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Hoseini SM, Montazeri F. The influence of cell source on the senescence of human mesenchymal stem/stromal cells. Hum Cell 2025; 38:87. [PMID: 40221541 DOI: 10.1007/s13577-025-01213-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
While mesenchymal stem/stromal cells (MSCs) exhibit the ability to self-renew, they are not immortal; they eventually reach a point of irreversible growth cessation and functional deterioration following a limited series of population doublings, referred to as replicative senescence. When evaluated according to the criteria set by the International Society for Cell Therapy (ISCT), MSCs show significant differences in their senescence patterns and other characteristics related to their phenotype and function. These differences are attributed to the source of the MSCs and the conditions in which they are grown. MSCs derived from fetal or adult sources have variations in their genome stability, as well as in the expression and epigenetic profile of the cells, which in turn affects their secretome. Understanding the key factors of MSC senescence based on cell source can help to develop effective strategies for regulating senescence and improving the therapeutic potential.
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Affiliation(s)
- Seyed Mehdi Hoseini
- Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Hematology and Oncology Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Montazeri
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, No. 1. Safaeyeh. Bou-Al Ave., Yazd, 8916877391, Iran.
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2
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Ding N, Luo R, Zhang Q, Li H, Zhang S, Chen H, Hu R. Current Status and Progress in Stem Cell Therapy for Intracerebral Hemorrhage. Transl Stroke Res 2025; 16:512-534. [PMID: 38001353 DOI: 10.1007/s12975-023-01216-7] [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: 09/11/2023] [Revised: 10/23/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023]
Abstract
Intracerebral hemorrhage is a highly prevalent and prognostically poor disease, imposing immeasurable harm on human life and health. However, the treatment options for intracerebral hemorrhage are severely limited, particularly in terms of improving the microenvironment of the lesion, promoting neuronal cell survival, and enhancing neural function. This review comprehensively discussed the application of stem cell therapy for intracerebral hemorrhage, providing a systematic summary of its developmental history, types of transplants, transplantation routes, and transplantation timing. Moreover, this review presented the latest research progress in enhancing the efficacy of stem cell transplantation, including pretransplantation preconditioning, genetic modification, combined therapy, and other diverse strategies. Furthermore, this review pioneeringly elaborated on the barriers to clinical translation for stem cell therapy. These discussions were of significant importance for promoting stem cell therapy for intracerebral hemorrhage, facilitating its clinical translation, and improving patient prognosis.
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Affiliation(s)
- Ning Ding
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Ran Luo
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Qian Zhang
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Huanhuan Li
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Shuixian Zhang
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Huanran Chen
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Rong Hu
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
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Noorizadeh R, Sax B, Javaheri T, Radic-Sarikas B, Fock V, Suresh V, Kauer M, Bykov A, Kurija D, Schlederer M, Kenner L, Weber G, Mikulits W, Halbritter F, Moriggl R, Kovar H. YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1-mediated reprogramming of bone mesenchymal stem cells. Cell Rep 2025; 44:115381. [PMID: 40080499 PMCID: PMC11936874 DOI: 10.1016/j.celrep.2025.115381] [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: 08/14/2024] [Revised: 12/15/2024] [Accepted: 02/11/2025] [Indexed: 03/15/2025] Open
Abstract
Ewing sarcoma (EwS) is an aggressive cancer of adolescents in need of effective treatment. Insulin-like growth factor (IGF)-1 is an autocrine growth factor for EwS, but only 10% of patients respond to IGF-1 receptor (IGF-1R) blockade. Although EwS is presumed to originate from mesenchymal progenitors during bone development, targeting of the EwS driver oncogene EWS::FLI1 to the mesenchymal lineage in a mouse model does not result in tumor formation but in skeletal malformations and perinatal death. We report that transient exposure to IGF-1 concentrations mimicking serum levels during puberty reprograms limb-derived mesenchymal cells of EWS::FLI1-mutant mice to stable transformation and tumorigenicity. We identify a modular mechanism of IGF-1-driven tumor promotion in the early steps of EwS pathogenesis, in which Yap1 plays a central role. Pharmacologic Yap1/Tead inhibition reverses the transformed phenotype of EWS::FLI1-expressing cells. Our data provide a rationale for combined IGF-1R and YAP/TEAD inhibition in the treatment of EwS patients.
