhui No.2 Provincial People's Hospital, Hefei, Anhui, China
| | - Maryam Amini
- Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research, Saarland University, Saar, Germany
| | - Nóra Szentmáry
- Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research, Saarland University, Saar, Germany
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de Camargo GC, da Cruz Landim-Alvarenga F, Maciel AP, Dos Santos DB, de Paula Freitas Dell'Aqua C, E Alvarenga ML, de Barros Piffer A, de Souza FF. Polyvinyl alcohol can replace the fetal bovine serum during cryopreservation of canine adipose mesenchymal stromal cells. In Vitro Cell Dev Biol Anim 2025; 61:369-373. [PMID: 40399738 DOI: 10.1007/s11626-025-01046-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 04/02/2025] [Indexed: 05/23/2025]
Abstract
Mesenchymal stromal cells (MSCs) are cells with multipotent characteristics present in various tissues and used as a promising alternative in cell therapy protocols in animals and humans. Creating stem cell banks for various purposes through cryopreservation is a common practice with MSCs. In this regard, the association between 10% dimethyl sulfoxide (Me2SO) and 90% fetal bovine serum (FBS) is widely used as a cryoprotective protocol for MSCs. However, these components have disadvantages, with possible risks to therapy receivers, contamination, and cytotoxic effects on MSCs. To replacing and reducing the use of FBS in the MSCs cryopreservation protocols, four agents were selected, being FBS at 10%, methylcellulose (MC) at 0.1%, polyvinyl alcohol (PVA) at 1%, and bovine albumin (BSA) at 1%, all associated with 10% Me2SO and 80% DMEM high glucose media. In the cell viability test with flow cytometry, the group with MC at 0.1% performed significantly worse than other treatments, except for BSA, which had a similar performance to MC. The expression of membrane proteins evaluation with flow cytometry showed that the cells treated with PVA and 10% FBS performed better at expressing lower values of CD34 and MHC-II. There were no differences regarding the osteogenic and adipogenic differentiation induction between the groups. We concluded that low concentrations of FBS (10% in DMEM) associated with BSA or PVA have a similar protective effect on cell viability during cryopreservation with Me2SO as 90% FBS. PVA showed an additional effect since the MSCs expressed lower concentrations of MHC-II and CD34.
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Affiliation(s)
- Gabriel Corrêa de Camargo
- Department of Veterinary Surgery and Animal Reproduction, Faculty of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.
| | - Fernanda da Cruz Landim-Alvarenga
- Department of Veterinary Surgery and Animal Reproduction, Faculty of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Alice Pereira Maciel
- Department of Veterinary Surgery and Animal Reproduction, Faculty of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Driéle Bretones Dos Santos
- Department of Veterinary Surgery and Animal Reproduction, Faculty of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
- Omics Animal Biotechnology, Botucatu, São Paulo, Brazil
| | - Camilla de Paula Freitas Dell'Aqua
- Department of Veterinary Surgery and Animal Reproduction, Faculty of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | | | - Amanda de Barros Piffer
- Department of Veterinary Surgery and Animal Reproduction, Faculty of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Fabiana Ferreira de Souza
- Department of Veterinary Surgery and Animal Reproduction, Faculty of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
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Zhu K, Ding Y, Chen Y, Su K, Zheng J, Zhang Y, Hu Y, Wei J, Wang Z. Advancing regenerative medicine: the Aceman system's pioneering automation and machine learning in mesenchymal stem cell biofabrication. Biofabrication 2025; 17:025021. [PMID: 39970480 DOI: 10.1088/1758-5090/adb803] [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: 09/19/2024] [Accepted: 02/19/2025] [Indexed: 02/21/2025]
Abstract
Mesenchymal stem cells (MSCs) are pivotal in advancing regenerative medicine; however, the large-scale production of MSCs for clinical applications faces significant challenges related to efficiency, cost, and quality assurance. We introduce the Automated Cell Manufacturing System (Aceman), a revolutionary solution that leverages machine learning and robotics integration to optimize MSC production. This innovative system enhances both efficiency and quality in the field of regenerative medicine. With a modular design that adheres to good manufacturing practice standards, Aceman allows for scalable adherent cell cultures. A sophisticated machine learning algorithm has been developed to streamline cell counting and confluence assessment, while the accompanying control software features customization options, robust data management, and real-time monitoring capabilities. Comparative studies reveal that Aceman achieves superior efficiency in analytical and repeatable tasks compared to traditional manual methods. The system's continuous operation minimizes human error, offering substantial long-term benefits. Comprehensive cell biology assays, including Bulk RNA-Seq analysis and flow cytometry, support that the cells produced by Aceman function comparably to those cultivated through conventional techniques. Importantly, Aceman maintains the characteristic immunophenotype of MSCs during automated subcultures, representing a significant advancement in cell production technology. This system lays a solid foundation for future innovations in healthcare biomanufacturing, ultimately enhancing the potential of MSCs in therapeutic applications.
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Affiliation(s)
- Kai Zhu
- School of Automation and Electrical Engineering, University of Jinan, Jinan, Shandong, People's Republic of China
- Tronz Biomedical Engineering Pte. Ltd, Jinan, Shandong, People's Republic of China
- Shenzhen Key Laboratory of Minimally Invasive Surgical Robotics and System, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, People's Republic of China
| | - Yi Ding
- Artificial Intelligence Institute (School of Information Science ϑ Engineering), University of Jinan, Jinan, Shandong, People's Republic of China
| | - Yuqiang Chen
- Tronz Biomedical Engineering Pte. Ltd, Jinan, Shandong, People's Republic of China
| | - Kechuan Su
- Tronz Biomedical Engineering Pte. Ltd, Jinan, Shandong, People's Republic of China
| | - Jintu Zheng
- Shenzhen Key Laboratory of Minimally Invasive Surgical Robotics and System, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, People's Republic of China
| | - Yu Zhang
- Institute of Marine Science and Technology, Shandong University, Qingdao, Shandong, People's Republic of China
| | - Ying Hu
- Shenzhen Key Laboratory of Minimally Invasive Surgical Robotics and System, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, People's Republic of China
| | - Jun Wei
- School of Automation and Electrical Engineering, University of Jinan, Jinan, Shandong, People's Republic of China
| | - Zenan Wang
- Shenzhen Key Laboratory of Minimally Invasive Surgical Robotics and System, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, People's Republic of China
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Cheng T, Mao M, Liu Y, Xie L, Shi F, Liu H, Li X. The potential therapeutic effect of human umbilical cord mesenchymal stem cell-derived exosomes in bronchopulmonary dysplasia. Life Sci 2024; 357:123047. [PMID: 39260518 DOI: 10.1016/j.lfs.2024.123047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 08/25/2024] [Accepted: 09/07/2024] [Indexed: 09/13/2024]
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants, with its incidence rising due to improved survival rates of these infants. BPD results from a combination of prenatal and postnatal factors, such as mechanical ventilation, oxygen toxicity, and infections, all of which significantly impact the prognosis and growth of affected infants. Current treatment options for BPD are largely supportive and do not address the underlying pathology. Exosomes are cell-derived bilayer-enclosed membrane structures enclosing proteins, lipids, RNAs, growth factors, cytokines and metabolites. They have become recognized as crucial regulators of intercellular communication in various physiological and pathological processes. Previous studies have revealed the therapeutic potential of human umbilical cord mesenchymal stem cells-derived exosomes (HUCMSCs-Exos) in promoting tissue repair and regeneration. Therefore, HUCMSCs-Exos maybe a promising and effective therapeutic modality for BPD. In this review, we firstly provide a comprehensive overview of BPD, including its etiology and the mechanisms of lung injury. Then we detail the isolation, characterization, and contents of HUCMSCs-Exos, and discuss their potential mechanisms of HUCMSCs-Exos in BPD treatment. Additionally, we summarize current clinical trials and discuss the challenges in translating these findings from bench to bedside. This review aims to lay the groundwork for future clinical applications of HUCMSCs-Exos in treating BPD.
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Affiliation(s)
- Tianyu Cheng
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Min Mao
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yang Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Liang Xie
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Fang Shi
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Hanmin Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Xin Li
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China.
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McDonald J, Mohak S, Fabian Z. Stem Cell-Derived Extracellular Vesicles in the Treatment of Cardiovascular Diseases. Pharmaceutics 2024; 16:381. [PMID: 38543275 PMCID: PMC10974254 DOI: 10.3390/pharmaceutics16030381] [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: 01/30/2024] [Revised: 02/26/2024] [Accepted: 03/06/2024] [Indexed: 01/03/2025] Open
Abstract
Cardiovascular disease constitutes a noteworthy public health challenge characterized by a pronounced incidence, frequency, and mortality rate, particularly impacting specific demographic groups, and imposing a substantial burden on the healthcare infrastructure. Certain risk factors, such as age, gender, and smoking, contribute to the prevalence of fatal cardiovascular disease, highlighting the need for targeted interventions. Current challenges in clinical practice involve medication complexities, the lack of a systematic decision-making approach, and prevalent drug therapy problems. Stem cell-derived extracellular vesicles stand as versatile entities with a unique molecular fingerprint, holding significant therapeutic potential across a spectrum of applications, particularly in the realm of cardio-protection. Their lipid, protein, and nucleic acid compositions, coupled with their multifaceted functions, underscore their role as promising mediators in regenerative medicine and pave the way for further exploration of their intricate contributions to cellular physiology and pathology. Here, we overview our current understanding of the possible role of stem cell-derived extracellular vesicles in the clinical management of human cardiovascular pathologies.
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Affiliation(s)
- Jennifer McDonald
- School of Medicine and Dentistry, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Fylde Road, Preston PR1 2HE, UK;
| | - Sidhesh Mohak
- Department of Internal Medicine, South Texas Health System, McAllen, TX 78503, USA;
| | - Zsolt Fabian
- School of Medicine and Dentistry, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Fylde Road, Preston PR1 2HE, UK;
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Yang Z, Liang Z, Rao J, Xie H, Zhou M, Xu X, Lin Y, Lin F, Wang C, Chen C. Hypoxic-preconditioned mesenchymal stem cell-derived small extracellular vesicles promote the recovery of spinal cord injury by affecting the phenotype of astrocytes through the miR-21/JAK2/STAT3 pathway. CNS Neurosci Ther 2024; 30:e14428. [PMID: 37641874 PMCID: PMC10915983 DOI: 10.1111/cns.14428] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/14/2023] [Accepted: 08/15/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Secondary injury after spinal cord injury (SCI) is a major obstacle to their neurological recovery. Among them, changes in astrocyte phenotype regulate secondary injury dominated by neuroinflammation. Hypoxia-preconditioned mesenchymal stem cells (MSCs)-derived extracellular vesicle (H-EV) plays a multifaceted role in secondary injury by interacting with cellular components and signaling pathways. They possess anti-inflammatory properties, regulate oxidative stress, and modulate apoptotic pathways, promoting cell survival and reducing neuronal loss. Given the unique aspects of secondary injury, H-EV shows promise as a therapeutic approach to mitigate its devastating consequences. Our study aimed to determine whether H-EV could promote SCI repair by altering the phenotype of astrocytes. METHODS Rat bone marrow MSCs (BMSCs) and EVs secreted by them were extracted and characterized. After the SCI model was successfully constructed, EV and H-EV were administered into the tail vein of the rats, respectively, and then their motor function was evaluated by the Basso-Beattie-Bresnahan (BBB) score, Catwalk footprint analysis, and electrophysiological monitoring. The lesion size of the spinal cord was evaluated by hematoxylin-eosin (HE) staining. The key point was to use glial fibrillary acidic protein (GFAP) as a marker of reactive astrocytes to co-localize with A1-type marker complement C3 and A2-type marker S100A10, respectively, to observe phenotypic changes in astrocytes within tissues. The western blot (WB) of the spinal cord was also used to verify the results. We also compared the efficacy differences in apoptosis and inflammatory responses using terminal deoxynucleotidyl transferase dUTP terminal labeling (TUNEL) assay, WB, and enzyme-linked immunosorbent assay (ELISA). Experiments in vitro were also performed to verify the results. Subsequently, we performed microRNA (miRNA) sequencing analysis of EV and H-EV and carried out a series of knockdown and overexpression experiments to further validate the mechanism by which miRNA in H-EV plays a role in promoting astrocyte phenotypic changes, as well as the regulated signaling pathways, using WB both in vivo and in vitro. RESULTS Our findings suggest that H-EV is more effective than EV in the recovery of motor function, anti-apoptosis, and anti-inflammatory effects after SCI, both in vivo and in vitro. More importantly, H-EV promoted the conversion of A1 astrocytes into A2 astrocytes more than EV. Moreover, miR-21, which was found to be highly expressed in H-EV by miRNA sequencing results, was also demonstrated to influence changes in astrocyte phenotype through a series of knockdown and overexpression experiments. At the same time, we also found that H-EV might affect astrocyte phenotypic alterations by delivering miR-21 targeting the JAK2/STAT3 signaling pathway. CONCLUSION H-EV exerts neuroprotective effects by delivering miR-21 to promote astrocyte transformation from the A1 phenotype to the A2 phenotype, providing new targets and ideas for the treatment of SCI.
