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Wang Y, Luo P, Wuren T. Narrative Review of Mesenchymal Stem Cell Therapy in Renal Diseases: Mechanisms, Clinical Applications, and Future Directions. Stem Cells Int 2024; 2024:8658246. [PMID: 39698513 PMCID: PMC11655143 DOI: 10.1155/sci/8658246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 11/27/2024] [Indexed: 12/20/2024] Open
Abstract
Renal diseases, particularly acute kidney injury (AKI) and chronic kidney disease (CKD), are significant global health challenges. These conditions impair kidney function and can lead to serious complications, including cardiovascular diseases, which further exacerbate the public health burden. Currently, the global AKI mortality rate is alarmingly high (20%-50%); CKD is projected to emerge as a major global health burden by 2040. Existing treatments such as hemodialysis and kidney transplantation have limited effectiveness and are often associated with adverse effects. Mesenchymal stem cells (MSCs) offer considerable potential for treating renal diseases owing to their regenerative and immunomodulatory properties. Thus, this review focuses on the application of MSCs in renal disease, discusses fundamental research findings, and evaluates their application in clinical trials. Moreover, we discuss the impact and safety of MSCs as a therapeutic option and highlight challenges and potential directions for their clinical application. We selected research articles from PubMed published within the last 5 years (from 2019), focusing on high-impact journals and clinical trial data, and included a few key studies predating 2019. Considerations included the novelty of the research, sample size, experimental design, and data reliability. With advancements in single-cell sequencing, CRISPR/Cas9 gene editing, and other cutting-edge technologies, future MSC research will explore combination therapies and personalized treatments to provide more promising, safer treatments with reduced adverse reactions and enhanced therapeutic outcomes. These advances will improve kidney disease treatment methods, enhance patient quality of life, and maximize the benefits of MSC therapies.
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Affiliation(s)
- Yanjun Wang
- Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China
- High-Altitude Medicine Key Laboratory of the Ministry of Education, Xining 810001, China
- Qinghai Provincial Key Laboratory for Application of High-Altitude Medicine (Qinghai-Utah Joint Key Laboratory for Plateau Medicine), Xining 810001, China
- Nephrology Department, Affiliated Hospital of Qinghai University, Xining 810001, China
| | - Pengli Luo
- Nephrology Department, Affiliated Hospital of Qinghai University, Xining 810001, China
| | - Tana Wuren
- Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China
- High-Altitude Medicine Key Laboratory of the Ministry of Education, Xining 810001, China
- Qinghai Provincial Key Laboratory for Application of High-Altitude Medicine (Qinghai-Utah Joint Key Laboratory for Plateau Medicine), Xining 810001, China
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2
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Mathis K, Chan CTY, Meckes B. Controlling Cell Interactions with DNA Directed Assembly. Adv Healthc Mater 2024; 13:e2402876. [PMID: 39402803 DOI: 10.1002/adhm.202402876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/30/2024] [Indexed: 12/28/2024]
Abstract
The creation of complex cellular environments is critical to mimicking tissue environments that will play a critical role in next-generation tissue engineering, stem cell programming, and therapeutic screening. To address this growing need, techniques capable of manipulating cell-cell and cell-material interactions are required that span single-cell to 3D tissue architectures. DNA programmed assembly and placement of cells present a powerful technique for the bottom-up synthesis of living microtissues for probing key questions in cell-cell and cell-material-driven behaviors through its refined control over placement and architecture. This review examines the current state of the art in the programming of cellular interactions with DNA and its applications spanning tissue model building, fundamental cellular biology, and cell manipulation for measurements across a host of applications.
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Affiliation(s)
- Katelyn Mathis
- Department of Biomedical Engineering, University of North Texas, 3940 N Elm St., Denton, TX, 76207, USA
- BioDiscovery Institute, University of North Texas, 1155 Union Circle, Denton, TX, 76203 5017, USA
| | - Clement T Y Chan
- Department of Biomedical Engineering, University of North Texas, 3940 N Elm St., Denton, TX, 76207, USA
- BioDiscovery Institute, University of North Texas, 1155 Union Circle, Denton, TX, 76203 5017, USA
| | - Brian Meckes
- Department of Biomedical Engineering, University of North Texas, 3940 N Elm St., Denton, TX, 76207, USA
- BioDiscovery Institute, University of North Texas, 1155 Union Circle, Denton, TX, 76203 5017, USA
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Rivera Orsini MA, Ozmen EB, Miles A, Newby SD, Springer N, Millis D, Dhar M. Isolation and Characterization of Canine Adipose-Derived Mesenchymal Stromal Cells: Considerations in Translation from Laboratory to Clinic. Animals (Basel) 2024; 14:2974. [PMID: 39457904 PMCID: PMC11503832 DOI: 10.3390/ani14202974] [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: 09/06/2024] [Revised: 10/03/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024] Open
Abstract
In allogeneic MSC implantation, the cells are isolated from a donor different from the recipient. When tested, allogeneic MSCs have several advantages over autologous ones: faster cell growth, sufficient cell concentration, and readily available cells for clinics. To ensure the safe and efficient use of allogeneic MSCs in clinics, the MSCs need to be first tested in vitro. With this study, we paved the way by addressing the in vitro aspects of canine adipose-derived MSCs, considering the limited studies on the clinical use of canine cells. We isolated cAD-MSCs from canine falciform ligament fat and evaluated their viability and proliferation using an MTS assay. Then, we characterized the MSC-specific antigens using immunophenotyping and immunofluorescence and demonstrated their potential for in vitro differentiation. Moreover, we established shipping and cryobanking procedures to lead the study to become an off-the-shelf therapy. During expansion, the cells demonstrated a linear increase in cell numbers, confirming their proliferation quantitatively. The cells showed viability before and after cryopreservation, demonstrating that cell viability can be preserved. From a clinical perspective, the established shipping conditions demonstrated that the cells retain their viability for up to 48 h. This study lays the groundwork for the potential use of allogeneic cAD-MSCs in clinical applications.
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Affiliation(s)
- Michael A. Rivera Orsini
- Regenerative Medicine and Tissue Engineering, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA; (M.A.R.O.); (E.B.O.); (S.D.N.)
| | - Emine Berfu Ozmen
- Regenerative Medicine and Tissue Engineering, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA; (M.A.R.O.); (E.B.O.); (S.D.N.)