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Affiliation(s)
- Rahil Noorizadeh
- St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Barbara Sax
- Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria
| | - Tahereh Javaheri
- Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria
| | - Branka Radic-Sarikas
- St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria; Department of Pediatric Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Valerie Fock
- St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria
| | - Veveeyan Suresh
- St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria
| | - Maximilian Kauer
- St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria
| | - Aleksandr Bykov
- St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria
| | - Danijela Kurija
- Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Michaela Schlederer
- Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria; Department of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, 1090 Vienna, Austria
| | - Lukas Kenner
- Department of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, 1090 Vienna, Austria; Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; Christian Doppler Laboratory for Applied Metabolomics, Medical University of Vienna, 1090 Vienna, Austria; Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
| | - Gerhard Weber
- Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Wolfgang Mikulits
- Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Florian Halbritter
- St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria
| | - Richard Moriggl
- Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria; Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, 5020 Salzburg, Austria; Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Heinrich Kovar
- St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria; Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
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Li J, Wu M, He L. Immunomodulatory effects of mesenchymal stem cell therapy in chronic kidney disease: a literature review. BMC Nephrol 2025; 26:107. [PMID: 40033224 DOI: 10.1186/s12882-025-04029-y] [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: 12/09/2024] [Accepted: 02/19/2025] [Indexed: 03/05/2025] Open
Abstract
Chronic kidney disease (CKD) has been a growing public medical concern in recent years which calls for effective interventions. Mesenchymal stem cells (MSCs) have garnered increased interest in past decades due to their potential to repair and regenerate damaged tissues. Many clinical trials have highlighted the safety and effectiveness of kidney disease with this novel cell therapy. MSC infusion can improve renal function indices such as glomerular filtration rate, urine protein, serum creatinine, and blood urea nitrogen, while inhibiting immune response by increasing regulatory T cells. The therapeutic mechanisms may be primarily attributed to a function combined with immunomodulation, anti-inflammation, anti-fibrosis, promoting angiogenesis, anti-oxidation, anti-apoptosis, or tissue healing produced by cell secretsome. However, CKD is a broad concept due to many pathological etiologies including diabetes, hypertension, heart disease, immunological damage, a family history of renal failure, and so on. Furthermore, the therapeutic efficacy of MSCs may be influenced by different cell sources, injection methods, medication dosage, or homing proportion. As a result, it is timely and essential to access recent advancements in the MSC application on CKD.
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Affiliation(s)
- Jipeng Li
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China
| | - Mengting Wu
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China
| | - Lijie He
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China.
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Wang W, Wang Y, Gao L. Stem Cells Treatment for Subarachnoid Hemorrhage. Neurologist 2025; 30:80-86. [PMID: 39450602 DOI: 10.1097/nrl.0000000000000589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024]
Abstract
BACKGROUND Subarachnoid hemorrhage (SAH) refers to bleeding in the subarachnoid space, which is a serious neurologic emergency. However, the treatment effects of SAH are limited. In recent years, stem cell (SC) therapy has gradually become a very promising therapeutic method and advanced scientific research area for SAH. REVIEW SUMMARY The SCs used for SAH treatment are mainly bone marrow mesenchymal stem cells (BMSCs), umbilical cord mesenchymal stem cells (hUC-MSCs), dental pulp stem cells (DPSCs), neural stem cells (NSCs)/neural progenitor cell (NPC), and endothelial progenitor cell (EPC). The mechanisms mainly included differentiation and migration of SCs for tissue repair; alleviating neuronal apoptosis; anti-inflammatory effects; and blood-brain barrier (BBB) protection. The dosage of SCs was generally 10 6 orders of magnitude. The administration methods included intravenous injection, nasal, occipital foramen magnum, and intraventricular administration. The administration time is generally 1 hour after SAH modeling, but it may be as late as 24 hours or 6 days. Existing studies have confirmed the neuroprotective effect of SCs in the treatment of SAH. CONCLUSIONS SC has great potential application value in SAH treatment, a few case reports have provided support for this. However, the relevant research is still insufficient and there is still a lack of clinical research on the SC treatment for SAH to further evaluate the effectiveness and safety before it can go from experiment to clinical application.