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Affiliation(s)
- Zhelun Yang
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Zeyan Liang
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Jian Rao
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Haishu Xie
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Maochao Zhou
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Xiongjie Xu
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Yike Lin
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Fabin Lin
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Chunhua Wang
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
| | - Chunmei Chen
- Department of NeurosurgeryFujian Medical University Union HospitalFuzhouFujianChina
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Cacciottola L, Vitale F, Donnez J, Dolmans MM. Use of mesenchymal stem cells to enhance or restore fertility potential: a systematic review of available experimental strategies. Hum Reprod Open 2023; 2023:hoad040. [PMID: 37954935 PMCID: PMC10637864 DOI: 10.1093/hropen/hoad040] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 09/15/2023] [Indexed: 11/14/2023] Open
Abstract
STUDY QUESTION To what extent does regenerative medicine with stem cell therapy help to address infertility issues for future clinical application? SUMMARY ANSWER Regenerative medicine using different stem cell sources is yielding promising results in terms of protecting the ovarian reserve from damage and senescence, and improving fertility potential in various preclinical settings. WHAT IS KNOWN ALREADY Regenerative medicine using stem cell therapy is emerging as a potential strategy to address a number of issues in the field of human reproduction. Indeed, different types of adult and fetal mesenchymal stem cells (MSCs) have been tested with promising results, owing to their ability to differentiate into different tissue lineages, move toward specific injured sites (homing), and generate a secretome with wound-healing, proangiogenic, and antioxidant capacities. STUDY DESIGN SIZE DURATION Guided by the checklist for preferred reporting items for systematic reviews and meta-analyses, we retrieved relevant studies from PubMed, Medline, and Embase databases until June 2023 using the following keywords: 'mesenchymal stem cells' AND 'ovarian follicles' OR 'ovarian tissue culture' OR 'ovarian follicle culture' OR 'cumulus oocyte complex'. Only peer-reviewed published articles written in English were included. PARTICIPANTS/MATERIALS SETTING METHODS The primary outcome for the experimental strategies was evaluation of the ovarian reserve, with a focus on follicle survival, number, and growth. Secondary outcomes involved analyses of other parameters associated with the follicle pool, such as hormones and growth factors, ovarian tissue viability markers including oxidative stress levels, oocyte growth and maturation rates, and of course pregnancy outcomes. MAIN RESULTS AND THE ROLE OF CHANCE Preclinical studies exploring MSCs from different animal origins and tissue sources in specific conditions were selected (n = 112), including: in vitro culture of granulosa cells, ovarian tissue and isolated ovarian follicles; ovarian tissue transplantation; and systemic or intraovarian injection after gonadotoxic or age-related follicle pool decline. Protecting the ovarian reserve from aging and gonadotoxic damage has been widely tested in vitro and in vivo using murine models and is now yielding initial data in the first ever case series of patients with premature ovarian insufficiency. Use of MSCs as feeder cells in ovarian tissue culture was found to improve follicle outcomes and oocyte competence, bringing us one step closer to future clinical application. MSCs also have proved effective at boosting revascularization in the transplantation site when grafting ovarian tissue in experimental animal models. LIMITATIONS REASONS FOR CAUTION While preclinical results look promising in terms of protecting the ovarian reserve in different experimental models (especially those in vitro using various mammal experimental models and in vivo using murine models), there is still a lot of work to do before this approach can be considered safe and successfully implemented in a clinical setting. WIDER IMPLICATIONS OF THE FINDINGS All gathered data on the one hand show that regenerative medicine techniques are quickly gaining ground among innovative techniques being developed for future clinical application in the field of reproductive medicine. After proving MSC effectiveness in preclinical settings, there is still a lot of work to do before MSCs can be safely and effectively used in different clinical applications. STUDY FUNDING/COMPETING INTERESTS This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (FNRS-PDR T.0077.14, FNRS-CDR J.0063.20, and grant 5/4/150/5 awarded to Marie-Madeleine Dolmans), Fonds Spéciaux de Recherche, and the Fondation St Luc. None of the authors have any competing interest to disclose. REGISTRATION NUMBER N/A.
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Affiliation(s)
- L Cacciottola
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - F Vitale
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - J Donnez
- Society for Research into Infertility, Brussels, Belgium
- Université Catholique de Louvain, Brussels, Belgium
| | - M M Dolmans
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
- Department of Gynecology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
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Helsper S, Yuan X, Bagdasarian FA, Athey J, Li Y, Borlongan CV, Grant SC. Multinuclear MRI Reveals Early Efficacy of Stem Cell Therapy in Stroke. Transl Stroke Res 2023; 14:545-561. [PMID: 35900719 PMCID: PMC10733402 DOI: 10.1007/s12975-022-01057-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/28/2022] [Accepted: 06/16/2022] [Indexed: 10/16/2022]
Abstract
Compromised adult human mesenchymal stem cells (hMSC) can impair cell therapy efficacy and further reverse ischemic recovery. However, in vitro assays require extended passage to characterize cells, limiting rapid assessment for therapeutic potency. Multinuclear magnetic resonance imaging and spectroscopy (MRI/S) provides near real-time feedback on disease progression and tissue recovery. Applied to ischemic stroke, 23Na MRI evaluates treatment efficacy within 24 h after middle cerebral artery occlusion, showing recovery of sodium homeostasis and lesion reduction in specimens treated with hMSC while 1H MRS identifies reduction in lactate levels. This combined metric was confirmed by evaluating treatment groups receiving healthy or compromised hMSC versus vehicle (sham saline injection) over 21 days. Behavioral tests to assess functional recovery and cell analysis for immunomodulatory and macrophage activity to detect hMSC potency confirm MR findings. Clinically, these MR metrics may prove critical to early evaluations of therapeutic efficacy and overall stroke recovery.
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Affiliation(s)
- Shannon Helsper
- The National High Magnetic Field Laboratory, Florida State University, 1800 E. Paul Dirac Dr, Tallahassee, FL, 32310, USA
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Xuegang Yuan
- The National High Magnetic Field Laboratory, Florida State University, 1800 E. Paul Dirac Dr, Tallahassee, FL, 32310, USA
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - F Andrew Bagdasarian
- The National High Magnetic Field Laboratory, Florida State University, 1800 E. Paul Dirac Dr, Tallahassee, FL, 32310, USA
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Jacob Athey
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Yan Li
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Cesario V Borlongan
- Center of Excellence for Aging & Brain Repair, University of South Florida, Tampa, FL, 33612, USA
| | - Samuel C Grant
- The National High Magnetic Field Laboratory, Florida State University, 1800 E. Paul Dirac Dr, Tallahassee, FL, 32310, USA.
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA.
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9
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Gao T, Zhao X, Hao J, Tian Y, Ma H, Liu W, An B, Sun F, Liu S, Guo B, Niu S, Li Z, Wang C, Wang Y, Feng G, Wang L, Li W, Wu J, Guo M, Zhou Q, Gu Q. A scalable culture system incorporating microcarrier for specialised mesenchymal stem cells from human embryonic stem cells. Mater Today Bio 2023; 20:100662. [PMID: 37214547 PMCID: PMC10196860 DOI: 10.1016/j.mtbio.2023.100662] [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: 03/07/2023] [Revised: 04/20/2023] [Accepted: 05/05/2023] [Indexed: 05/24/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) derived from human embryonic stem cells (hESCs) are a desirable cell source for cell therapy owing to their capacity to be produced stably and homogeneously in large quantities. However, a scalable culture system for hPSC-derived MSCs is urgently needed to meet the cell quantity and quality requirements of practical clinical applications. In this study, we developed a new microcarrier with hyaluronic acid (HA) as the core material, which allowed scalable serum-free suspension culture of hESC-derived MSCs (IMRCs). We used optimal microcarriers with a coating collagen concentration of 100 μg/mL or concave-structured surface (cHAMCs) for IMRC amplification in a stirred bioreactor, expanding IMRCs within six days with the highest yield of over one million cells per milliliter. In addition, the harvested cells exhibited high viability, immunomodulatory and regenerative therapeutic promise comparable to monolayer cultured MSCs while showing more increased secretion of extracellular matrix (ECM), particularly collagen-related proteins. In summary, we have established a scalable culture system for hESC-MSCs, providing novel approaches for future cell therapies.
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Affiliation(s)
- Tingting Gao
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiyuan Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jie Hao
- National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yao Tian
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huike Ma
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Wenjing Liu
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Bin An
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Faguo Sun
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shasha Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Baojie Guo
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shuaishuai Niu
- National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Zhongwen Li
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Chenxin Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yukai Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guihai Feng
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Liu Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wei Li
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jun Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Meijin Guo
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qi Gu
- State Key Laboratory of Stem Cell and Reproductive Biology, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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10
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Gopalarethinam J, Nair AP, Iyer M, Vellingiri B, Subramaniam MD. Advantages of mesenchymal stem cell over the other stem cells. Acta Histochem 2023; 125:152041. [PMID: 37167794 DOI: 10.1016/j.acthis.2023.152041] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/21/2023] [Accepted: 04/22/2023] [Indexed: 05/13/2023]
Abstract
A stem cell is a particular group of cells that has the extraordinary potential to convert within the body into particular cell types. They are used to regenerate tissues and cells in the body that have been damaged or destroyed by the disease. Stem cells come in three different varieties: adult stem cells, embryonic stem cells and induced pluripotent stem cells (iPSCs). Embryonic stem cells have a high chance of immune rejection and also have ethical dilemmas and iPSCs have genetic instability. Adult stem cells are difficult to analyze and extract for research since they are frequently insufficient in native tissues. However, mesenchymal stem cells (MSC) one of the categories of adult stem cells are stromal cells with a variety of potentials that can differentiate into a wide range of cell types. MSCs can be transplanted into a variety of people without worrying about rejection because they have demonstrated the ability to prevent an adverse reaction from the immune system. These transplants have powerful anti-inflammatory and immunosuppressive effects and greatly enhance the body's inherent healing capacity. While MSCs do not offer treatment for illnesses, the idea behind them is to enable the body to recover sufficiently for a protracted reduction in symptoms. In many cases, this is sufficient to significantly enhance the patient's well-being. Inspite of several advantages some potential long-term concerns connected to MSC therapy are maldifferentiation, immunosuppression and cancerous tumor growth. In this review, we will compare the mesenchymal stem cells with other stem cells with respect to the source of origin, their properties and therapeutic applications, and discuss the MSC's disadvantages.
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Affiliation(s)
- Janani Gopalarethinam
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India
| | - Aswathy P Nair
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India
| | - Mahalaxmi Iyer
- Department of Biotechnology, Karpagam Academy of Higher Education (Deemed to be University), Coimbatore 641021, India
| | - Balachandar Vellingiri
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda, India
| | - Mohana Devi Subramaniam
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India.
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11
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Qu S, Ma N, Wang W, Chen S, Wu Q, Li Y, Yang Z. Human adipose-derived stem cells can optimize the filling material in rats. Biomed Mater Eng 2023:BME222503. [PMID: 36710667 DOI: 10.3233/bme-222503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Human adipose-derived stem cells have been identified as a promising candidate for cell-assisted therapy to improve graft survival. OBJECTIVE To objective of the study was to add human adipose-derived stem cells into filling materials. METHODS The filling materials were prepared and divided into 6 groups: fat particles with phosphate buffer saline or human adipose-derived stem cells; acellular dermal matrix particles with phosphate buffer saline or human adipose-derived stem cells; mixture of fat particles and acellular dermal matrix particles with phosphate buffer saline or human adipose-derived stem cells. The survival rate, vascular density and histological at 2, 6 and 12 weeks were investigated. RESULTS Human adipose-derived stem cells significantly improved survival rate in each group at 6 and 12 weeks, and it significantly increased the vascular density in the fat particles and porcine acellular dermal matrix combined group and porcine acellular dermal matrix group at three time points, but human adipose-derived stem cells did not have a significant effect in the fat particles group. CONCLUSION Human adipose-derived stem cells as assisted cells added into filling material can improve survival rate and vascular density in rats.