- Genome Science and Technology, University of Tennessee Knoxville, Knoxville, TN 37996, USA
| | - Alyssa Miles
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA; (A.M.); (N.S.)
| | - Steven D. Newby
- Regenerative Medicine and Tissue Engineering, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA; (M.A.R.O.); (E.B.O.); (S.D.N.)
| | - Nora Springer
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA; (A.M.); (N.S.)
| | - Darryl Millis
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA;
| | - Madhu Dhar
- Regenerative Medicine and Tissue Engineering, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA; (M.A.R.O.); (E.B.O.); (S.D.N.)
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Dai W, Yang H, Xu B, He T, Liu L, Zhang Z, Ding L, Pei X, Fu X. 3D hUC-MSC spheroids exhibit superior resistance to autophagy and apoptosis of granulosa cells in POF rat model. Reproduction 2024; 168:e230496. [PMID: 38912966 PMCID: PMC11301424 DOI: 10.1530/rep-23-0496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 06/24/2024] [Indexed: 06/25/2024]
Abstract
In brief This study reveals that orthotopic transplantation of 3D hUC-MSC spheroids is more effective than monolayer-cultured hUC-MSCs in improving POF and distinctly reducing oxidative stress through the paracrine effect, thereby preventing apoptosis and autophagy of GCs. Abstract Premature ovarian failure (POF) is a common reproductive disease in women younger than 40 years old, and studies have demonstrated that the application of human umbilical cord mesenchymal stem cells (hUC-MSCs) is a promising therapy strategy for POF. Given the previously established therapeutic advantages of 3D MSC spheroids, and to evaluate their effectiveness, both 3D hUC-MSC spheroids and monolayer-cultured hUC-MSCs were employed to treat a cyclophosphamide-induced POF rat model through orthotopic transplantation. The effects of these two forms on POF were subsequently assessed by examining apoptosis, autophagy, and oxidative damage in ovarian granulosa cells (GCs). The results indicated that hUC-MSC spheroids exhibited superior treatment effects on resisting autophagy, apoptosis, and oxidative damage in GCs compared to monolayer-cultured hUC-MSCs. To further elucidate the impact of hUC-MSC spheroids in vitro, a H2O2-induced KGN cells model was established and co-cultured with both forms of hUC-MSCs. As expected, the hUC-MSC spheroids also exhibited superior effects in resisting apoptosis and autophagy caused by oxidative damage. Therefore, this study demonstrates that 3D hUC-MSC spheroids have potential advantages in POF therapy; however, the detailed mechanisms need to be further investigated. Furthermore, this study will provide a reference for the clinical treatment strategy of POF.
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Affiliation(s)
- Wenjie Dai
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Hong Yang
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Bo Xu
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Tiantian He
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Ling Liu
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Zhen Zhang
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Liyang Ding
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xiuying Pei
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xufeng Fu
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
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Zhao H, Zhao H, Ji S. A Mesenchymal stem cell Aging Framework, from Mechanisms to Strategies. Stem Cell Rev Rep 2024; 20:1420-1440. [PMID: 38727878 DOI: 10.1007/s12015-024-10732-4] [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] [Accepted: 05/02/2024] [Indexed: 08/13/2024]
Abstract
Mesenchymal stem cells (MSCs) are extensively researched for therapeutic applications in tissue engineering and show significant potential for clinical use. Intrinsic or extrinsic factors causing senescence may lead to reduced proliferation, aberrant differentiation, weakened immunoregulation, and increased inflammation, ultimately limiting the potential of MSCs. It is crucial to comprehend the molecular pathways and internal processes responsible for the decline in MSC function due to senescence in order to devise innovative approaches for rejuvenating senescent MSCs and enhancing MSC treatment. We investigate the main molecular processes involved in senescence, aiming to provide a thorough understanding of senescence-related issues in MSCs. Additionally, we analyze the most recent advancements in cutting-edge approaches to combat MSC senescence based on current research. We are curious whether the aging process of stem cells results in a permanent "memory" and if cellular reprogramming may potentially revert the aging epigenome to a more youthful state.
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Affiliation(s)
- Hongqing Zhao
- Nanbu County People's Hospital, Nanchong City, 637300, Sichuan Province, China
- Jinzhou Medical University, No.82 Songpo Road, Guta District, Jinzhou, 121001, Liaoning Province, China
| | - Houming Zhao
- Graduate School of PLA Medical College, Chinese PLA General Hospital, Beijing, 100083, China
| | - Shuaifei Ji
- Graduate School of PLA Medical College, Chinese PLA General Hospital, Beijing, 100083, China.
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Chrościńska-Kawczyk M, Zdolińska-Malinowska I, Boruczkowski D. The Impact of Umbilical Cord Mesenchymal Stem Cells on Motor Function in Children with Cerebral Palsy: Results of a Real-world, Compassionate use Study. Stem Cell Rev Rep 2024; 20:1636-1649. [PMID: 38877284 DOI: 10.1007/s12015-024-10742-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2024] [Indexed: 06/16/2024]
Abstract
The aim of this study was to analyze the impact of human umbilical cord-derived MSCs (hUC-MSCs) on motor function in children with cerebral palsy (CP). The study enrolled 152 children with CP who received up to two courses of five hUC-MSCs injections. Children's motor functions were assessed with the Gross Motor Function Measure (GMFM), 6-Minute Walk Test (6-MWT), Timed Up and Go test (Up&Go test), and Lovett's test, and mental abilities were assessed with the Clinical Global Impression (CGI) scale. Data collected at visit 1 (baseline) and visit 5 (after four injections) were analyzed retrospectively. After four hUC-MSCs administrations, all evaluated parameters improved. The change in GMFM score, by a median of 1.9 points (IQR: 0.0-8.0), correlated with age. This change was observed in all GFMCS groups and was noticed in all assessed GMFM areas. A median increase of 75 m (IQR: 20.0-115.0) was noted on the 6-MWT, and this correlated with GMFM score change. Time on the Up&Go test was reduced by a median of 2 s (IQR: -3 to - 1) and the change correlated with age, GMFM score at baseline, and the difference observed on the 6-MWT. Results of Lovett's test indicated slight changes in muscle strength. According to the CGI, 75.5% (96/151) of children were seriously (level VI) or significantly ill (level V) at the 1st visit, with any improvement observed in 63.6% (96/151) of patients at the 5th visit, 23.8% (36/151) with improvement (level II) or great improvement (level I). In conclusion, the application of hUC-MSCs generally enhanced functional performance, but individual responses varied. The therapy also benefited children with high level of disability but not to the same extent as the initially less disabled children. Although younger patients responded better to the treatment, older children can also benefit. Trial Registration 152/2018/KB/VII and 119/2021/KB/VIII. Retrospective registration in ClinicalTrials: ongoing.