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Affiliation(s)
| | | | - Liansheng Gao
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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John PS, John AM, Mathew J, Joshy V. Biological and Pharmacological Enhancement of Regeneration in Chronic Spinal Cord Injury. Indian J Orthop 2025; 59:438-449. [PMID: 40201914 PMCID: PMC11972996 DOI: 10.1007/s43465-024-01328-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 12/11/2024] [Indexed: 04/10/2025]
Abstract
Study Design Prospective, randomized, single-blind, comparative study. Primary Objective To compare the efficacy of multiple bone marrow implantations and co-administration of citicoline to multiple bone marrow implantations alone in the treatment of chronic Spinal Cord Injury (SCI). Setting The study was conducted at Fathima Matha Physiotherapy and Rehabilitation Center in Kottayam, India. Methods Twenty-three participants with chronic traumatic SCI, classified as American Spinal Injury Association Impairment Scale (AIS) A, B, or C, were recruited and randomized into two groups. The first group (BMCT group) received multiple intrathecal implantations of autologous non-manipulated bone marrow aspirate along with oral citicoline (Cytidine Diphosphate Choline). The second group (BM group) received only multiple intrathecal bone marrow implantations. Patients were assessed at baseline and followed up every three months for 24 months. Results Comprehensive evaluation upon completion of the treatment demonstrated statistically significant improvements in AIS, Spinal Cord Independence Measure (SCIM) score, Walking Index for Spinal Cord Injury (WISCI) score and modified Ashworth score in the BMCT group compared to the BM group. The BMCT group demonstrated statistically significant improvement in motor and sensory scores also. Fractional Anisotropy (FA) values of Diffusion Tensor Imaging (DTI) recorded statistically significant improvement in both the groups after treatment. The Diffusion Tensor Tractography (DTT) recorded considerable improvement only in the BMCT group. Conclusions This study observed statistically significant functional and neurological recovery in the BMCT group. The statistically significant increase in FA values recorded in both groups and the post-treatment improvements in DTT and MRI in the BMCT group are imaging evidences of spinal cord regeneration. Supplementary Information The online version contains supplementary material available at 10.1007/s43465-024-01328-8.
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Affiliation(s)
- P. S. John
- Fathima Matha Physiotherapy and Rehabilitation Center, Kottayam, Kerala India
| | - Ann Maria John
- Department of Orthopaedics, Government Medical College, Gandhi Nagar, P.O. Pin- 686008, Kottayam, Kerala India
| | - Jobin Mathew
- Department of Biotechnology, CMS College, Kottayam, Kerala India
| | - Vidhu Joshy
- Department of Community Medicine, Andaman & Nicobar Islands Institute of Medical Sciences, Port Blair, 744 104 India
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Yamaguchi N, Horio E, Sonoda J, Yamagishi M, Miyakawa S, Murakami F, Hasegawa H, Katahira Y, Mizoguchi I, Fujii Y, Chikazu D, Yoshimoto T. Immortalization of Mesenchymal Stem Cells for Application in Regenerative Medicine and Their Potential Risks of Tumorigenesis. Int J Mol Sci 2024; 25:13562. [PMID: 39769322 PMCID: PMC11676347 DOI: 10.3390/ijms252413562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/13/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
Regenerative medicine utilizes stem cells to repair damaged tissues by replacing them with their differentiated cells and activating the body's inherent regenerative abilities. Mesenchymal stem cells (MSCs) are adult stem cells that possess tissue repair and regenerative capabilities and immunomodulatory properties with a much lower risk of tumorigenicity, making them a focus of numerous clinical trials worldwide. MSCs primarily exert their therapeutic effects through paracrine effects via secreted factors, such as cytokines and exosomes. This has led to increasing interest in cell-free therapy, where only the conditioned medium (also called secretome) from MSC cultures is used for regenerative applications. However, MSCs face certain limitations, including cellular senescence, scarcity, donor heterogeneity, complexity, short survival post-implantation, and regulatory and ethics hurdles. To address these challenges, various types of immortalized MSCs (ImMSCs) capable of indefinite expansion have been developed. These cells offer significant promise and essential tools as a reliable source for both cell-based and cell-free therapies with the aim of translating them into practical medicine. However, the process of immortalization, often involving the transduction of immortalizing genes, poses potential risks of genetic instability and resultant malignant transformation. Cell-free therapy is particularly attractive, as it circumvents the risks of tumorigenicity and ethical concerns associated with live cell therapies. Rigorous safety tests, such as monitoring chromosomal abnormalities, are critical to ensure safety. Technologies like inducible or suicide genes may allow for the controlled proliferation of MSCs and induce apoptosis after their therapeutic task is completed. This review highlights recent advancements in the immortalization of MSCs and the associated risks of tumorigenesis.