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Affiliation(s)
- Siwei Qu
- Second Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ning Ma
- Second Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weixin Wang
- Second Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Sen Chen
- Second Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi Wu
- Second Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yangqun Li
- Second Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhe Yang
- Second Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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12
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Extracellular Vesicles and Cellular Ageing. Subcell Biochem 2023; 102:271-311. [PMID: 36600137 DOI: 10.1007/978-3-031-21410-3_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Ageing is a complex process characterized by deteriorated performance at multiple levels, starting from cellular dysfunction to organ degeneration. Stem cell-based therapies aim to administrate stem cells that eventually migrate to the injured site to replenish the damaged tissue and recover tissue functionality. Stem cells can be easily obtained and cultured in vitro, and display several qualities such as self-renewal, differentiation, and immunomodulation that make them suitable candidates for stem cell-based therapies. Current animal studies and clinical trials are being performed to assess the safety and beneficial effects of stem cell engraftments for regenerative medicine in ageing and age-related diseases.Since alterations in cell-cell communication have been associated with the development of pathophysiological processes, new research is focusing on the modulation of the microenvironment. Recent research has highlighted the important role of some microenvironment components that modulate cell-cell communication, thus spreading signals from damaged ageing cells to neighbor healthy cells, thereby promoting systemic ageing. Extracellular vesicles (EVs) are small-rounded vesicles released by almost every cell type. EVs cargo includes several bioactive molecules, such as lipids, proteins, and genetic material. Once internalized by target cells, their specific cargo can induce epigenetic modifications and alter the fate of the recipient cells. Also, EV's content is dependent on the releasing cells, thus, EVs can be used as biomarkers for several diseases. Moreover, EVs have been proposed to be used as cell-free therapies that focus on their administration to slow or even reverse some hallmarks of physiological ageing. It is not surprising that EVs are also under study as next-generation therapies for age-related diseases.
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13
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Soleimani M, Masoumi A, Momenaei B, Cheraqpour K, Koganti R, Chang AY, Ghassemi M, Djalilian AR. Applications of mesenchymal stem cells in ocular surface diseases: sources and routes of delivery. Expert Opin Biol Ther 2023; 23:509-525. [PMID: 36719365 PMCID: PMC10313829 DOI: 10.1080/14712598.2023.2175605] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 01/30/2023] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Mesenchymal stem cells (MSCs) are novel, promising agents for treating ocular surface disorders. MSCs can be isolated from several tissues and delivered by local or systemic routes. They produce several trophic factors and cytokines, which affect immunomodulatory, transdifferentiating, angiogenic, and pro-survival pathways in their local microenvironment via paracrine secretion. Moreover, they exert their therapeutic effect through a contact-dependent manner. AREAS COVERED In this review, we discuss the characteristics, sources, delivery methods, and applications of MSCs in ocular surface disorders. We also explore the potential application of MSCs to inhibit senescence at the ocular surface. EXPERT OPINION Therapeutic application of MSCs in ocular surface disorders are currently under investigation. One major research area is corneal epitheliopathies, including chemical or thermal burns, limbal stem cell deficiency, neurotrophic keratopathy, and infectious keratitis. MSCs can promote corneal epithelial repair and prevent visually devastating sequelae of non-healing wounds. However, the optimal dosages and delivery routes have yet to be determined and further clinical trials are needed to address these fundamental questions.
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Affiliation(s)
- Mohammad Soleimani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Masoumi
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Bita Momenaei
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Kasra Cheraqpour
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Raghuram Koganti
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Arthur Y Chang
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Mahmoud Ghassemi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
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14
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Nagy G, Szekely TE, Somogyi A, Herold M, Herold Z. New therapeutic approaches for type 1 diabetes: Disease-modifying therapies. World J Diabetes 2022; 13:835-850. [PMID: 36312000 PMCID: PMC9606789 DOI: 10.4239/wjd.v13.i10.835] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/08/2022] [Accepted: 09/15/2022] [Indexed: 02/05/2023] Open
Abstract
It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.
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Affiliation(s)
- Geza Nagy
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Tekla Evelin Szekely
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Aniko Somogyi
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Magdolna Herold
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Zoltan Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest H-1083, Hungary
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15
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Lozano Navarro LV, Chen X, Giratá Viviescas LT, Ardila-Roa AK, Luna-Gonzalez ML, Sossa CL, Arango-Rodríguez ML. Mesenchymal stem cells for critical limb ischemia: their function, mechanism, and therapeutic potential. Stem Cell Res Ther 2022; 13:345. [PMID: 35883198 PMCID: PMC9327195 DOI: 10.1186/s13287-022-03043-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/07/2022] [Indexed: 11/21/2022] Open
Abstract
Peripheral arterial disease is atherosclerotic occlusive disease of the lower extremity arteries and afflicts hundreds of millions of individuals worldwide. Its most severe manifestation is chronic limb-threatening ischemia (Petersen et al. (Science 300(5622):1140–2, 2003)), which is associated with severe pain at rest in the limbs, which progresses to necrosis, limb amputation, and/or death of the patient. Consequently, the care of these patients is considered a financial burden for both patients and health systems. Multidisciplinary endeavors are required to address this refractory disease and to find definitive solutions that lead to improved living conditions. Revascularization is the cornerstone of therapy for preventing limb amputation, and both open vascular surgery and endovascular therapy play a key role in the treatment of patients with CLI. Around one-third of these patients are not candidates for conventional surgical treatment, however, leading to higher amputation rates (approaching 20–25% at one year) with high morbidity and lower quality of life. Advances in regenerative medicine have enabled the development of cell-based therapies that promote the formation of new blood vessels. Particularly, mesenchymal stem cells (MSCs) have emerged as an attractive therapeutic agent in various diseases, including CLI, due to their role in tissue regeneration and immunomodulation. This review discusses the characteristics of MSCs, as well as their regenerative properties and their action mechanisms on CLI.
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Affiliation(s)
- Laura V Lozano Navarro
- Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), 681004153, Bucaramanga, Colombia
| | - Xueyi Chen
- Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), 681004153, Bucaramanga, Colombia
| | - Lady Tatiana Giratá Viviescas
- Banco Multitejidos y Centro de Terapias Avanzadas, Fundación Oftalmológica de Santander-FOSCAL, 681004153, Floridablanca, Colombia
| | - Andrea K Ardila-Roa
- Banco Multitejidos y Centro de Terapias Avanzadas, Fundación Oftalmológica de Santander-FOSCAL, 681004153, Floridablanca, Colombia
| | - Maria L Luna-Gonzalez
- Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), 681004153, Bucaramanga, Colombia.,Programa Para el Tratamiento y Estudio de Enfermedades Hematológicas y Oncológicas de Santander (PROTEHOS), 681004153, Floridablanca, Colombia
| | - Claudia L Sossa
- Faculty of Health Sciences, Universidad Autónoma de Bucaramanga (UNAB), 681004153, Bucaramanga, Colombia.,Banco Multitejidos y Centro de Terapias Avanzadas, Fundación Oftalmológica de Santander-FOSCAL, 681004153, Floridablanca, Colombia.,Programa Para el Tratamiento y Estudio de Enfermedades Hematológicas y Oncológicas de Santander (PROTEHOS), 681004153, Floridablanca, Colombia.,Universidad de Valencia, Valencia, Spain
| | - Martha L Arango-Rodríguez
- Banco Multitejidos y Centro de Terapias Avanzadas, Fundación Oftalmológica de Santander-FOSCAL, 681004153, Floridablanca, Colombia.
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16
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The Combined Use of Platelet-Rich Plasma Clot Releasate and Allogeneic Human Umbilical Cord Mesenchymal Stem Cells Rescue Glucocorticoid-Induced Osteonecrosis of the Femoral Head. Stem Cells Int 2022; 2022:7432665. [PMID: 35547633 PMCID: PMC9085365 DOI: 10.1155/2022/7432665] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/10/2022] [Accepted: 04/13/2022] [Indexed: 11/17/2022] Open
Abstract
Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is a refractory disease. The treatment options for ONFH, especially nonsurgical ones, merit further investigation. To evaluate the combinatorial therapeutic effects of platelet-rich plasma clot releasate (PRCR) and umbilical cord mesenchymal stem cells (UC-MSCs) on glucocorticoid-induced ONFH, a dexamethasone (DEX)-treated cell model and a high-dose methylprednisolone (MPS)-treated rat model were established. Cell counting kit-8 (CCK-8) assay was performed in vitro to determine the optimum dosage of PRCR for UC-MSC viability. The effects of PRCR, UC-MSCs, and PRCR + UC-MSCs on cell viability, apoptosis, migration, and differentiation capacities of DEX-treated bone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cell (HUVECs) were explored via Transwell assays. Western blotting was conducted to evaluate the expression levels of RUNX2, VEGF, caspase-3, and Bcl-2 in the coculture systems. Ultrasound-guided intra-articular PRCR, UC-MSCs, and PRCR + UC-MSC injections were performed on the ONFH model rats. Microcomputed tomography, histological and immunohistochemical analyses, tartrate-resistant acid phosphatase (TRAP) staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess the therapeutic effects of PRCR and UC-MSCs on bone loss and necrosis induced by high-dose MPS. Results of this study revealed that the in vitro application of PRCR, UC-MSCs, and PRCR + UC-MSCs reversed the impaired proliferation and migration capacities and resisted apoptosis of BMSCs and HUVECs induced by DEX. Moreover, the PRCR and UC-MSC application significantly improved the alkaline phosphatase (ALP) and alizarin red (ALR) staining of BMSCs and tube formation capacity of HUVECs and promoted the protein expression of RUNX2 in BMSCs and VEGF in HUVECs. Similarly, in the ONFH rat model, the intra-articular injection of UC-MSCs and PRCR improved the subchondral bone mass parameters; promoted the expression of ALP, RUNX2, and VEGF; suppressed osteoclast overactivity; and resisted cell apoptosis. The combination of PRCR and UC-MSCs shows promising therapeutic effects in treating glucocorticoid-induced ONFH. The current study provides important information on intra-articular therapy, paving the way for the clinical management of ONFH in the future.
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Wu Z, Xu X, Cai J, Chen J, Huang L, Wu W, Pugliese A, Li S, Ricordi C, Tan J. Prevention of chronic diabetic complications in type 1 diabetes by co-transplantation of umbilical cord mesenchymal stromal cells and autologous bone marrow: a pilot randomized controlled open-label clinical study with 8-year follow-up. Cytotherapy 2022; 24:421-427. [PMID: 35086778 DOI: 10.1016/j.jcyt.2021.09.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 08/21/2021] [Accepted: 09/18/2021] [Indexed: 01/25/2023]
Abstract
BACKGROUND AIMS To explore the long-term safety and benefit of umbilical cord mesenchymal stromal cell (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). METHODS In the primary completion of this trial (ClinicalTrials.gov identifier: NCT01374854), the authors randomized patients (n = 21 per group) to either SCT or standard care (control) and previously reported effects on insulin secretion. The authors report about the incidence of chronic diabetes complications (primary endpoint) after 8 years of follow-up. The authors also report on secondary endpoints, safety, islet function and metabolic control. RESULTS Data were obtained from 14 of 21 patients in the SCT group and 15 of 21 patients in the control group who completed follow-up. At 8 years, the incidence of peripheral neuropathy was 7.1% (one of 14) in the SCT group versus 46.7% (seven of 15) in the control group (P = 0.017). The incidence of diabetic nephropathy was 7.1% (one of 14) in the SCT group versus 40.0% (six of 15) in the control group (P = 0.039). The incidence of retinopathy was 7.1% (one of 14) in the SCT group versus 33.3% (five of 15) in the control group (P = 0.081). Two patients (two of 14, 14.3%) in the SCT group and 11 patients (11 of 15, 73.3%) in the control group developed at least one complication (P = 0.001). One and six patients in the SCT group and control group, respectively, had at least two complications (P = 0.039). No malignancies were reported in the treated group. CONCLUSIONS Co-transplantation of umbilical cord MSCs and aBM-MNCs in patients with established T1D was associated with reduced incidence of chronic diabetes complications.