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Christoffers S, Seiler L, Wiebe E, Blume C. Possibilities and efficiency of MSC co-transfection for gene therapy. Stem Cell Res Ther 2024; 15:150. [PMID: 38783353 PMCID: PMC11119386 DOI: 10.1186/s13287-024-03757-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are not only capable of self-renewal, trans-differentiation, homing to damaged tissue sites and immunomodulation by secretion of trophic factors but are also easy to isolate and expand. Because of these characteristics, they are used in numerous clinical trials for cell therapy including immune and neurological disorders, diabetes, bone and cartilage diseases and myocardial infarction. However, not all trials have successful outcomes, due to unfavourable microenvironmental factors and the heterogenous nature of MSCs. Therefore, genetic manipulation of MSCs can increase their prospect. Currently, most studies focus on single transfection with one gene. Even though the introduction of more than one gene increases the complexity, it also increases the effectivity as different mechanism are triggered, leading to a synergistic effect. In this review we focus on the methodology and efficiency of co-transfection, as well as the opportunities and pitfalls of these genetically engineered cells for therapy.
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Affiliation(s)
- Sina Christoffers
- Institute for Technical Chemistry, Leibniz University Hannover, Callinstr. 3-5, 30167, Hannover, Germany.
- Cluster of Excellence Hearing4all, Hannover, Germany.
| | - Lisa Seiler
- Institute for Technical Chemistry, Leibniz University Hannover, Callinstr. 3-5, 30167, Hannover, Germany
| | - Elena Wiebe
- Institute for Technical Chemistry, Leibniz University Hannover, Callinstr. 3-5, 30167, Hannover, Germany
- Cluster of Excellence Hearing4all, Hannover, Germany
| | - Cornelia Blume
- Institute for Technical Chemistry, Leibniz University Hannover, Callinstr. 3-5, 30167, Hannover, Germany
- Cluster of Excellence Hearing4all, Hannover, Germany
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Feng X, Qi F, Wang H, Li W, Gan Y, Qi C, Lin Z, Chen L, Wang P, Hu Z, Miao Y. Sorting Technology for Mesenchymal Stem Cells from a Single Tissue Source. Stem Cell Rev Rep 2024; 20:524-537. [PMID: 38112926 DOI: 10.1007/s12015-023-10635-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2023] [Indexed: 12/21/2023]
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells that can be obtained, enriched and proliferated in vitro. They owned enormous potential in fields like regenerative medicine, tissue engineering and immunomodulation. However, though isolated from the same origin, MSCs are still essentially heterogeneous cell populations with different phenotypes and functions. This heterogeneity of MSCs significantly affects their therapeutic efficacy and brings obstacles to scientific research. Thus, reliable sorting technology which can isolate or purify MSC subpopulations with various potential and differentiation pathways is urgently needed. This review summarized principles, application status and clinical implications for these sorting methods, aiming at improving the understanding of MSC heterogeneity as well as providing fresh perspectives for subsequent clinical applications.
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Affiliation(s)
- Xinyi Feng
- The First Clinical School of Southern Medical University, Guangzhou, China
| | - Fangfang Qi
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Hailin Wang
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Wenzhen Li
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Yuyang Gan
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Caiyu Qi
- The First Clinical School of Southern Medical University, Guangzhou, China
| | - Zhen Lin
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Lu Chen
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Piao Wang
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Zhiqi Hu
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China.
| | - Yong Miao
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China.
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Wu H, Sun W, Cheng G, Zheng M, Zhao Y, Cao Z. Human Mesenchymal Stem Cells Improve Angiogenesis and Bone Formation in Severed Finger Rats through SIRT1/Nrf2 Signaling. Curr Stem Cell Res Ther 2024; 19:389-399. [PMID: 37183461 DOI: 10.2174/1574888x18666230512112735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/15/2023] [Accepted: 03/20/2023] [Indexed: 05/16/2023]
Abstract
BACKGROUND This study employed a severed finger rat model to analyze the effects of human mesenchymal stem cells (MSCs) on angiogenesis, inflammatory response, apoptosis, and oxidative stress, to evaluate the possible mechanism of the repair effect of MSCs on severed finger (SF) rats. METHODS Sixty Sprague-Dawley (SD) rats were categorized into five groups (n = 12). The pathological changes of severed finger tissues were investigated by Hematoxylin and eosin (H&E) staining on day 14 after the rats were sacrificed. The levels of inflammatory factors and oxidative stress factors were detected by ELISA. Terminal Deoxynucleotidyl Transferase (TdT) dUTP Nick End Labeling (TUNEL) was employed to assess the apoptosis of chondrocytes in severed finger tissues. The expression of osteocalcin (OCN), osteopontin (OPN), Collagen I (Col-1), and CD31 were detected by immunohistochemistry or immunofluorescence assay, respectively. The expression levels of related proteins were determined by western blot. RESULT Our study presented evidence that MSCs treatment improved pathological changes of skin and bone tissue, diminished the inflammatory response, prevented oxidative stress injury, suppressed chondrocyte apoptosis, and promoted angiogenesis, and bone formation compared to the model group. In addition, EX527 treatment attenuated the effect of MSCs, SRT1720 and ML385 co-treatment also attenuated the effect of MSCs. Importantly, the MSCs treatment increased the expression of Sirtuin 1(SIRT1)/Nuclear factor erythroid2-related factor 2(Nrf2) relate proteins. CONCLUSION Our study indicated that the mechanism of the effect of MSCs on a severed finger was related to the SIRT1/ Nrf2 signaling pathway.