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Affiliation(s)
- Natsuki Yamaguchi
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Eri Horio
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Jukito Sonoda
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Miu Yamagishi
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Satomi Miyakawa
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Fumihiro Murakami
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Hideaki Hasegawa
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Yasuhiro Katahira
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Izuru Mizoguchi
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Yasuyuki Fujii
- Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Daichi Chikazu
- Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Takayuki Yoshimoto
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
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Campos Gudiño R, Neudorf NM, Andromidas D, Lichtensztejn Z, McManus KJ. Loss of EMI1 compromises chromosome stability and is associated with cellular transformation in colonic epithelial cell contexts. Br J Cancer 2024; 131:1516-1528. [PMID: 39358461 PMCID: PMC11519589 DOI: 10.1038/s41416-024-02855-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/10/2024] [Accepted: 09/12/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is still a leading cause of cancer deaths worldwide. Thus, identifying the aberrant genes and proteins underlying disease pathogenesis is critical to improve early detection methods and develop novel therapeutic strategies. Chromosome instability (CIN), or ongoing changes in chromosome complements, is a predominant form of genome instability. It is a driver of genetic heterogeneity found in ~85% of CRCs. Although CIN contributes to CRC pathogenesis, the molecular determinants underlying CIN remain poorly understood. Recently, EMI1, an F-box protein, was identified as a candidate CIN gene. In this study, we sought to determine the impact reduced EMI1 expression has on CIN and cellular transformation. METHODS Coupling siRNA-based silencing and CRISPR/Cas9 knockout clones with quantitative imaging microscopy we evaluated the impact reduced EMI1 expression has on CIN and cellular transformation in four colonic epithelial cell contexts. RESULTS Quantitative imaging microscopy data revealed that reduced EMI1 expression induces increases in CIN phenotypes in both transient (siRNA) and constitutive (CRISPR/Cas9) cell models that are associated with increases in DNA damage and cellular transformation phenotypes in long-term studies. CONCLUSIONS This study determined that reduced EMI1 expression induces CIN and promotes cellular transformation, which is consistent with a role in early CRC development.
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Affiliation(s)
- Rubi Campos Gudiño
- Paul Albrechtsen Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada
- Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Nicole M Neudorf
- Paul Albrechtsen Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada
| | - Demi Andromidas
- Paul Albrechtsen Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada
- Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Zelda Lichtensztejn
- Paul Albrechtsen Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada
- Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Kirk J McManus
- Paul Albrechtsen Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada.
- Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
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Pal D, Das P, Roy S, Mukherjee P, Halder S, Ghosh D, Nandi SK. Recent trends of stem cell therapies in the management of orthopedic surgical challenges. Int J Surg 2024; 110:6330-6344. [PMID: 38716973 PMCID: PMC11487011 DOI: 10.1097/js9.0000000000001524] [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: 12/29/2023] [Accepted: 04/14/2024] [Indexed: 10/20/2024]
Abstract
Emerged health-related problems especially with increasing population and with the wider occurrence of these issues have always put the utmost concern and led medicine to outgrow its usual mode of treatment, to achieve better outcomes. Orthopedic interventions are one of the most concerning hitches, requiring advancement in several issues, that show complications with conventional approaches. Advanced studies have been undertaken to address the issue, among which stem cell therapy emerged as a better area of growth. The capacity of the stem cells to renovate themselves and adapt into different cell types made it possible to implement its use as a regenerative slant. Harvesting the stem cells, particularly mesenchymal stem cells (MSCs) is easier and can be further grown in vitro . In this review, we have discussed orthopedic-related issues including bone defects and fractures, nonunions, ligament and tendon injuries, degenerative changes, and associated conditions, which require further approaches to execute better outcomes, and the advanced strategies that can be tagged along with various ways of application of MSCs. It aims to objectify the idea of stem cells, with a major focus on the application of MSCs from different sources in various orthopedic interventions. It also discusses the limitations, and future scopes for further approaches in the field of regenerative medicine. The involvement of MSCs may transition the procedures in orthopedic interventions from predominantly surgical substitution and reconstruction to bio-regeneration and prevention. Nevertheless, additional improvements and evaluations are required to explore the effectiveness and safety of mesenchymal stem cell treatment in orthopedic regenerative medicine.
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Affiliation(s)
| | - Pratik Das
- Department of Veterinary Surgery and Radiology
| | - Subhasis Roy
- Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal
| | - Prasenjit Mukherjee
- Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal
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Shi X, Zhang K, Yu F, Qi Q, Cai X, Zhang Y. Advancements and Innovative Strategies in Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cell Therapy: A Comprehensive Review. Stem Cells Int 2024; 2024:4073485. [PMID: 39377039 PMCID: PMC11458320 DOI: 10.1155/2024/4073485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 06/24/2024] [Accepted: 09/04/2024] [Indexed: 10/09/2024] Open
Abstract
The effectiveness and safety of mesenchymal stem cell (MSC) therapy have been substantiated across various diseases. Nevertheless, challenges such as the restricted in vitro expansion capacity of tissue-derived MSCs and the clinical instability due to the high heterogeneity of isolated cells require urgent resolution. The induced pluripotent stem cell-derived MSCs (iPSC-MSCs), which is differentiated from iPSCs via specific experimental pathways, holds considerable potential as a substitute for tissue derived MSCs. Multiple studies have demonstrated that iPSCs can be differentiated into iPSC-MSCs through diverse differentiation strategies. Research suggests that iPSC-MSCs, when compared to tissue derived MSCs, exhibit superior characteristics in terms of proliferation ability, immune modulation capacity, and biological efficiency. In this review, we meticulously described and summarized the experimental methods of iPSC differentiation into iPSC-MSCs, the application of iPSC-MSCs in various disease models, the latest advancements in clinically relevant iPSC-derived cell products, and the development strategies for the next generation of iPSC-derived therapy products (not only cell products but also their derivatives).
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Affiliation(s)
- Xiaoyu Shi
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Kun Zhang
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Fengshi Yu
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Qi Qi
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Xiaoyu Cai
- State Industrial Base for Stem Cell Engineering Products, Tianjin 300384, China
| | - Yu Zhang
- VCANBIO Cell and Gene Engineering Corp. Ltd., Tianjin, China
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11
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Akabane M, Imaoka Y, Kawashima J, Endo Y, Schenk A, Sasaki K, Pawlik TM. Innovative Strategies for Liver Transplantation: The Role of Mesenchymal Stem Cells and Their Cell-Free Derivatives. Cells 2024; 13:1604. [PMID: 39404368 PMCID: PMC11475694 DOI: 10.3390/cells13191604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/11/2024] [Accepted: 09/23/2024] [Indexed: 10/19/2024] Open
Abstract
Despite being the standard treatment for end-stage liver disease, liver transplantation has limitations like donor scarcity, high surgical costs, and immune rejection risks. Mesenchymal stem cells (MSCs) and their derivatives offer potential for liver regeneration and transplantation. MSCs, known for their multipotency, low immunogenicity, and ease of obtainability, can differentiate into hepatocyte-like cells and secrete bioactive factors that promote liver repair and reduce immune rejection. However, the clinical application of MSCs is limited by risks such as aberrant differentiation and low engraftment rates. As a safer alternative, MSC-derived secretomes and extracellular vesicles (EVs) offer promising therapeutic benefits, including enhanced graft survival, immunomodulation, and reduced ischemia-reperfusion injury. Current research highlights the efficacy of MSC-derived therapies in improving liver transplant outcomes, but further studies are necessary to standardize clinical applications. This review highlights the potential of MSCs and EVs to address key challenges in liver transplantation, paving the way for innovative therapeutic strategies.