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Affiliation(s)
- Zhixian Wu
- Organ Transplant Institute, Fuzhou General Hospital (Fuzong Clinical College), Fujian Medical University, Fuzhou, People's Republic of China; Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), Xiamen University, Fuzhou, People's Republic of China
| | - Xiumin Xu
- Diabetes Research Institute and Cell Transplant Center, University of Miami, Miami, Florida, USA; Diabetes Research Institute Federation, Hollywood, Florida, USA; The Cure Alliance, Miami, Florida, USA; Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Jinquan Cai
- Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), Xiamen University, Fuzhou, People's Republic of China
| | - Jin Chen
- Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), Xiamen University, Fuzhou, People's Republic of China
| | - Lianghu Huang
- Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), Xiamen University, Fuzhou, People's Republic of China
| | - Weizhen Wu
- Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), Xiamen University, Fuzhou, People's Republic of China
| | - Alberto Pugliese
- Diabetes Research Institute and Cell Transplant Center, University of Miami, Miami, Florida, USA; Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Shasha Li
- Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), Xiamen University, Fuzhou, People's Republic of China
| | - Camillo Ricordi
- Diabetes Research Institute and Cell Transplant Center, University of Miami, Miami, Florida, USA; Diabetes Research Institute Federation, Hollywood, Florida, USA; The Cure Alliance, Miami, Florida, USA; Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
| | - Jianming Tan
- Organ Transplant Institute, Fuzhou General Hospital (Fuzong Clinical College), Fujian Medical University, Fuzhou, People's Republic of China; Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), Xiamen University, Fuzhou, People's Republic of China; The Cure Alliance, Miami, Florida, USA.
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18
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Peláez P, Damiá E, Torres-Torrillas M, Chicharro D, Cuervo B, Miguel L, del Romero A, Carrillo JM, Sopena JJ, Rubio M. Cell and Cell Free Therapies in Osteoarthritis. Biomedicines 2021; 9:1726. [PMID: 34829953 PMCID: PMC8615373 DOI: 10.3390/biomedicines9111726] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 12/18/2022] Open
Abstract
Osteoarthritis (OA) is the most common articular disease in adults and has a current prevalence of 12% in the population over 65 years old. This chronic disease causes damage to articular cartilage and synovial joints, causing pain and leading to a negative impact on patients' function, decreasing quality of life. There are many limitations regarding OA conventional therapies-pharmacological therapy can cause gastrointestinal, renal, and cardiac adverse effects, and some of them could even be a threat to life. On the other hand, surgical options, such as microfracture, have been used for the last 20 years, but hyaline cartilage has a limited regeneration capacity. In recent years, the interest in new therapies, such as cell-based and cell-free therapies, has been considerably increasing. The purpose of this review is to describe and compare bioregenerative therapies' efficacy for OA, with particular emphasis on the use of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). In OA, these therapies might be an alternative and less invasive treatment than surgery, and a more effective option than conventional therapies.
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Affiliation(s)
- Pau Peláez
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Elena Damiá
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Marta Torres-Torrillas
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Deborah Chicharro
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Belén Cuervo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Laura Miguel
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Ayla del Romero
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Jose Maria Carrillo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Joaquín J. Sopena
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Mónica Rubio
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; (P.P.); (M.T.-T.); (D.C.); (B.C.); (L.M.); (A.d.R.); (J.M.C.); (J.J.S.); (M.R.)
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
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Kim J, Hasegawa T, Wada A, Maeda Y, Ikeda S. Keratinocyte-Like Cells Trans-Differentiated from Human Adipose-Derived Stem Cells, Facilitate Skin Wound Healing in Mice. Ann Dermatol 2021; 33:324-332. [PMID: 34341633 PMCID: PMC8273321 DOI: 10.5021/ad.2021.33.4.324] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/05/2020] [Accepted: 11/19/2020] [Indexed: 12/24/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have been reported to promote wound healing in both animal models and human studies. Among MSCs, adipose-derived stem cells (ADSCs) can be easily harvested in large quantities. Objective We investigated whether skin wound healing in mice can be facilitated by keratinocyte-like cells differentiated from ADSCs (KC-ADSCs). Methods For the wound contraction and epithelialization model, a 20 mm×20 mm fullthickness skin wound was made on the dorsum. For the wound epithelialization model, a 6 mm×6 mm full-thickness skin wound was made on the dorsum. A nitrile rubber stent with an inner diameter of 8 mm was sutured around the wounds to minimize wound contraction. Undifferentiated ADSCs (uADSCs) or KC-ADSCs was injected around the wound base in both models. To evaluate whether the injected ADSCs could enhance wound contraction in a skin wound, the contractile activity of ADSCs was assessed by an in vitro type I collagen gel contraction assay. Alpha-smooth muscle actin (αSMA) expressions in uADSCs and KC-ADSCs were also evaluated by flow cytometry and real-time polymerase chain reaction. Results In a wound contraction and epithelialization model, KC-ADSCs further facilitated wound healing compared with uADSCs. In a wound epithelialization model, KC-ADSCs also further facilitated wound epithelialization compared with uADSCs. The contractile activity of KC-ADSCs was lower than that of uADSCs. The uADSCs expressed high levels of αSMA, which decreased after the differentiation into keratinocyte-like cells. Conclusion Our results suggest that the wound healing effect of KC-ADSCs depends primarily on re-epithelialization rather than wound contraction.
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Affiliation(s)
- Jonghun Kim
- Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Toshio Hasegawa
- Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Akino Wada
- Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuichiro Maeda
- Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigaku Ikeda
- Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
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20
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Mesenchymal Stem Cells for Mitigating Radiotherapy Side Effects. Cells 2021; 10:cells10020294. [PMID: 33535574 PMCID: PMC7912747 DOI: 10.3390/cells10020294] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/19/2021] [Accepted: 01/29/2021] [Indexed: 12/14/2022] Open
Abstract
Radiation therapy for cancers also damages healthy cells and causes side effects. Depending on the dosage and exposure region, radiotherapy may induce severe and irreversible injuries to various tissues or organs, especially the skin, intestine, brain, lung, liver, and heart. Therefore, promising treatment strategies to mitigate radiation injury is in pressing need. Recently, stem cell-based therapy generates great attention in clinical care. Among these, mesenchymal stem cells are extensively applied because it is easy to access and capable of mesodermal differentiation, immunomodulation, and paracrine secretion. Here, we summarize the current attempts and discuss the future perspectives about mesenchymal stem cells (MSCs) for mitigating radiotherapy side effects.
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21
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Khoury M, Tabben M, Rolón AU, Levi L, Chamari K, D'Hooghe P. Promising improvement of chronic lateral elbow tendinopathy by using adipose derived mesenchymal stromal cells: a pilot study. J Exp Orthop 2021; 8:6. [PMID: 33501619 PMCID: PMC7838228 DOI: 10.1186/s40634-020-00320-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023] Open
Abstract
Purpose Study the effect of Adipose derived stromal cells (ASCs) injection as therapeutic procedure on the common extensor tendinopathy. Methods Eighteen Tennis players with chronic, recalcitrant LET (who have previously been unsuccessfully treated with nonoperative treatments) underwent clinical evaluation and magnetic resonance imaging (MRI) before intervention. Stromal vascular fraction cells (SVF) were expanded by in vitro culture and ASCs were obtained and characterized by flow cytometry. ASCs were injected into the site of tendinopathy (identified by ultrasound imaging at the origin of the common extensor tendon) on a single occasion followed by physiotherapy. Players underwent serial clinical evaluations during a 12-month period and repeated MRI at 6-month post-injection. Results At 6-month clinical evaluation revealed significant improvements compared to baseline in mean Visual Analog Scale (VAS) scores for: (1) maximum pain score (from 6.28 ± 1.65, to 1.0 ± 0.43; p < .001); (2) Mean quick Disabilities of the Arm, Shoulder and Hand (QuickDASH-Compulsory score: 51.38 ± 12.02 to 12.33 ± 4.66; p < .001); (3) QuickDASH-Sport score: 56.94 ± 15.44 to 8.68 ± 8.86; p < .001). Validated MRI scoring system grade of tendinopathy also improved significantly: 4.22 ± 0.26 to 2.22 ± 0.10 (p < .001). At 12-month from injection, VAS maximun pain score further decreased to 0.74 ± 0.44 (p < .001) and QuickDASH-Compulsory score to 5.56 ± 3.58 (p < .001). Average time to return to play tennis was 3,31 ± 0,61 month post-intervention. Conclusion Tennis players with recalcitrant LET showed significant clinical improvement and structural repair at the origin of the common tendon origin after injection of autologous ASCs. Results of this study are promising and open a new biological therapeutic modality to treat LET. Even if the results of this pilot study are positive, future well-designed studies, i.e. prospective randomized trials are needed to define the role of cell therapy in treating LET.
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Affiliation(s)
| | - Montassar Tabben
- Aspetar Qatar Orthopaedic and Sports Medicine Hospital, P.O. Box 29222, Doha, Qatar.
| | | | - Lorena Levi
- Regenerar Laboratory, Buenos Aires, Argentina
| | - Karim Chamari
- Aspetar Qatar Orthopaedic and Sports Medicine Hospital, P.O. Box 29222, Doha, Qatar
| | - Pieter D'Hooghe
- Aspetar Qatar Orthopaedic and Sports Medicine Hospital, P.O. Box 29222, Doha, Qatar
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22
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Radmanesh F, Mahmoudi M, Yazdanpanah E, Keyvani V, Kia N, Nikpoor AR, Zafari P, Esmaeili SA. The immunomodulatory effects of mesenchymal stromal cell-based therapy in human and animal models of systemic lupus erythematosus. IUBMB Life 2020; 72:2366-2381. [PMID: 33006813 DOI: 10.1002/iub.2387] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/11/2020] [Accepted: 09/12/2020] [Indexed: 12/17/2022]
Abstract
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune inflammatory disease with no absolute cure. Although the exact etiopathogenesis of SLE is still enigmatic, it has been well demonstrated that a combination of genetic predisposition and environmental factors trigger a disturbance in immune responses and thereby participate in the development of this condition. Almost all available therapeutic strategies in SLE are primarily based on the administration of immunosuppressive drugs and are not curative. Mesenchymal stromal cells (MSCs) are a subset of non-hematopoietic adult stem cells that can be isolated from many adult tissues and are increasingly recognized as immune response modulating agents. MSC-mediated inhibition of immune responses is a complex mechanism that involves almost every aspect of the immune response. MSCs suppress the maturation of antigen-presenting cells (DC and MQ), proliferation of T cells (Th1, T17, and Th2), proliferation and immunoglobulin production of B cells, the cytotoxic activity of CTL and NK cells in addition to increasing regulatory cytokines (TGF-β and IL10), and decreasing inflammatory cytokines (IL17, INF-ϒ, TNF-α, and IL12) levels. MSCs have shown encouraging results in the treatment of several autoimmune diseases, in particular SLE. This report aims to review the beneficial and therapeutic properties of MSCs; it also focuses on the results of animal model studies, preclinical studies, and clinical trials of MSC therapy in SLE from the immunoregulatory aspect.
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Affiliation(s)
| | - Mahmoud Mahmoudi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Esmaeil Yazdanpanah
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahideh Keyvani
- Molecular Genetics, Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Nadia Kia
- Skin Cancer Prevention Research Center, Torvergata University of Medical Sciences, Rome, Italy
| | - Amin Reza Nikpoor
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Parisa Zafari
- Department of Immunology, School of Medicine, Mazandaran University of Medical Science, Sari, Iran.,Student Research Committee, Mazandaran University of Medical Science, Sari, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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23
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Ma ZJ, Yang JJ, Lu YB, Liu ZY, Wang XX. Mesenchymal stem cell-derived exosomes: Toward cell-free therapeutic strategies in regenerative medicine. World J Stem Cells 2020; 12:814-840. [PMID: 32952861 PMCID: PMC7477653 DOI: 10.4252/wjsc.v12.i8.814] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/23/2020] [Accepted: 06/27/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with marked potential for regenerative medicine because of their strong immunosuppressive and regenerative abilities. The therapeutic effects of MSCs are based in part on their secretion of biologically active factors in extracellular vesicles known as exosomes. Exosomes have a diameter of 30-100 nm and mediate intercellular communication and material exchange. MSC-derived exosomes (MSC-Exos) have potential for cell-free therapy for diseases of, for instance, the kidney, liver, heart, nervous system, and musculoskeletal system. Hence, MSC-Exos are an alternative to MSC-based therapy for regenerative medicine. We review MSC-Exos and their therapeutic potential for a variety of diseases and injuries.
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Affiliation(s)
- Zhan-Jun Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Jing-Jing Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yu-Bao Lu
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Zhao-Yang Liu
- Department of Medical Imaging, Shanxi Medical University, Jinzhong 030600, Shaanxi Province, China
| | - Xue-Xi Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China.