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Affiliation(s)
- Hao Wu
- Department of Sports Medicine, Yantaishan Hospital, 264003, Yantai, Shandong, China
| | - Weixue Sun
- Department of Arthrology Surgery, Yantai Yuhuangding Hospital, 264000, Yantai, Shandong, China
| | - Gong Cheng
- Department of Sports Medicine, Yantaishan Hospital, 264003, Yantai, Shandong, China
| | - Mingdi Zheng
- Department of Sports Medicine, Yantaishan Hospital, 264003, Yantai, Shandong, China
| | - Yuchi Zhao
- Department of Articulation Surgery, Yantaishan Hospital, 264003, Yantai, Shandong, China
| | - Zhilin Cao
- Department of Sports Medicine, Yantaishan Hospital, 264003, Yantai, Shandong, China
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Yan B, Li Z, Su H, Xue H, Qiu D, Xu Z, Tan G. Regulatory mechanisms of autophagy-related ncRNAs in bone metabolic diseases. Front Pharmacol 2023; 14:1178310. [PMID: 38146458 PMCID: PMC10749346 DOI: 10.3389/fphar.2023.1178310] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 11/27/2023] [Indexed: 12/27/2023] Open
Abstract
Bone metabolic diseases have been tormented and are plaguing people worldwide due to the lack of effective and thorough medical interventions and the poor understanding of their pathogenesis. Non-coding RNAs (ncRNAs) are heterogeneous transcripts that cannot encode the proteins but can affect the expressions of other genes. Autophagy is a fundamental mechanism for keeping cell viability, recycling cellular contents through the lysosomal pathway, and maintaining the homeostasis of the intracellular environment. There is growing evidence that ncRNAs, autophagy, and crosstalk between ncRNAs and autophagy play complex roles in progression of metabolic bone disease. This review investigated the complex mechanisms by which ncRNAs, mainly micro RNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), regulate autophagic pathway to assist in treating bone metabolism disorders. It aimed at identifying the autophagy role in bone metabolism disorders and understanding the role, potential, and challenges of crosstalk between ncRNAs and autophagy for bone metabolism disorders treatment.
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Affiliation(s)
- Binghan Yan
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhichao Li
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hui Su
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Haipeng Xue
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Daodi Qiu
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhanwang Xu
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Guoqing Tan
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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11
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Mathis K, Kohon AI, Black S, Meckes B. Light-Controlled Cell-Cell Assembly Using Photocaged Oligonucleotides. ACS MATERIALS AU 2023; 3:386-393. [PMID: 38090125 PMCID: PMC10347689 DOI: 10.1021/acsmaterialsau.3c00020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/08/2023] [Accepted: 05/08/2023] [Indexed: 09/29/2024]
Abstract
The interactions between heterogeneous cell populations play important roles in dictating various cell behaviors. Cell-cell contact mediates communication through the exchange of signaling molecules, electrical coupling, and direct membrane-linked ligand-receptor interactions. In vitro culturing of multiple cell types with control over their specific arrangement is difficult, especially in three-dimensional (3D) systems. While techniques that allow one to control the arrangement of cells and direct contact between different cell types have been developed that expand upon simple co-culture methods, specific control over heterojunctions that form between cells is not easily accomplished with current methods, such as 3D cell-printing. In this article, DNA-mediated cell interactions are combined with cell-compatible photolithographic approaches to control cell assembly. Specifically, cells are coated with oligonucleotides containing DNA nucleobases that are protected with photocleavable moieties; this coating facilitated light-controlled cell assembly when these cells were mixed with cells coated with complementary oligonucleotides. By combining this technology with digital micromirror devices mounted on a microscope, selective activation of specific cell populations for interactions with other cells was achieved. Importantly, this technique is rapid and uses non-UV light sources. Taken together, this technique opens new pathways for on-demand programming of complex cell structures.
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Affiliation(s)
- Katelyn Mathis
- Department
of Biomedical Engineering, University of
North Texas, 3940 N Elm Street, Denton, Texas 76207, United States
- BioDiscovery
Institute, University of North Texas, 1155 Union Circle, Denton, Texas 76203, United States
| | - Afia Ibnat Kohon
- Department
of Biomedical Engineering, University of
North Texas, 3940 N Elm Street, Denton, Texas 76207, United States
- BioDiscovery
Institute, University of North Texas, 1155 Union Circle, Denton, Texas 76203, United States
| | - Stephen Black
- Department
of Biomedical Engineering, University of
North Texas, 3940 N Elm Street, Denton, Texas 76207, United States
- BioDiscovery
Institute, University of North Texas, 1155 Union Circle, Denton, Texas 76203, United States
| | - Brian Meckes
- Department
of Biomedical Engineering, University of
North Texas, 3940 N Elm Street, Denton, Texas 76207, United States
- BioDiscovery
Institute, University of North Texas, 1155 Union Circle, Denton, Texas 76203, United States
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12
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Zhou L, Wang J, Huang J, Song X, Wu Y, Chen X, Tan Y, Yang Q. The role of mesenchymal stem cell transplantation for ischemic stroke and recent research developments. Front Neurol 2022; 13:1000777. [PMID: 36468067 PMCID: PMC9708730 DOI: 10.3389/fneur.2022.1000777] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 10/03/2022] [Indexed: 09/08/2023] Open
Abstract
Ischemic stroke is a common cerebrovascular disease that seriously affects human health. However, most patients do not practice self-care and cannot rely on the current clinical treatment for guaranteed functional recovery. Stem cell transplantation is an emerging treatment studied in various central nervous system diseases. More importantly, animal studies show that transplantation of mesenchymal stem cells (MSCs) can alleviate neurological deficits and bring hope to patients suffering from ischemic stroke. This paper reviews the biological characteristics of MSCs and discusses the mechanism and progression of MSC transplantation to provide new therapeutic directions for ischemic stroke.
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Affiliation(s)
| | | | | | | | | | | | | | - Qin Yang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Thamm K, Möbus K, Towers R, Baertschi S, Wetzel R, Wobus M, Segeletz S. A chemically defined biomimetic surface for enhanced isolation efficiency of high-quality human mesenchymal stromal cells under xenogeneic/serum-free conditions. Cytotherapy 2022; 24:1049-1059. [PMID: 35931601 DOI: 10.1016/j.jcyt.2022.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 05/23/2022] [Accepted: 06/10/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) are one of the most frequently used cell types in regenerative medicine and cell therapy. Generating sufficient cell numbers for MSC-based therapies is constrained by (i) their low abundance in tissues of origin, which imposes the need for significant ex vivo cell expansion; (ii) donor-specific characteristics, including MSC frequency/quality, that decline with disease state and increasing age; and (iii) cellular senescence, which is promoted by extensive cell expansion and results in decreased therapeutic functionality. The final yield of a manufacturing process is therefore primarily determined by the applied isolation procedure and its efficiency in isolating therapeutically active cells from donor tissue. To date, MSCs are predominantly isolated using media supplemented with either serum or its derivatives, which poses safety and consistency issues. METHODS To overcome these limitations while enabling robust MSC production with constant high yield and quality, the authors developed a chemically defined biomimetic surface coating called isoMATRIX (denovoMATRIX GmbH, Dresden, Germany) and tested its performance during isolation of MSCs. RESULTS The isoMATRIX facilitates the isolation of significantly higher numbers of MSCs in xenogeneic (xeno)/serum-free and chemically defined conditions. The isolated cells display a smaller cell size and higher proliferation rate than those derived from a serum-containing isolation procedure and a strong immunomodulatory capacity. The high proliferation rates can be maintained up to 5 passages after isolation and cells even benefit from a switch towards a proliferation-specific MSC matrix (myMATRIX MSC) (denovoMATRIX GmbH, Dresden, Germany). CONCLUSION In sum, isoMATRIX promotes enhanced xeno/serum-free and chemically defined isolation of human MSCs and supports consistent and reliable cell performance for improved stem cell-based therapies.