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Affiliation(s)
- Miho Akabane
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Yuki Imaoka
- Division of Abdominal Transplant, Department of Surgery, Stanford University, Stanford, CA 94305, USA; (Y.I.); (K.S.)
| | - Jun Kawashima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Yutaka Endo
- Department of Transplant Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA;
| | - Austin Schenk
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Kazunari Sasaki
- Division of Abdominal Transplant, Department of Surgery, Stanford University, Stanford, CA 94305, USA; (Y.I.); (K.S.)
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
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12
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Zhang Y, Wang C, Li JJ. Revisiting the role of mesenchymal stromal cells in cancer initiation, metastasis and immunosuppression. Exp Hematol Oncol 2024; 13:64. [PMID: 38951845 PMCID: PMC11218091 DOI: 10.1186/s40164-024-00532-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 06/26/2024] [Indexed: 07/03/2024] Open
Abstract
Immune checkpoint blockade (ICB) necessitates a thorough understanding of intricate cellular interactions within the tumor microenvironment (TME). Mesenchymal stromal cells (MSCs) play a pivotal role in cancer generation, progression, and immunosuppressive tumor microenvironment. Within the TME, MSCs encompass both resident and circulating counterparts that dynamically communicate and actively participate in TME immunosurveillance and response to ICB. This review aims to reevaluate various facets of MSCs, including their potential self-transformation to function as cancer-initiating cells and contributions to the creation of a conducive environment for tumor proliferation and metastasis. Additionally, we explore the immune regulatory functions of tumor-associated MSCs (TA-MSCs) and MSC-derived extracellular vesicles (MSC-EVs) with analysis of potential connections between circulating and tissue-resident MSCs. A comprehensive understanding of the dynamics of MSC-immune cell communication and the heterogeneous cargo of tumor-educated versus naïve MSCs may unveil a new MSC-mediated immunosuppressive pathway that can be targeted to enhance cancer control by ICB.
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Affiliation(s)
- Yanyan Zhang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Radiation Oncology, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Charles Wang
- Department of Radiation Oncology, School of Medicine, University of California Davis, Sacramento, CA, USA
| | - Jian Jian Li
- Department of Radiation Oncology, School of Medicine, University of California Davis, Sacramento, CA, USA.
- NCI-Designated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, 95817, USA.
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13
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Bak S, Kim KS, Na K. Human adipose-derived stem cells genetically programmed to induce necroptosis for cancer immunotherapy. Cancer Gene Ther 2024; 31:995-1006. [PMID: 38858535 DOI: 10.1038/s41417-024-00794-4] [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: 03/06/2024] [Revised: 05/23/2024] [Accepted: 05/29/2024] [Indexed: 06/12/2024]
Abstract
Herein, we present human adipose-derived stem cells (ADSCs) inserted with the receptor-interacting protein kinase-3 (RIP3) gene (RP@ADSCs), which induces cell necroptosis, for tumor immunotherapy. Necroptosis has characteristics of both apoptosis, such as programmed cell death, and necrosis, such as swelling and plasma membrane rupture, during which damage-related molecular patterns are released, triggering an immune response. Therefore, necroptosis has the potential to be used as an effective anticancer immunotherapy. RP@ADSCs were programmed to necroptosis after a particular time after being injected in vivo, and various pro-inflammatory cytokines secreted during the stem cell death process stimulated the immune system, showing local and sustained anticancer effects. It was confirmed that RIP3 protein expression increased in ADSCs after RP transfection. RP@ADSCs continued to induce ADSCs death for 7 days, and various pro-inflammatory cytokines were secreted through ADSCs death. The efficacy of RP@ADSCs-mediated immunotherapy was evaluated in mouse models bearing GL-26 (glioblastoma) and K1735 (melanoma), and it was found that RP resulted in an increase in the population of long-term cytotoxic T cells and a decrease in the population of regulatory T cells. This shows that RP@ADSCs have potential and applicability as an excellent anticancer immunotherapy agent in clinical practice.