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Identifying the Therapeutic Significance of Mesenchymal Stem Cells. Cells 2020; 9:cells9051145. [PMID: 32384763 PMCID: PMC7291143 DOI: 10.3390/cells9051145] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/04/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022] Open
Abstract
The pleiotropic behavior of mesenchymal stem cells (MSCs) has gained global attention due to their immense potential for immunosuppression and their therapeutic role in immune disorders. MSCs migrate towards inflamed microenvironments, produce anti-inflammatory cytokines and conceal themselves from the innate immune system. These signatures are the reason for the uprising in the sciences of cellular therapy in the last decades. Irrespective of their therapeutic role in immune disorders, some factors limit beneficial effects such as inconsistency of cell characteristics, erratic protocols, deviating dosages, and diverse transfusion patterns. Conclusive protocols for cell culture, differentiation, expansion, and cryopreservation of MSCs are of the utmost importance for a better understanding of MSCs in therapeutic applications. In this review, we address the immunomodulatory properties and immunosuppressive actions of MSCs. Also, we sum up the results of the enhancement, utilization, and therapeutic responses of MSCs in treating inflammatory diseases, metabolic disorders and diabetes.
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25
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Zhang S, Yang Y, Fan L, Zhang F, Li L. The clinical application of mesenchymal stem cells in liver disease: the current situation and potential future. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:565. [PMID: 32775366 PMCID: PMC7347776 DOI: 10.21037/atm.2020.03.218] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver disease is a major health issue which present poor clinical treatment performance. Cirrhosis and liver failure are common clinical manifestations of liver diseases. Liver transplantation is recognized as the ultimate and most efficient therapy to the end stage of liver disease. But it was limited by the shortage of honor organs and high cost. Nowadays, stem cell therapy gained more and more attention due to its attractive efficacy in treating liver disease especially in cirrhosis during the clinical trials. Mesenchymal stem cell (MSC) can be differentiated into hepatocytes, promote liver regeneration, inhibit liver fibrosis and induce liver apoptosis, particularly via paracrine mechanisms. This review will highlight recent clinical applications of MSC, providing the available evidence and discussing some unsolved questions in treating liver disease.
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Affiliation(s)
- Sainan Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Linxiao Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Fen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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The Effects of Hypoxia on the Immune-Modulatory Properties of Bone Marrow-Derived Mesenchymal Stromal Cells. Stem Cells Int 2019; 2019:2509606. [PMID: 31687031 PMCID: PMC6800910 DOI: 10.1155/2019/2509606] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 08/11/2019] [Accepted: 09/09/2019] [Indexed: 01/09/2023] Open
Abstract
The therapeutic repertoire for life-threatening inflammatory conditions like sepsis, graft-versus-host reactions, or colitis is very limited in current clinical practice and, together with chronic ones, like the osteoarthritis, presents growing economic burden in developed countries. This urges the development of more efficient therapeutic modalities like the mesenchymal stem cell-based approaches. Despite the encouraging in vivo data, however, clinical trials delivered ambiguous results. Since one of the typical features of inflamed tissues is decreased oxygenation, the success of cellular therapy in inflammatory pathologies seems to be affected by the impact of oxygen depletion on transplanted cells. Here, we examine our current knowledge on the effect of hypoxia on the physiology of bone marrow-derived mesenchymal stromal cells, one of the most popular tools of practical cellular therapy, in the context of their immune-modulatory capacity.
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27
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Yang Y, Chen J, Shang X, Feng Z, Chen C, Lu J, Cai J, Chen Y, Zhang J, Hao Y, Yang X, Li Y, Chen S. Visualizing the Fate of Intra-Articular Injected Mesenchymal Stem Cells In Vivo in the Second Near-Infrared Window for the Effective Treatment of Supraspinatus Tendon Tears. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1901018. [PMID: 31592419 PMCID: PMC6774022 DOI: 10.1002/advs.201901018] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/29/2019] [Indexed: 05/13/2023]
Abstract
Mesenchymal stem cells (MSCs) are capable of exerting strong therapeutic potential for the treatment of supraspinatus tendon tear. However, MSC therapy remains underutilized and perhaps underrated due to the limited evidence of dynamic visualization of cellular behavior in vivo. Here, second near-infrared fluorescence imaging with biocompatible PbS quantum dots (QDs) provides a cellular migration map and information on the biodistribution and clearance processes of three densities of intra-articularly injected, labeled MSCs to treat supraspinatus tendon tear in mice. Intra-articular injection avoids entrapment of MSCs by filter organs and reduces the QD-induced organ toxicity. Notably, the MSCs share a similar migration direction, but the moderate density group is somewhat more efficient, showing the longest residence time and highest cell retention rate around the footprint during the repair stage. Furthermore, quantitative kinetic investigation demonstrates that labeled MSCs are cleared by feces and urine. Histomorphometric analysis demonstrates that the moderate density group achieves maximum therapeutic effect and labeled MSCs do not induce any injury or inflammation to major organs, which suggests that administration of too many or few MSCs may decrease their effectiveness. Such an imaging approach provides spatiotemporal evidence for response to MSC therapy in vivo, facilitating the optimization of MSC therapy.
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Affiliation(s)
- Yimeng Yang
- Department of Sports MedicineHuashan HospitalFudan UniversityShanghai200040China
| | - Jun Chen
- Department of Sports MedicineHuashan HospitalFudan UniversityShanghai200040China
| | - Xiliang Shang
- Department of Sports MedicineHuashan HospitalFudan UniversityShanghai200040China
| | - Zhujun Feng
- Department of Anatomy and PhysiologySchool of MedicineShanghai Jiao Tong UniversityShanghai200025China
| | - Chen Chen
- Department of Sports MedicineShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong UniversityShanghai200233China
| | - Jingyi Lu
- Department of Sports MedicineHuashan HospitalFudan UniversityShanghai200040China
| | - Jiangyu Cai
- Department of Sports MedicineHuashan HospitalFudan UniversityShanghai200040China
| | - Yuzhou Chen
- Department of Sports MedicineHuashan HospitalFudan UniversityShanghai200040China
| | - Jian Zhang
- Department of Sports MedicineHuashan HospitalFudan UniversityShanghai200040China
| | - Yuefeng Hao
- Department of OrthopedicsAffiliated Suzhou Hospital of Nanjing Medical UniversitySuzhouJiangsu215500China
| | - Xing Yang
- Department of OrthopedicsAffiliated Suzhou Hospital of Nanjing Medical UniversitySuzhouJiangsu215500China
| | - Yunxia Li
- Department of Sports MedicineHuashan HospitalFudan UniversityShanghai200040China
| | - Shiyi Chen
- Department of Sports MedicineHuashan HospitalFudan UniversityShanghai200040China
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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.
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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
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Yaghoubi Y, Movassaghpour A, Zamani M, Talebi M, Mehdizadeh A, Yousefi M. Human umbilical cord mesenchymal stem cells derived-exosomes in diseases treatment. Life Sci 2019; 233:116733. [PMID: 31394127 DOI: 10.1016/j.lfs.2019.116733] [Citation(s) in RCA: 179] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 08/04/2019] [Indexed: 02/08/2023]
Abstract
Exosomes are extracellular vesicles with the size of 40-100 nm in diameter and a density of 1.13-1.19 g/mL, containing proteins, mRNAs, miRNAs, and DNAs. Exosomes change the recipient cells biochemical features through biomolecules delivery and play a role in cellular communication. These vesicles are produced from body fluids and different cell types like mesenchymal stem cells (MSCs). Evidence suggests that mesenchymal stem cells-derived exosome (MSC-EXO) exhibit functions similar to MSCs with low immunogenicity and no tumorization. MSCs can also be isolated from a variety of sources including human umbilical cord (HUC). Because of the non-invasive collection method, higher proliferation and lower immunogenicity, HUCMSC-EXO has been frequently used in regenerative medicine and various diseases treatment compared to the other MSC-EXO resources. This review aimed to investigate the applications of HUCMSC-EXO in different diseases.
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Affiliation(s)
- Yoda Yaghoubi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - AliAkbar Movassaghpour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Majid Zamani
- Department of Immunology, Tabriz university of Medical Sciences, Tabriz, Iran
| | - Mehdi Talebi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Endocrine Research Center, Tabriz university of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Endocrine Research Center, Tabriz university of Medical Sciences, Tabriz, Iran.
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Borgovan T, Crawford L, Nwizu C, Quesenberry P. Stem cells and extracellular vesicles: biological regulators of physiology and disease. Am J Physiol Cell Physiol 2019; 317:C155-C166. [PMID: 30917031 PMCID: PMC12057699 DOI: 10.1152/ajpcell.00017.2019] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/25/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023]
Abstract
Many different subpopulations of subcellular extracellular vesicles (EVs) have been described. EVs are released from all cell types and have been shown to regulate normal physiological homeostasis, as well as pathological states by influencing cell proliferation, differentiation, organ homing, injury and recovery, as well as disease progression. In this review, we focus on the bidirectional actions of vesicles from normal and diseased cells on normal or leukemic target cells; and on the leukemic microenvironment as a whole. EVs from human bone marrow mesenchymal stem cells (MSC) can have a healing effect, reversing the malignant phenotype in prostate and colorectal cancer, as well as mitigating radiation damage to marrow. The role of EVs in leukemia and their bimodal cross talk with the encompassing microenvironment remains to be fully characterized. This may provide insight for clinical advances via the application of EVs as potential therapy and the employment of statistical and machine learning models to capture the pleiotropic effects EVs endow to a dynamic microenvironment, possibly allowing for precise therapeutic intervention.
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Affiliation(s)
- Theodor Borgovan
- Division of Hematology and Oncology, Rhode Island Hospital, The Warren Alpert Medical School of Brown University , Providence, Rhode Island
| | - Lorin Crawford
- School of Public Health, Center for Computational Molecular Biology, Brown University , Providence, Rhode Island
| | - Chibuikem Nwizu
- Division of Hematology and Oncology, Rhode Island Hospital, The Warren Alpert Medical School of Brown University , Providence, Rhode Island
| | - Peter Quesenberry
- Division of Hematology and Oncology, Rhode Island Hospital, The Warren Alpert Medical School of Brown University , Providence, Rhode Island
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Torres-Torrillas M, Rubio M, Damia E, Cuervo B, Del Romero A, Peláez P, Chicharro D, Miguel L, Sopena JJ. Adipose-Derived Mesenchymal Stem Cells: A Promising Tool in the Treatment of Musculoskeletal Diseases. Int J Mol Sci 2019; 20:ijms20123105. [PMID: 31242644 PMCID: PMC6627452 DOI: 10.3390/ijms20123105] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/20/2019] [Accepted: 06/20/2019] [Indexed: 02/08/2023] Open
Abstract
Chronic musculoskeletal (MSK) pain is one of the most common medical complaints worldwide and musculoskeletal injuries have an enormous social and economical impact. Current pharmacological and surgical treatments aim to relief pain and restore function; however, unsatiscactory outcomes are commonly reported. In order to find an accurate treatment to such pathologies, over the last years, there has been a significantly increasing interest in cellular therapies, such as adipose-derived mesenchymal stem cells (AMSCs). These cells represent a relatively new strategy in regenerative medicine, with many potential applications, especially regarding MSK disorders, and preclinical and clinical studies have demonstrated their efficacy in muscle, tendon, bone and cartilage regeneration. Nevertheless, several worries about their safety and side effects at long-term remain unsolved. This article aims to review the current state of AMSCs therapy in the treatment of several MSK diseases and their clinical applications in veterinary and human medicine.
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Affiliation(s)
- Marta Torres-Torrillas
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
| | - Monica Rubio
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
| | - Elena Damia
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
| | - Belen Cuervo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
| | - Ayla Del Romero
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
| | - Pau Peláez
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
| | - Deborah Chicharro
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
| | - Laura Miguel
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
| | - Joaquin J Sopena
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
- García Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain.
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Al-Jaibaji O, Swioklo S, Connon CJ. Mesenchymal stromal cells for ocular surface repair. Expert Opin Biol Ther 2019; 19:643-653. [PMID: 30979344 DOI: 10.1080/14712598.2019.1607836] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Cornea is a transparent, robust tissue that comprises highly organized cells. Disruption of this specialized tissue can lead to scarring and subsequent blindness, making corneal damage a considerable challenge worldwide. At present, the available medical treatments are unable to address the wide range of corneal diseases. Mesenchymal stem cells (MSCs) have increasingly been investigated for their regenerative effect on ocular surface injury due to their unique ability for growth factor production, anti-inflammatory activity, immunomodulatory capacity and differentiation into multiple cell lineages. AREAS COVERED Within this review, we explore the pathogenesis of corneal disorders in response to injury and disease, and the potential for MSCs to modulate this process as a treatment. Through the review of over 25 animal studies, we investigate the common mechanisms of action by which MSCs have their effect and discuss their potential for treating and/or preventing corneal deterioration EXPERT OPINION Depending on the environmental cues, MSCs can exert a potent effect on corneal wound healing through reducing opacity and vascularization, whilst promoting re-epithelialization. Whilst their mechanism is multifactorial, it seems clear that the anti-inflammatory/immunomodulatory factors they produce in response to damage are key to their control of cellular milieu and improving healing outcomes.