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Affiliation(s)
| | - Kristin Möbus
- Universitätskrankenhaus Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
| | - Russell Towers
- Universitätskrankenhaus Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
| | | | | | - Manja Wobus
- Universitätskrankenhaus Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
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14
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Ray SK, Mukherjee S. Mesenchymal Stem Cells Derived from Umbilical Cord Blood having Excellent Stemness Properties with Therapeutic Benefits - a New Era in Cancer Treatment. Curr Stem Cell Res Ther 2022; 17:328-338. [PMID: 35469574 DOI: 10.2174/1574888x17666220425102154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/18/2022] [Accepted: 03/03/2022] [Indexed: 11/22/2022]
Abstract
Mesenchymal stem cells (MSCs) are the most promising candidates for cellular therapies, and most therapeutic applications have focused on MSCs produced from adult bone marrow, despite mounting evidence that MSCs are present in a wide range of conditions. Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells, but its therapeutic potential extends beyond the hematopoietic component, which also suggests solid organ regenerative potential. With potential ranging from embryonic-like to lineage-committed progenitor cells, many different stems and progenitor cell populations have been postulated. MSC is currently inferred by numerous clinical applications for human UCB. aAs stem cell therapy kicks off some new research and these cells show such a boon to stem cell therapy, it is nevertheless characteristic that the prospect of UCB conservation is gaining momentum. Taken together, the experience described here shows that MSCs derived from UCB are seen as attractive therapeutic candidates for various human disorders including cancer. It is argued that a therapeutic stem cell transplant, using stem cells from UCB, provides a reliable repository of early precursor cells that can be useful in a large number of different conditions, considering issues of safety, availability, transplant methodology, rejection, and side effects. In particular, we focus on the concept of isolation and expansion, comparing the phenotype with MSC derived from the UCB, describing the ability to differentiate, and lastly, the therapeutic potential concerning stromal support, stemness characteristic, immune modulation, and cancer stem cell therapy. Thus it is an overview of the therapeutic application of UCB derived MSCs, with a special emphasis on cancer. Besides, the current evidence on the double-edged sword of MSCs in cancer treatment and the latest advances in UCB-derived MSC in cancer research will be discussed.
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Affiliation(s)
| | - Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh-462020, India
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15
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HLA-A2 Promotes the Therapeutic Effect of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Hyperoxic Lung Injury. Bioengineering (Basel) 2022; 9:bioengineering9040177. [PMID: 35447737 PMCID: PMC9029550 DOI: 10.3390/bioengineering9040177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/30/2022] [Accepted: 04/01/2022] [Indexed: 12/03/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are one of the most extensively studied stem cell types owing to their capacity for differentiation into multiple lineages as well as their ability to secrete regenerative factors and modulate immune functions. However, issues remain regarding their further application for cell therapy. Here, to demonstrate the superiority of the improvement of MSCs, we divided umbilical cord blood-derived MSCs (UCB-MSCs) from 15 donors into two groups based on efficacy and revealed donor-dependent variations in the anti-inflammatory effect of MSCs on macrophages as well as their immunoregulatory effect on T cells. Through surface marker analyses (242 antibodies), we found that HLA-A2 was positively related to the anti-inflammatory and immunoregulatory function of MSCs. Additionally, HLA-A2 mRNA silencing in MSCs attenuated their therapeutic effects in vitro; namely, the suppression of LPS-stimulated macrophages and phytohemagglutinin-stimulated T cells. Moreover, HLA-A2 silencing in MSCs significantly decreased their therapeutic effects in a rat model of hyperoxic lung damage. The present study provides novel insights into the quality control of donor-derived MSCs for the treatment of inflammatory conditions and diseases.
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16
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Mallis P, Chatzistamatiou T, Dimou Z, Sarri EF, Georgiou E, Salagianni M, Triantafyllia V, Andreakos E, Stavropoulos-Giokas C, Michalopoulos E. Mesenchymal stromal cell delivery as a potential therapeutic strategy against COVID-19: Promising evidence from in vitro results. World J Biol Chem 2022; 13:47-65. [PMID: 35432769 PMCID: PMC8966500 DOI: 10.4331/wjbc.v13.i2.47] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/28/2021] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic, which was initiated in December 2019. COVID-19 is characterized by a low mortality rate (< 6%); however, this percentage is higher in elderly people and patients with underlying disorders. COVID-19 is characterized by mild to severe outcomes. Currently, several therapeutic strategies are evaluated, such as the use of anti-viral drugs, prophylactic treatment, monoclonal antibodies, and vaccination. Advanced cellular therapies are also investigated, thus representing an additional therapeutic tool for clinicians. Mesenchymal stromal cells (MSCs), which are known for their immunoregulatory properties, may halt the induced cytokine release syndrome mediated by SARS-CoV-2, and can be considered as a potential stem cell therapy. AIM To evaluate the immunoregulatory properties of MSCs, upon stimulation with COVID-19 patient serum. METHODS MSCs derived from the human Wharton's Jelly (WJ) tissue and bone marrow (BM) were isolated, cryopreserved, expanded, and defined according to the criteria outlined by the International Society for Cellular Therapies. Then, WJ and BM-MSCs were stimulated with a culture medium containing 15% COVID-19 patient serum, 1% penicillin-streptomycin, and 1% L-glutamine for 48 h. The quantification of interleukin (IL)-1 receptor a (Ra), IL-6, IL-10, IL-13, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF)-a, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and indoleamine-2,3-dioxygenase (IDO) was performed using commercial ELISA kits. The expression of HLA-G1, G5, and G7 was evaluated in unstimulated and stimulated WJ and BM-MSCs. Finally, the interactions between MSCs and patients' macrophages were established using co-culture experiments. RESULTS Thawed WJ and BM-MSCs exhibited a spindle-shaped morphology, successfully differentiated to "osteocytes", "adipocytes", and "chondrocytes", and in flow cytometric analysis were characterized by positivity for CD73, CD90, and CD105 (> 95%) and negativity for CD34, CD45, and HLA-DR (< 2%). Moreover, stimulated WJ and BM-MSCs were characterized by increased cytoplasmic granulation, in comparison to unstimulated cells. The HLA-G isoforms (G1, G5, and G7) were successfully expressed by the unstimulated and stimulated WJ-MSCs. On the other hand, only weak expression of HLA-G1 was identified in BM-MSCs. Stimulated MSCs secreted high levels of IL-1Ra, IL-6, IL-10, IL-13, TGF-β1, FGF, VEGF, PDGF, and IDO in comparison to unstimulated cells (P < 0.05) after 12 and 24 h. Finally, macrophages derived from COVID-19 patients successfully adapted the M2 phenotype after co-culturing with stimulated WJ and BM-MSCs. CONCLUSION WJ and BM-MSCs successfully produced high levels of immunoregulatory agents, which may efficiently modulate the over-activated immune responses of critically ill COVID-19 patients.
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Affiliation(s)
- Panagiotis Mallis
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | | | - Zetta Dimou
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Eirini-Faidra Sarri
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Eleni Georgiou
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Maria Salagianni
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Vasiliki Triantafyllia
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Evangelos Andreakos
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | | | - Efstathios Michalopoulos
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
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17
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Saito Y, Miyajima M, Yamamoto S, Miura N, Sato T, Kita A, Ijima S, Fujimiya M, Chikenji TS. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:644-658. [PMID: 35466994 PMCID: PMC9216504 DOI: 10.1093/stcltm/szac021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 03/06/2022] [Indexed: 11/15/2022] Open
Affiliation(s)
- Yuki Saito
- Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Maki Miyajima
- Graduate School of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Sena Yamamoto
- Graduate School of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Norihiro Miura
- Graduate School of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Tsukasa Sato
- Graduate School of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Arisa Kita
- Department of Plastic and Reconstructive Surgery, Sapporo Medical University, Sapporo, Japan
| | - Shogo Ijima
- Department of Oral Surgery, Sapporo Medical University, Sapporo, Japan
| | - Mineko Fujimiya
- Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takako S Chikenji
- Corresponding author: Takako S. Chikenji, PhD. , North 12 West 5, Kitaku, Sapporo 060-0812, Japan. Tel: +011 706 3382; Fax: +011 706 3382;
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Calcat-i-Cervera S, Sanz-Nogués C, O'Brien T. When Origin Matters: Properties of Mesenchymal Stromal Cells From Different Sources for Clinical Translation in Kidney Disease. Front Med (Lausanne) 2021; 8:728496. [PMID: 34616756 PMCID: PMC8488400 DOI: 10.3389/fmed.2021.728496] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022] Open
Abstract
Advanced therapy medicinal products (ATMPs) offer new prospects to improve the treatment of conditions with unmet medical needs. Kidney diseases are a current major health concern with an increasing global prevalence. Chronic renal failure appears after many years of impairment, which opens a temporary window to apply novel therapeutic approaches to delay or halt disease progression. The immunomodulatory, anti-inflammatory, and pro-regenerative properties of mesenchymal stromal cells (MSCs) have sparked interest for their use in cell-based regenerative therapies. Currently, several early-phase clinical trials have been completed and many are ongoing to explore MSC safety and efficacy in a wide range of nephropathies. However, one of the current roadblocks to the clinical translation of MSC therapies relates to the lack of standardization and harmonization of MSC manufacturing protocols, which currently hinders inter-study comparability. Studies have shown that cell culture processing variables can have significant effects on MSC phenotype and functionality, and these are highly variable across laboratories. In addition, heterogeneity within MSC populations is another obstacle. Furthermore, MSCs may be isolated from several sources which adds another variable to the comparative assessment of outcomes. There is now a growing body of literature highlighting unique and distinctive properties of MSCs according to the tissue origin, and that characteristics such as donor, age, sex and underlying medical conditions may alter the therapeutic effect of MSCs. These variables must be taken into consideration when developing a cell therapy product. Having an optimal scale-up strategy for MSC manufacturing is critical for ensuring product quality while minimizing costs and time of production, as well as avoiding potential risks. Ideally, optimal scale-up strategies must be carefully considered and identified during the early stages of development, as making changes later in the bioprocess workflow will require re-optimization and validation, which may have a significant long-term impact on the cost of the therapy. This article provides a summary of important cell culture processing variables to consider in the scale-up of MSC manufacturing as well as giving a comprehensive review of tissue of origin-specific biological characteristics of MSCs and their use in current clinical trials in a range of renal pathologies.
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Affiliation(s)
| | | | - Timothy O'Brien
- Regenerative Medicine Institute (REMEDI), CÚRAM, Biomedical Science Building, National University of Ireland, Galway, Ireland
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19
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PTX-3 Secreted by Intra-Articular-Injected SMUP-Cells Reduces Pain in an Osteoarthritis Rat Model. Cells 2021; 10:cells10092420. [PMID: 34572070 PMCID: PMC8466059 DOI: 10.3390/cells10092420] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/10/2021] [Accepted: 09/11/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are accessible, abundantly available, and capable of regenerating; they have the potential to be developed as therapeutic agents for diseases. However, concerns remain in their further application. In this study, we developed a SMall cell+Ultra Potent+Scale UP cell (SMUP-Cell) platform to improve whole-cell processing, including manufacturing bioreactors and xeno-free solutions for commercialization. To confirm the superiority of SMUP-Cell improvements, we demonstrated that a molecule secreted by SMUP-Cells is capable of polarizing inflammatory macrophages (M1) into their anti-inflammatory phenotype (M2) at the site of injury in a pain-associated osteoarthritis (OA) model. Lipopolysaccharide-stimulated macrophages co-cultured with SMUP-Cells expressed low levels of M1-phenotype markers (CD11b, tumor necrosis factor-α, interleukin-1α, and interleukin-6), but high levels of M2 markers (CD163 and arginase-1). To identify the paracrine action underlying the anti-inflammatory effect of SMUP-Cells, we employed a cytokine array and detected increased levels of pentraxin-related protein-3 (PTX-3). Additionally, PTX-3 mRNA silencing was applied to confirm PTX-3 function. PTX-3 silencing in SMUP-Cells significantly decreased their therapeutic effects against monosodium iodoacetate (MIA)-induced OA. Thus, PTX-3 expression in injected SMUP-Cells, applied as a therapeutic strategy, reduced pain in an OA model.