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Affiliation(s)
- Olla Al-Jaibaji
- a Institute of Genetic Medicine , Newcastle University, International Centre for Life , Newcastle upon Tyne , UK
| | - Stephen Swioklo
- a Institute of Genetic Medicine , Newcastle University, International Centre for Life , Newcastle upon Tyne , UK
| | - Che J Connon
- a Institute of Genetic Medicine , Newcastle University, International Centre for Life , Newcastle upon Tyne , UK
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Immunohematology Mesenchymal Stromal Cell-based Therapy: From Research to Clinic. Appl Immunohistochem Mol Morphol 2019; 26:e26-e43. [PMID: 29271793 DOI: 10.1097/pai.0000000000000629] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Mesenchymal stromal cells (MSC) are nonhematopoietic cells that can be isolated from several adult and fetal tissues. MSC present specific features as the capacity to support hematopoiesis and to regulate immune response. Thus, the use of MSC as a cell therapeutic product in the field of immune-hematology is of great importance. In this review, we focused on human MSC and discussed their immune-hematologic properties and their translation toward therapeutic clinical applications. Thus, these features hold great promise for cell-based therapy and are of important relevance for the field.
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Martínez-Carrasco R, Sánchez-Abarca LI, Nieto-Gómez C, Martín García E, Sánchez-Guijo F, Argüeso P, Aijón J, Hernández-Galilea E, Velasco A. Subconjunctival injection of mesenchymal stromal cells protects the cornea in an experimental model of GVHD. Ocul Surf 2019; 17:285-294. [PMID: 30630121 DOI: 10.1016/j.jtos.2019.01.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 12/26/2018] [Accepted: 01/04/2019] [Indexed: 12/18/2022]
Abstract
PURPOSE To evaluate the therapeutic effect of subconjunctival injection of human mesenchymal stromal cells (hMSCs) in the cornea of mice with graft versus host disease (GVHD). METHODS GVHD was induced in mice after hematopoietic stem cell transplantation (HSCT) between MHC-mismatched mouse strains. Subconjunctival injection of hMSCs was applied at day 10 post-HSCT. Infiltration of CD3+ cells in the cornea and epithelial alterations were analyzed by immunofluorescence. Tear was assessed using the PRT test and TearLab Osmolarity System. qPCR was used to evaluate changes in cytokines, Pax6 and Sprr1b expression. To evaluate the effect of irradiation, we analyzed the expression of these genes in TBI mice. RESULTS Immune cell invasion occurs in mice with GVHD, as shown by the presence of CD3+ cells in the cornea. Interestingly, eyes treated with hMSC did not present CD3+ cells. Tear osmolarity was increased in GVHD eyes, but not in treated eyes. TNFa expression was highly increased in all corneas except in Control and treated eyes. Pax6 in corneal epithelium showed a similar pattern in GVHD and Control mice, and its gene expression was enhanced in GVHD corneas. In contrast, Pax6 was reduced in GVHD + MSC corneas. We also found an increase in SPRR1B staining in GVHD eyes that was lower in GVHD + MSC mice, demonstrating that corneal keratinization is less frequent after treatment with hMSC. CONCLUSIONS The treatment with hMSCs by subconjunctival injection is effective in reducing corneal inflammation and squamous metaplasia in ocular GVHD (oGVHD). Local treatment with hMSCs is a promising strategy for oGVHD.
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Affiliation(s)
- Rafael Martínez-Carrasco
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, 37007, Spain; Department Cell Biology & Pathology, University of Salamanca, Salamanca, 37007, Spain; INCyL, University of Salamanca, Salamanca, 37007, Spain.
| | - Luis Ignacio Sánchez-Abarca
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, 37007, Spain; Department of Hematology, IBSAL-University Hospital of Salamanca, Salamanca, 37007, Spain; Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain
| | - Cristina Nieto-Gómez
- Department of Surgery, Ophthalmology Service, University Hospital of Salamanca, University of Salamanca, Salamanca, 37007, Spain
| | - Elisabet Martín García
- Department of Surgery, Ophthalmology Service, University Hospital of Salamanca, University of Salamanca, Salamanca, 37007, Spain
| | - Fermín Sánchez-Guijo
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, 37007, Spain; Department of Hematology, IBSAL-University Hospital of Salamanca, Salamanca, 37007, Spain; Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain; RETIC TerCel, y CIBERONC, Instituto de Salud Carlos III (ISCIII), Spain
| | - Pablo Argüeso
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - José Aijón
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, 37007, Spain; Department Cell Biology & Pathology, University of Salamanca, Salamanca, 37007, Spain; INCyL, University of Salamanca, Salamanca, 37007, Spain
| | - Emiliano Hernández-Galilea
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, 37007, Spain; Department of Surgery, Ophthalmology Service, University Hospital of Salamanca, University of Salamanca, Salamanca, 37007, Spain
| | - Almudena Velasco
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, 37007, Spain; Department Cell Biology & Pathology, University of Salamanca, Salamanca, 37007, Spain; INCyL, University of Salamanca, Salamanca, 37007, Spain
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Aydin S, Sağraç D, Şahin F. Differentiation Potential of Mesenchymal Stem Cells into Pancreatic β-Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1247:135-156. [PMID: 32002800 DOI: 10.1007/5584_2019_476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Stem cells having the capability to differentiate into other type of cells and renewing themselves, gained so much importance in recent years. Investigations in stem cells revealed that mesenchymal stem cells can successfully differentiate into other type of cells like adipocytes, hepatocytes, osteocytes, neurocytes and chondrocytes. In addition, these cells can also differentiate into insulin-producing beta cells. Insulin is a crucial hormone for glucose balance of the body. Insufficiency or unavailability of insulin is called diabetes. External insulin intake, as well as pancreas or islet transplantation, is the most basic treatment of diabetes. In vivo and in vitro studies demonstrate that stem cell therapy is also used in the cure of diabetes. Differentiation process of stem cells into beta cells releasing insulin is quite complicated. There are many different reports for the differentiation of stem cells in the literature. The success of differentiation of stem cells into beta cells depends on several factors like the source of stem cells, chemicals added into the differentiation medium and the duration of differentiation protocol. Distinct studies for the differentiation of stem cells into insulin-secreting cells are available in the literature. Moreover, thanks to the superior differentiation capacity of stem cells, they are being preferred in clinical studies. Stem cells were clinically used to heal diabetic ulcer, to increase c-peptide level and insulin secretion in both type 1 and type 2 diabetes. Mesenchymal stem cells having high differentiation potential to insulin-secreting cells are encouraging vehicles for both in vivo and in vitro studies together with clinical trials for diabetes mellitus.
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Affiliation(s)
- Safa Aydin
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, İstanbul, Turkey.
| | - Derya Sağraç
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, İstanbul, Turkey
| | - Fikrettin Şahin
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, İstanbul, Turkey
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Zhao J, Qi YJ, Wang X, Jiao Y, Gong HM, Zhang JX, Jiang DY. Transforming Growth Factor-β Partially Reversed the Immunosuppressive Effect of Mesenchymal Stem Cells in Mice. Transplant Proc 2018; 50:3851-3857. [PMID: 30577277 DOI: 10.1016/j.transproceed.2018.08.054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 07/26/2018] [Accepted: 08/16/2018] [Indexed: 11/16/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) possess powerful immunosuppression capacity. Transforming growth factor-β (TGF-β) is a well-known anti-inflammatory cytokine and plays an important role in various inflammatory processes. We hypothesized that TGF-β could synergize with MSCs in suppressing immune responses, and therefore established a mouse skin graft model to evaluate the effect of MSCs and MSCs combined with TGF-β on transplantation immunity in vivo. METHODS Balb/c and C57BL/6 mice were used to establish the skin graft model. The recipients were divided into 3 groups and received intravenous bone marrow mesenchymal stem cells (BMSCs), BMSCs pretreated with TGF-β, and 0.9% saline solution, respectively. Skin graft survival time, pathological detection, the ratio of CD4+CD25+Foxp3+Treg cell of spleens, and the level of IFN-γ, IL-2, IL-10, and TGF-β expression were tested. RESULTS The survival time of skin grafts were prolonged in both BMSC (12.5 ± 1.35 days) and BMSC-TGF-β (10.6 ± 1.90 days) recipients compared to the blank control recipients (8.0 ± 1.05 days). The ratio of CD4+CD25+Foxp3+Treg cell of spleens from BMSC and BMSC-TGF-β recipients was higher than that of the blank control, and the upregulated proliferation in the BMSC group occurred earlier and was prolonged compared to the BMSC-TGF-β group. The expression of IFN-γ and IL-2 was inhibited in both the BMSC and BMSC-TGF-β groups compared to the blank, while the expression of IL-10 and TGF-β was boosted. In contrast to the BMSC group, the BMSC-TGF-β group exhibited a weaker effect on the expression of cytokines. CONCLUSION TGF-β partially reversed the immunosuppressive effect of MSCs in vivo. This immunoregulatory feature may have potential applications for treating transplant rejection.
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Affiliation(s)
- J Zhao
- Department of Emergency and Department of Burns and Plastic Surgery, The Second Hospital of Shandong University, Jinan, China
| | - Y-J Qi
- Department of Emergency and Department of Burns and Plastic Surgery, The Second Hospital of Shandong University, Jinan, China
| | - X Wang
- Department of Emergency and Department of Burns and Plastic Surgery, The Second Hospital of Shandong University, Jinan, China
| | - Y Jiao
- Department of Emergency and Department of Burns and Plastic Surgery, The Second Hospital of Shandong University, Jinan, China
| | - H-M Gong
- Department of Emergency and Department of Burns and Plastic Surgery, The Second Hospital of Shandong University, Jinan, China
| | - J-X Zhang
- Department of Emergency and Department of Burns and Plastic Surgery, The Second Hospital of Shandong University, Jinan, China
| | - D-Y Jiang
- Department of Emergency and Department of Burns and Plastic Surgery, The Second Hospital of Shandong University, Jinan, China.
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Resch A, Wolf S, Mann A, Weiss T, Stetco AL, Radtke C. Co-Culturing Human Adipose Derived Stem Cells and Schwann Cells on Spider Silk-A New Approach as Prerequisite for Enhanced Nerve Regeneration. Int J Mol Sci 2018; 20:E71. [PMID: 30586946 PMCID: PMC6337114 DOI: 10.3390/ijms20010071] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 10/07/2018] [Accepted: 10/12/2018] [Indexed: 12/14/2022] Open
Abstract
Fast recovery is crucial for a successful nerve repair and an optimal functional outcome after peripheral nerve injury. Regarding donor site morbidity, autologous transplantation shows great limitations, which urge the need for alternative options in nerve reconstruction. Spider silk was reported as an advantageous material for cell adhesion, migration and proliferation, and its use in conduits is of great interest, especially in combination with cells to improve nerve regeneration. We here described the behavior of a co-culture of human Schwann cells and human adipose-derived stem cells (ADSCs) on spider silk as a new approach. After characterized by immunostaining ADSCs and Schwann cells were seeded in the co-culture on a spider silk scaffold and observed for 21 days. Results showed that cells were attached to the silk and aligned along the silk fibers. With further culture time, cells migrated along the silk and increased in number and formed an almost confluent cell layer. In immunostaining, results suggest that the cell layer was equally composed of ADSCs and Schwann cells. In conclusion, we showed that by providing a guiding structure for directed growth and cells to support nerve regeneration and remyelination, a valid alternative to autologous nerve grafts could have been found.
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Affiliation(s)
- Annika Resch
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
- Experimental Laboratory of the Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
| | - Sonja Wolf
- Experimental Laboratory of the Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
| | - Anda Mann
- Experimental Laboratory of the Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
| | - Tamara Weiss
- Experimental Laboratory of the Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
| | - Alexandra-Larissa Stetco
- Experimental Laboratory of the Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
| | - Christine Radtke
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
- Experimental Laboratory of the Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
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Ferreira JR, Teixeira GQ, Santos SG, Barbosa MA, Almeida-Porada G, Gonçalves RM. Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning. Front Immunol 2018; 9:2837. [PMID: 30564236 PMCID: PMC6288292 DOI: 10.3389/fimmu.2018.02837] [Citation(s) in RCA: 370] [Impact Index Per Article: 52.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are self-renewing, culture-expandable adult stem cells that have been isolated from a variety of tissues, and possess multipotent differentiation capacity, immunomodulatory properties, and are relatively non-immunogenic. Due to this unique set of characteristics, these cells have attracted great interest in the field of regenerative medicine and have been shown to possess pronounced therapeutic potential in many different pathologies. MSCs' mode of action involves a strong paracrine component resulting from the high levels of bioactive molecules they secrete in response to the local microenvironment. For this reason, MSCs' secretome is currently being explored in several clinical contexts, either using MSC-conditioned media (CM) or purified MSC-derived extracellular vesicles (EVs) to modulate tissue response to a wide array of injuries. Rather than being a constant mixture of molecular factors, MSCs' secretome is known to be dependent on the diverse stimuli present in the microenvironment that MSCs encounter. As such, the composition of the MSCs' secretome can be modulated by preconditioning the MSCs during in vitro culture. This manuscript reviews the existent literature on how preconditioning of MSCs affects the therapeutic potential of their secretome, focusing on MSCs' immunomodulatory and regenerative features, thereby providing new insights for the therapeutic use of MSCs' secretome.
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Affiliation(s)
- Joana R Ferreira
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Graciosa Q Teixeira
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Susana G Santos
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Mário A Barbosa
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Graça Almeida-Porada
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States
| | - Raquel M Gonçalves
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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Wang YJ, Zhao P, Sui BD, Liu N, Hu CH, Chen J, Zheng CX, Liu AQ, Xuan K, Pan YP, Jin Y. Resveratrol enhances the functionality and improves the regeneration of mesenchymal stem cell aggregates. Exp Mol Med 2018; 50:1-15. [PMID: 29959311 PMCID: PMC6026147 DOI: 10.1038/s12276-018-0109-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 03/20/2018] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cell (MSC)-based regeneration, specifically cell aggregate or cell sheet engineering, is a promising approach for tissue reconstruction. Considering the advantages of ease of harvest and lack of immune rejection, the application of autologous MSCs (i.e., patients' own MSCs) in regenerative medicine has developed considerable interest. However, the impaired cell viability and regenerative potential following MSCs impacted by disease remain a major challenge. Resveratrol (RSV) exhibits reliable and extensive rejuvenative activities that have received increasing clinical attention. Here, we uncovered that resveratrol enhances the functionality and improves the regeneration of mesenchymal stem cell aggregates. Periodontal ligament MSCs (PDLSCs) from normal control subjects (N-PDLSCs) and periodontitis patients (P-PDLSCs) were investigated. Compared to N-PDLSCs, P-PDLSCs were less capable of forming cell aggregates, and P-PDLSC aggregates showed impaired osteogenesis and regeneration. These functional declines could be mimicked in N-PDLSCs by tumor necrosis factor alpha (TNF-α) treatment. Notably, a TNF-α-induced functional decline in N-PDLSC aggregates was rescued by RSV application. More importantly, in both N-PDLSCs and P-PDLSCs, RSV promoted cell aggregate formation and improved their osteogenic potential. Furthermore, as proven ectopically in vivo, the tissue regenerative capability of P-PDLSC aggregates was also enhanced after RSV treatment during aggregate formation in vitro. Finally, in a rat in situ regeneration model, we successfully applied both N-PDLSC aggregates and P-PDLSC aggregates to repair periodontal defects upon long-term functional improvements by RSV preconditioning. Together, our data unravel a novel methodology for using pharmacology (i.e., RSV)-based cell aggregate engineering to improve the functionality and facilitate the regeneration of MSCs from both healthy and inflammatory microenvironments, shedding light on improving the application of autologous MSC-mediated regenerative medicine.
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Affiliation(s)
- Yi-Jing Wang
- Department of Periodontics and Oral Biology, School of Stomatology, China Medical University, Shenyang, Liaoning, 110002, China.,General Hospital of Shenyang Military Region, Shenyang, Liaoning, 110016, China
| | - Pan Zhao
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China
| | - Bing-Dong Sui
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Nu Liu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.,Department of Periodontology, Stomatological Hospital, Zunyi Medical College, Zunyi, Guizhou, 563003, China
| | - Cheng-Hu Hu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China
| | - Ji Chen
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Chen-Xi Zheng
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - An-Qi Liu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Kun Xuan
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Ya-Ping Pan
- Department of Periodontics and Oral Biology, School of Stomatology, China Medical University, Shenyang, Liaoning, 110002, China.
| | - Yan Jin
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
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Li G, Zhang Y, Cai S, Sun M, Wang J, Li S, Li X, Tighe S, Chen S, Xie H, Zhu Y. Human limbal niche cells are a powerful regenerative source for the prevention of limbal stem cell deficiency in a rabbit model. Sci Rep 2018; 8:6566. [PMID: 29700361 PMCID: PMC5919904 DOI: 10.1038/s41598-018-24862-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 04/09/2018] [Indexed: 12/13/2022] Open
Abstract
In this article, human limbal niche cells (LNC) or bone marrow derived mesenchymal stem cells (BMMSC) were used to prevent limbal stem cell deficiency (LSCD) in an alkali burn rabbit model and their results were compared. The epithelial cell defect area, corneal neovascularization, and the print cell cytometry were quantified to grade the severity of LSCD. Three months after the alkali burn, a partial LSCD was observed in the control group (no treatment) indicated by chronic corneal epithelial defects, positive corneal fluorescein staining, neovascularization and goblet cell migration. In contrast, the severity of LSCD in both the LNC and BMMSC transplantation groups was dramatically reduced as shown by smaller epithelial cell defects, decreased fluorescein sodium staining, decreased neovascularization and decreased goblet cell density. Interestingly, the LNC group was shown to more effectively prevent LSCD than the BMMSC group. Further analysis indicated subconjunctivally transplanted LNCs were more powerful than BMMSCs to prevent LSCD, at least partially, due to increased activation of SCF-c-Kit signal. We conclude that LNCs are a more powerful resource than BMMSCs to prevent LSCD in an alkali burn rabbit model, at least partially due to increased activation of SCF signaling.
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Affiliation(s)
- Guigang Li
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Research and Development Department, Tissue Tech, Inc, Miami, FL, 33126, USA
| | - Yuan Zhang
- Research and Development Department, Tissue Tech, Inc, Miami, FL, 33126, USA
| | - Subo Cai
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ming Sun
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Juan Wang
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shen Li
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xinyu Li
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Sean Tighe
- Research and Development Department, Tissue Tech, Inc, Miami, FL, 33126, USA
| | - Shuangling Chen
- Research and Development Department, Tissue Tech, Inc, Miami, FL, 33126, USA
| | - Huatao Xie
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yingting Zhu
- Research and Development Department, Tissue Tech, Inc, Miami, FL, 33126, USA.
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Cotter EJ, Wang KC, Yanke AB, Chubinskaya S. Bone Marrow Aspirate Concentrate for Cartilage Defects of the Knee: From Bench to Bedside Evidence. Cartilage 2018; 9:161-170. [PMID: 29126349 PMCID: PMC5871125 DOI: 10.1177/1947603517741169] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Objective To critically evaluate the current basic science, translational, and clinical data regarding bone marrow aspirate concentrate (BMAC) in the setting of focal cartilage defects of the knee and describe clinical indications and future research questions surrounding the clinical utility of BMAC for treatment of these lesions. Design A literature search was performed using the PubMed and Ovid MEDLINE databases for studies in English (1980-2017) using keywords, including ["bone marrow aspirate" and "cartilage"], ["mesenchymal stem cells" and "cartilage"], and ["bone marrow aspirate" and "mesenchymal stem cells" and "orthopedics"]. A total of 1832 articles were reviewed by 2 independent authors and additional literature found through scanning references of cited articles. Results BMAC has demonstrated promising results in the clinical application for repair of chondral defects as an adjuvant procedure or as an independent management technique. A subcomponent of BMAC, bone marrow derived-mesenchymal stem cells (MSCs) possess the ability to differentiate into cells important for osteogenesis and chondrogenesis. Modulation of paracrine signaling is perhaps the most important function of BM-MSCs in this setting. In an effort to increase the cellular yield, authors have shown the ability to expand BM-MSCs in culture while maintaining phenotype. Conclusions Translational studies have demonstrated good clinical efficacy of BMAC both concomitant with cartilage restoration procedures, at defined time points after surgery, and as isolated injections. Early clinical data suggests BMAC may help stimulate a more robust hyaline cartilage repair tissue response. Numerous questions remain regarding BMAC usage, including cell source, cell expansion, optimal pathology, and injection timing and quantity.
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Affiliation(s)
- Eric J. Cotter
- Georgetown University School of Medicine, Washington, DC, USA
| | - Kevin C. Wang
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Adam B. Yanke
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Susan Chubinskaya
- Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA
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Abstract
Purpose of Review The aim of the study is to provide an overview on the possibility of treating congenital disorders prenatally with mesenchymal stromal cells (MSCs). Recent Findings MSCs have multilineage potential and a low immunogenic profile and are immunomodulatory and more easy to expand in culture. Their ability to migrate, engraft and differentiate, or act via a paracrine effect on target tissues makes MSCs candidates for clinical therapies. Fetal and extra-fetal MSCs offer higher therapeutic potential compared to MSCs derived from adult sources. Summary MSCs may be safely transplanted prenatally via ultrasound-guided injection into the umbilical cord. Due to these characteristics, fetal MSCs are of great interest in the field of in utero stem cell transplantation for treatment of congenital disease.
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Park S, Lee DR, Nam JS, Ahn CW, Kim H. Fetal bovine serum-free cryopreservation methods for clinical banking of human adipose-derived stem cells. Cryobiology 2018; 81:65-73. [PMID: 29448017 DOI: 10.1016/j.cryobiol.2018.02.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 01/23/2018] [Accepted: 02/12/2018] [Indexed: 12/16/2022]
Abstract
The use of fetal bovine serum (FBS) as a cryopreservation supplement is not suitable for the banking of mesenchymal stem cells (MSCs) due to the risk of transmission of disease as well as xenogeneic immune reactions in the transplanted host. Here, we investigated if human serum albumin (HSA), human serum (HS), or knockout serum replacement (KSR) can replace FBS for the cryopreservation of MSCs. In addition, we examined the characteristics of MSCs after multiple rounds of cryopreservation. Human adipose-derived stem cells (ASCs) cryopreserved with three FBS replacements, 9% HSA, 90% HS, or 90% KSR, in combination with 10% dimethyl sulfoxide (Me2SO) maintained stem cell properties including growth, immunophenotypes, gene expression patterns, and the potential to differentiate into adipogenic, osteogenic, and chondrogenic lineages, similar to ASCs frozen with FBS. Moreover, the immunophenotype, gene expression, and differentiation capabilities of ASCs were not altered by up to four freeze-thaw cycles. However, the performance of three or four freeze-thaw cycles significantly reduced the proliferation ability of ASCs, as indicated by the longer population doubling time and reduced colony-forming unit-fibroblast frequency. Together, our results suggest that HSA, HS, or KSR can replace FBS for the cryopreservation of ASCs, without altering their stemness, and should be processed with no more than two freeze-thaw cycles for clinical approaches.
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Affiliation(s)
- Seah Park
- Department of Biotechnology, Seoul Women's University, 621 Hwarangro, Nowon-Gu, Seoul, Republic of Korea.
| | - Dong Ryul Lee
- Department of Biomedical Science, CHA University, 120 Haeryong-ro, Pocheon-shi, Gyeongghi-do, Republic of Korea.
| | - Ji Sun Nam
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Chul Woo Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Haekwon Kim
- Department of Biotechnology, Seoul Women's University, 621 Hwarangro, Nowon-Gu, Seoul, Republic of Korea.