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20
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Gonçalves AI, Vinhas A, Rodrigues MT, Gomes ME. The impact of cryopreservation in signature markers and immunomodulatory profile of tendon and ligament derived cells. J Cell Physiol 2021; 237:675-686. [PMID: 34368976 DOI: 10.1002/jcp.30540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 06/09/2021] [Accepted: 07/10/2021] [Indexed: 11/07/2022]
Abstract
Tendon and ligament (T/L) engineering strategies towards clinical practice have been challenged by a paucity of understanding in the identification and still poorly described characterization of cellular niches. Prospecting how resident cell populations behave in vitro, and how cryopreservation may influence T/ L-promoting factors, can provide insights into T/ L-cellular profiles for novel regenerative solutions. Therefore, we studied human T/ L-derived cells isolated from patellar tendons and cruciate ligaments as suitable cellular models to anticipate tendon and ligament niches responses for advanced strategies with predictive tenogenic and ligamentogenic value. Our results show that the crude populations isolated from tendon and ligament tissues hold a stem cell subset and share a similar behavior in terms of tenogenic/ligamentogenic commitment. Both T/ L-derived cells successfully undergo cryopreservation/thawing maintaining the tenogenic/ligamentogenic profiles. The major differences between cryopreserved and fresh populations were observed at the gene expression of MKX, SCX, and TNMD as well as at the protein levels of collagen type I and III, in which cells from tendon origin (hTDCs) evidence increased values in comparison to the ones from ligament (hLDCs, p < 0.05). In addition, low-temperature storage was shown to potentiate an immunomodulatory profile of cells, especially in hTDCs leading to an increase in the gene expression of the anti-inflammatory factors IL-4 and IL-10 (p < 0.05), as well as in the protein secretion of IL-10 (p < 0.01) and IL-4 (p < 0.001). Overall, the outcomes highlight the relevance of the cryopreserved T/ L-derived cells and their promising immunomodulatory cues as in vitro models for investigating cell-mediated mechanisms driving tissue healing and regeneration.
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Affiliation(s)
- Ana I Gonçalves
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, Barco, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Adriana Vinhas
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, Barco, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Márcia T Rodrigues
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, Barco, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Manuela E Gomes
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, Barco, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
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21
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Positively Correlated CD47 Activation and Autophagy in Umbilical Cord Blood-Derived Mesenchymal Stem Cells during Senescence. Stem Cells Int 2021; 2021:5582792. [PMID: 33936211 PMCID: PMC8062176 DOI: 10.1155/2021/5582792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/15/2021] [Accepted: 03/26/2021] [Indexed: 12/19/2022] Open
Abstract
Autophagy plays a critical role in stem cell maintenance and is related to cell growth and cellular senescence. It is important to find a quality-control marker for predicting senescent cells. This study verified that CD47 could be a candidate to select efficient mesenchymal stem cells (MSCs) to enhance the therapeutic effects of stem cell therapy by analyzing the antibody surface array. CD47 expression was significantly decreased during the expansion of MSCs in vitro (p < 0.01), with decreased CD47 expression correlated with accelerated senescence phenotype, which affected cell growth. UCB-MSCs transfected with CD47 siRNA significantly triggered the downregulation of pRB and upregulation of pp38, which are senescence-related markers. Additionally, autophagy-related markers, ATG5, ATG12, Beclin1, and LC3B, revealed significant downregulation with CD47 siRNA transfection. Furthermore, autophagy flux following treatment with an autophagy inducer, rapamycin, has shown that CD47 is a key player in autophagy and senescence to maintain and regulate the growth of MSCs, suggesting that CD47 may be a critical key marker for the selection of effective stem cells in cell therapy.
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22
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Fröhlich E. Therapeutic Potential of Mesenchymal Stem Cells and Their Products in Lung Diseases-Intravenous Administration versus Inhalation. Pharmaceutics 2021; 13:232. [PMID: 33562240 PMCID: PMC7915745 DOI: 10.3390/pharmaceutics13020232] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 12/13/2022] Open
Abstract
The number of publications studying the therapeutic use of stem cells has steadily increased since 2000. Compared to other applications, there has been little interest in the evaluation of mesenchymal stem cells (MSCs) and MSC-derived products (mostly extracellular vesicles) for the treatment of respiratory diseases. Due to the lack of efficient treatments for acute respiratory distress syndrome caused by infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the action of MSCs has also been studied. This review describes mode of action and use of MSCs and MSC-derived products in the treatment of lung diseases including the respective advantages and limitations of the products. Further, issues related to standardized production are addressed. Administration by inhalation of MSCs, compared to intravenous injection, could decrease cell damage by shear stress, eliminate the barrier to reach target cells in the alveoli, prevent thrombus formation in the pulmonary vasculature and retention in filter for extracorporeal membrane oxygenation. There is more feasible to deliver extracellular vesicles than MSCs with inhalers, offering the advantage of non-invasive and repeated administration by the patient. Major obstacles for comparison of results are heterogeneity of the products, differences in the treatment protocols and small study cohorts.
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Affiliation(s)
- Eleonore Fröhlich
- Center for Medical Research, Medical University of Graz, Stiftingtalstr 24, 8010 Graz, Austria; ; Tel.: +43-316-385-73011
- Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria
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23
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MSC Based Therapies to Prevent or Treat BPD-A Narrative Review on Advances and Ongoing Challenges. Int J Mol Sci 2021; 22:ijms22031138. [PMID: 33498887 PMCID: PMC7865378 DOI: 10.3390/ijms22031138] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 12/15/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) remains one of the most devastating consequences of preterm birth resulting in life-long restrictions in lung function. Distorted lung development is caused by its inflammatory response which is mainly provoked by mechanical ventilation, oxygen toxicity and bacterial infections. Dysfunction of resident lung mesenchymal stem cells (MSC) represents one key hallmark that drives BPD pathology. Despite all progress in the understanding of pathomechanisms, therapeutics to prevent or treat BPD are to date restricted to a few drugs. The limited therapeutic efficacy of established drugs can be explained by the fact that they fail to concurrently tackle the broad spectrum of disease driving mechanisms and by the huge overlap between distorted signal pathways of lung development and inflammation. The great enthusiasm about MSC based therapies as novel therapeutic for BPD arises from the capacity to inhibit inflammation while simultaneously promoting lung development and repair. Preclinical studies, mainly performed in rodents, raise hopes that there will be finally a broadly acting, efficient therapy at hand to prevent or treat BPD. Our narrative review gives a comprehensive overview on preclinical achievements, results from first early phase clinical studies and challenges to a successful translation into the clinical setting.