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44
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Chen L, Jiang F, Qiao Y, Li H, Wei Z, Huang T, Lan J, Xia Y, Li J. Nucleoskeletal stiffness regulates stem cell migration and differentiation through lamin A/C. J Cell Physiol 2018; 233:5112-5118. [PMID: 29215717 DOI: 10.1002/jcp.26336] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 11/27/2017] [Indexed: 02/05/2023]
Abstract
Stem cell-based tissue engineering provides a prospective strategy to bone tissue repair. Bone tissue repair begins at the recruitment and directional movement of stem cells, and ultimately achieved on the directional differentiation of stem cells. The migration and differentiation of stem cells are regulated by nucleoskeletal stiffness. Mechanical properties of lamin A/C contribute to the nucleoskeletal stiffness and consequently to the regulation of cell migration and differentiation. Nuclear lamin A/C determines cell migration through the regulation of nucleoskeletal stiffness and rigidity and involve in nuclear-cytoskeletal coupling. Moreover, lamin A/C is the essential core module regulating stem cell differentiation. The cells with higher migration ability tend to have enhanced differentiation potential, while the optimum amount of lamin A/C in migration and differentiation of MSCs is in conflict. This contrary phenomenon may be the result of mechanical microenvironment modulation.
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Affiliation(s)
- Liujing Chen
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Fulin Jiang
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Yini Qiao
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Hong Li
- Hangzhou Dental Hospital, School of Stomatology, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhangming Wei
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Tu Huang
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Jingxiang Lan
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Yue Xia
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
| | - Juan Li
- Department of Orthodontics, West China Hospital of Stomatology, West China School of Stomatology Sichuan University, State Key Laboratory of Oral Diseases, Chengdu, Sichuan, China
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45
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Zhou Y, Zimber M, Yuan H, Naughton GK, Fernan R, Li WJ. Effects of Human Fibroblast-Derived Extracellular Matrix on Mesenchymal Stem Cells. Stem Cell Rev Rep 2017; 12:560-572. [PMID: 27342267 DOI: 10.1007/s12015-016-9671-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Stem cell fate is largely determined by the microenvironment called niche. The extracellular matrix (ECM), as a key component in the niche, is responsible for maintaining structural stability and regulating cell proliferation, differentiation, migration and other cellular activities. Each tissue has a unique ECM composition for its needs. Here we investigated the effect of a bioengineered human dermal fibroblast-derived ECM (hECM) on the regulation of human mesenchymal stem cell (hMSC) proliferation and multilineage differentiation. Human MSCs were maintained on hECM for two passages followed by the analysis of mRNA expression levels of potency- and lineage-specific markers to determine the capacity of MSC stemness and differentiation, respectively. Mesenchymal stem cells pre-cultured with or without hECM were then induced and analyzed for osteogenesis, adipogenesis and chondrogenesis. Our results showed that compared to MSCs maintained on control culture plates without hECM coating, cells on hECM-coated plates proliferated more rapidly with a higher percentage of cells in S phase of the cell cycle, resulting in an increase in the CD90+/CD105+/CD73+/CD45- subpopulation. In addition, hECM downregulated osteogenesis and adipogenesis of hMSCs but significantly upregulated chondrogenesis with increased production of collagen type 2. In sum, our findings suggest that hECM may be used to culture hMSCs for the application of cartilage tissue engineering.
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Affiliation(s)
- Yaxian Zhou
- Department of Orthopedics and Rehabilitation, Laboratory of Musculoskeletal Biology and Regenerative Medicine, University of Wisconsin-Madison, 1111 Highland Avenue, WIMR 5051, Madison, WI, 53705-2275, USA.,Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
| | | | - Huihua Yuan
- Department of Orthopedics and Rehabilitation, Laboratory of Musculoskeletal Biology and Regenerative Medicine, University of Wisconsin-Madison, 1111 Highland Avenue, WIMR 5051, Madison, WI, 53705-2275, USA.,College of Chemistry, Chemical Engineering & Biotechnology, Donghua University, Shanghai, China
| | | | | | - Wan-Ju Li
- Department of Orthopedics and Rehabilitation, Laboratory of Musculoskeletal Biology and Regenerative Medicine, University of Wisconsin-Madison, 1111 Highland Avenue, WIMR 5051, Madison, WI, 53705-2275, USA. .,Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.
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Gaetani M, Chinnici CM, Carreca AP, Di Pasquale C, Amico G, Conaldi PG. Unbiased and quantitative proteomics reveals highly increased angiogenesis induction by the secretome of mesenchymal stromal cells isolated from fetal rather than adult skin. J Tissue Eng Regen Med 2017; 12:e949-e961. [DOI: 10.1002/term.2417] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 01/13/2017] [Accepted: 01/16/2017] [Indexed: 01/12/2023]
Affiliation(s)
- Massimiliano Gaetani
- Fondazione Ri.MED Palermo Italy
- Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced BiotechnologiesIRCCS‐ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies) Palermo Italy
| | - Cinzia Maria Chinnici
- Fondazione Ri.MED Palermo Italy
- Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced BiotechnologiesIRCCS‐ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies) Palermo Italy
| | - Anna Paola Carreca
- Fondazione Ri.MED Palermo Italy
- Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced BiotechnologiesIRCCS‐ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies) Palermo Italy
| | - Claudia Di Pasquale
- Fondazione Ri.MED Palermo Italy
- Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced BiotechnologiesIRCCS‐ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies) Palermo Italy
| | - Giandomenico Amico
- Fondazione Ri.MED Palermo Italy
- Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced BiotechnologiesIRCCS‐ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies) Palermo Italy
| | - Pier Giulio Conaldi
- Fondazione Ri.MED Palermo Italy
- Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced BiotechnologiesIRCCS‐ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies) Palermo Italy
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Mesenchymal Stem Cells (MSCs) Attenuate Cutaneous Sclerodermatous Graft-Versus-Host Disease (Scl-GVHD) through Inhibition of Immune Cell Infiltration in a Mouse Model. J Invest Dermatol 2017; 137:1895-1904. [PMID: 28526296 DOI: 10.1016/j.jid.2017.02.986] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 02/10/2017] [Accepted: 02/23/2017] [Indexed: 12/30/2022]
Abstract
Human chronic graft-versus-host disease (GVHD) shares clinical characteristics with a murine sclerodermatous GVHD model that is characterized by skin thickening and lung fibrosis. A B10.D2 → BALB/c transplant model of sclerodermatous GVHD was used to address the therapeutic effect of mesenchymal stem cells (MSCs) on the development of chronic GVHD. The clinical and pathological severity of cutaneous sclerodermatous GVHD was significantly attenuated in MSC-treated recipients relative to sclerodermatous GVHD control subjects. After MSC treatment, skin collagen production was significantly reduced, with consistent down-regulation of Tgfb expression. Effects of MSCs on molecular markers implicated in persistent transforming growth factor-β signaling and fibrosis, such as PTEN, phosphorylated Smad-2/3, and matrix metalloproteinase-1, were observed in skin tissue. MSCs neither migrate to the skin nor affect the in vivo expansion of immune effector cells, but they inhibited the infiltration of immune effector cells into skin via down-regulation of CCR4 and CCR8 expression on CD4+ T cells and CCR1 on CD11b+ monocyte/macrophages. MSCs diminished expression of chemokines such as CCL1, CCL3, CCL8, CCL17, and CCL22 in skin. MSCs were also dependent on stimulated splenocytes to suppress fibroblast proliferation. Our findings indicate that MSCs attenuate the cutaneous sclerodermatous GVHD by selectively blocking immune cell migration and down-regulating chemokines and chemokine receptors.
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48
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Lee SY, Kwon B, Lee K, Son YH, Chung SG. Therapeutic Mechanisms of Human Adipose-Derived Mesenchymal Stem Cells in a Rat Tendon Injury Model. Am J Sports Med 2017; 45:1429-1439. [PMID: 28291954 DOI: 10.1177/0363546517689874] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Although survival of transplanted stem cells in vivo and differentiation of stem cells into tenocytes in vitro have been reported, there have been no in vivo studies demonstrating that mesenchymal stem cells (MSCs) could secrete their own proteins as differentiated tenogenic cells. Purpose/Hypothesis: Using a xenogeneic MSC transplantation model, we aimed to investigate whether MSCs could differentiate into the tenogenic lineage and secrete their own proteins. The hypothesis was that human MSCs would differentiate into the human tenogenic lineage and the cells would be able to secrete human-specific proteins in a rat tendon injury model. STUDY DESIGN Controlled laboratory study. METHODS The Achilles tendons of 57 Sprague Dawley rats received full-thickness rectangular defects. After the modeling, the defective tendons were randomly assigned to 3 groups: (1) cell group, implantation with human adipose-derived mesenchymal stem cells (hASCs) and fibrin glue (106 cells in 60 μL); (2) fibrin group, implantation with fibrin glue and same volume of cell media; and (3) sham group, identical surgical procedure without any treatment. Gross observation and biomechanical, histopathological, immunohistochemistry, and Western blot analyses were performed at 2 and 4 weeks after modeling. RESULTS hASCs implanted into the defective rat tendons were viable for 4 weeks as detected by immunofluorescence staining. Tendons treated with hASCs showed better gross morphological and biomechanical recovery than those in the fibrin and sham groups. Furthermore, the expression of both human-specific collagen type I and tenascin-C was significantly higher in the cell group than in the other 2 groups. CONCLUSION Transplantation of hASCs enhanced rat tendon healing biomechanically. hASCs implanted into the rat tendon defect model survived for at least 4 weeks and secreted human-specific collagen type I and tenascin-C. These findings suggest that transplanted MSCs may be able to differentiate into the tenogenic lineage and contribute their own proteins to tendon healing. CLINICAL RELEVANCE In tendon injury, MSCs can enhance tendon healing by secreting their own protein and have potential as a therapeutic option in human tendinopathy.
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Affiliation(s)
- Sang Yoon Lee
- Department of Physical Medicine & Rehabilitation, Chung-Ang University College of Medicine, Seoul, South Korea.,Department of Rehabilitation Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Bomi Kwon
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyoungbun Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Young Hoon Son
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, South Korea
| | - Sun G Chung
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Institute of Aging, Seoul National University, Seoul, South Korea.,Rheumatism Research Institute, Medical Research Center, Seoul National University, Seoul, South Korea
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49
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Shyam H, Singh SK, Kant R, Saxena SK. Mesenchymal stem cells in regenerative medicine: a new paradigm for degenerative bone diseases. Regen Med 2017; 12:111-114. [PMID: 28244826 DOI: 10.2217/rme-2016-0162] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Hari Shyam
- Department of Stem Cell & Cell Culture, Centre for Advance Research (CFAR), King George's Medical University, Lucknow 226003, India
| | - Satyendra K Singh
- Department of Stem Cell & Cell Culture, Centre for Advance Research (CFAR), King George's Medical University, Lucknow 226003, India
| | - Ravi Kant
- Department of Stem Cell & Cell Culture, Centre for Advance Research (CFAR), King George's Medical University, Lucknow 226003, India
| | - Shailendra K Saxena
- Department of Stem Cell & Cell Culture, Centre for Advance Research (CFAR), King George's Medical University, Lucknow 226003, India.,CSIR-Centre for Cellular & Molecular Biology, Uppal Road, Hyderabad 500007, India
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50
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Jasmin, de Souza GT, Louzada RA, Rosado-de-Castro PH, Mendez-Otero R, Campos de Carvalho AC. Tracking stem cells with superparamagnetic iron oxide nanoparticles: perspectives and considerations. Int J Nanomedicine 2017; 12:779-793. [PMID: 28182122 PMCID: PMC5279820 DOI: 10.2147/ijn.s126530] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Superparamagnetic iron oxide nanoparticles (SPIONs) have been used for diagnoses in biomedical applications, due to their unique properties and their apparent safety for humans. In general, SPIONs do not seem to produce cell damage, although their long-term in vivo effects continue to be investigated. The possibility of efficiently labeling cells with these magnetic nanoparticles has stimulated their use to noninvasively track cells by magnetic resonance imaging after transplantation. SPIONs are attracting increasing attention and are one of the preferred methods for cell labeling and tracking in preclinical and clinical studies. For clinical protocol approval of magnetic-labeled cell tracking, it is essential to expand our knowledge of the time course of SPIONs after cell incorporation and transplantation. This review focuses on the recent advances in tracking SPION-labeled stem cells, analyzing the possibilities and limitations of their use, not only focusing on myocardial infarction but also discussing other models.
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Affiliation(s)
- Jasmin
- NUMPEX-Bio, Federal University of Rio de Janeiro, Duque de Caxias, RJ
| | - Gustavo Torres de Souza
- Laboratory of Animal Reproduction, Embrapa Dairy Cattle, Juiz de Fora, MG
- Laboratory of Genetics, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Ruy Andrade Louzada
- Institute Gustave-Roussy of Oncology, Paris-Sud University, Villejuif, France
| | | | - Rosalia Mendez-Otero
- Institute Carlos Chagas Filho of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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