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24
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Kwon JH, Kim M, Um S, Lee HJ, Bae YK, Choi SJ, Hwang HH, Oh W, Jin HJ. Senescence-Associated Secretory Phenotype Suppression Mediated by Small-Sized Mesenchymal Stem Cells Delays Cellular Senescence through TLR2 and TLR5 Signaling. Cells 2021; 10:cells10010063. [PMID: 33401590 PMCID: PMC7824096 DOI: 10.3390/cells10010063] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/28/2020] [Accepted: 12/29/2020] [Indexed: 12/19/2022] Open
Abstract
In order to provide a sufficient number of cells for clinical use, mesenchymal stem cells (MSCs) must be cultured for long-term expansion, which inevitably triggers cellular senescence. Although the small size of MSCs is known as a critical determinant of their fate, the main regulators of stem cell senescence and the underlying signaling have not been addressed. Umbilical cord blood-derived MSCs (UCB-MSCs) were obtained using size-isolation methods and then cultured with control or small cells to investigate the major factors that modulate MSC senescence. Cytokine array data suggested that the secretion of interukin-8 (IL-8) or growth-regulated oncogene-alpha (GROa) by senescent cells was markedly inhibited during incubation of small cells along with suppression of cognate receptor (C-X-C motif chemokine receptor2, CXCR2) via blockade of the autocrine/paracrine positive loop. Moreover, signaling via toll-like receptor 2 (TLR2) and TLR5, both pattern recognition receptors, drove cellular senescence of MSCs, but was inhibited in small cells. The activation of TLRs (2 and 5) through ligand treatment induced a senescent phenotype in small cells. Collectively, our data suggest that small cell from UCB-MSCs exhibit delayed cellular senescence by inhibiting the process of TLR signaling-mediated senescence-associated secretory phenotype (SASP) activation.
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Affiliation(s)
- Ji Hye Kwon
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea; (J.H.K.); (M.K.); (S.U.); (H.J.L.); (Y.K.B.); (S.J.C.); (W.O.)
| | - Miyeon Kim
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea; (J.H.K.); (M.K.); (S.U.); (H.J.L.); (Y.K.B.); (S.J.C.); (W.O.)
| | - Soyoun Um
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea; (J.H.K.); (M.K.); (S.U.); (H.J.L.); (Y.K.B.); (S.J.C.); (W.O.)
| | - Hyang Ju Lee
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea; (J.H.K.); (M.K.); (S.U.); (H.J.L.); (Y.K.B.); (S.J.C.); (W.O.)
| | - Yun Kyung Bae
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea; (J.H.K.); (M.K.); (S.U.); (H.J.L.); (Y.K.B.); (S.J.C.); (W.O.)
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea; (J.H.K.); (M.K.); (S.U.); (H.J.L.); (Y.K.B.); (S.J.C.); (W.O.)
| | - Hyun Ho Hwang
- King Abdullah University of Science and Technology, Thuwal 47000, Makkah Province, Saudi Arabia;
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea; (J.H.K.); (M.K.); (S.U.); (H.J.L.); (Y.K.B.); (S.J.C.); (W.O.)
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea; (J.H.K.); (M.K.); (S.U.); (H.J.L.); (Y.K.B.); (S.J.C.); (W.O.)
- Correspondence:
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Um S, Ha J, Choi SJ, Oh W, Jin HJ. Prospects for the therapeutic development of umbilical cord blood-derived mesenchymal stem cells. World J Stem Cells 2020; 12:1511-1528. [PMID: 33505598 PMCID: PMC7789129 DOI: 10.4252/wjsc.v12.i12.1511] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/23/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Umbilical cord blood (UCB) is a primitive and abundant source of mesenchymal stem cells (MSCs). UCB-derived MSCs have a broad and efficient therapeutic capacity to treat various diseases and disorders. Despite the high latent self-renewal and differentiation capacity of these cells, the safety, efficacy, and yield of MSCs expanded for ex vivo clinical applications remains a concern. However, immunomodulatory effects have emerged in various disease models, exhibiting specific mechanisms of action, such as cell migration and homing, angiogenesis, anti-apoptosis, proliferation, anti-cancer, anti-fibrosis, anti-inflammation and tissue regeneration. Herein, we review the current literature pertaining to the UCB-derived MSC application as potential treatment strategies, and discuss the concerns regarding the safety and mass production issues in future applications.
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Affiliation(s)
- Soyoun Um
- Research Team for Immune Cell Therapy, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Jueun Ha
- Research Team for Osteoarthritis, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
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Human mesenchymal stem cells treatment improved hepatic lesions and reversed gut microbiome disorder in non-alcoholic steatohepatitis. Aging (Albany NY) 2020; 12:21660-21673. [PMID: 33168782 PMCID: PMC7695425 DOI: 10.18632/aging.103962] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 08/01/2020] [Indexed: 01/05/2023]
Abstract
Effective therapies for non-alcoholic steatohepatitis (NASH) are urgently needed. We investigated the effect of human mesenchymal stem cells (hMSCs) on the intestinal flora in NASH treatment. We isolated the hMSCs from the umbilical cords and divided male C57BL/6 mice into three groups, namely, chow, methionine-choline-deficient (MCD), and MCD+hMSCs. After collecting the feces and liver of the mice, we evaluated the histological changes in the liver and measured the inflammatory and fibrogenesis cytokines. Fecal microbiome and metabolome were analyzed using 16S rRNA gene sequencing analyses. The hMSCs treatment could alleviate hepatic steatosis, inflammation and fibrosis induced by MCD diet. It could also reverse the microbiome and metabolome disorders in the NASH model. Correlation analysis of the interaction among bacteria amplified the effects of the bacteria in host. In conclusion, hMSCs treatment could improve NASH-related lesions and reverse gut microbiome and metabolome disorder in NASH.
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