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Affiliation(s)
- Soyeon Bak
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
- Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Kyoung Sub Kim
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Kun Na
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
- Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
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14
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Kim JH, Schulte AJ, Sarver AL, Lee D, Angelos MG, Frantz AM, Forster CL, O'Brien TD, Cornax I, O'Sullivan MG, Cheng N, Lewellen M, Oseth L, Kumar S, Bullman S, Pedamallu CS, Goyal SM, Meyerson M, Lund TC, Breen M, Lindblad-Toh K, Dickerson EB, Kaufman DS, Modiano JF. Hemangiosarcoma Cells Promote Conserved Host-derived Hematopoietic Expansion. CANCER RESEARCH COMMUNICATIONS 2024; 4:1467-1480. [PMID: 38757809 PMCID: PMC11166094 DOI: 10.1158/2767-9764.crc-23-0441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 02/29/2024] [Accepted: 05/10/2024] [Indexed: 05/18/2024]
Abstract
Hemangiosarcoma and angiosarcoma are soft-tissue sarcomas of blood vessel-forming cells in dogs and humans, respectively. These vasoformative sarcomas are aggressive and highly metastatic, with disorganized, irregular blood-filled vascular spaces. Our objective was to define molecular programs which support the niche that enables progression of canine hemangiosarcoma and human angiosarcoma. Dog-in-mouse hemangiosarcoma xenografts recapitulated the vasoformative and highly angiogenic morphology and molecular characteristics of primary tumors. Blood vessels in the tumors were complex and disorganized, and they were lined by both donor and host cells. In a series of xenografts, we observed that the transplanted hemangiosarcoma cells created exuberant myeloid hyperplasia and gave rise to lymphoproliferative tumors of mouse origin. Our functional analyses indicate that hemangiosarcoma cells generate a microenvironment that supports expansion and differentiation of hematopoietic progenitor populations. Furthermore, gene expression profiling data revealed hemangiosarcoma cells expressed a repertoire of hematopoietic cytokines capable of regulating the surrounding stromal cells. We conclude that canine hemangiosarcomas, and possibly human angiosarcomas, maintain molecular properties that provide hematopoietic support and facilitate stromal reactions, suggesting their potential involvement in promoting the growth of hematopoietic tumors. SIGNIFICANCE We demonstrate that hemangiosarcomas regulate molecular programs supporting hematopoietic expansion and differentiation, providing insights into their potential roles in creating a permissive stromal-immune environment for tumor progression.
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Affiliation(s)
- Jong Hyuk Kim
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
- University of Florida Health Cancer Center, University of Florida, Gainesville, Florida
- Intelligent Critical Care Center, University of Florida, Gainesville, Florida
- Artificial Intelligence Academic Initiative (AI) Center, University of Florida, Gainesville, Florida
| | - Ashley J. Schulte
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Aaron L. Sarver
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
- Institute for Health Informatics, University of Minnesota, Minneapolis, Minnesota
| | - Donghee Lee
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Mathew G. Angelos
- Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota
- Department of Medicine (Division of Hematology, Oncology, and Transplantation), Medical School, University of Minnesota, Minneapolis, Minnesota
- Microbiology, Immunology and Cancer Biology (MICaB) Graduate Program, University of Minnesota, Minneapolis, Minnesota
- Department of Medicine, Division of Hematology and Oncology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Aric M. Frantz
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
- Capstan Therapeutics, San Diego, California
| | - Colleen L. Forster
- The University of Minnesota Biological Materials Procurement Network (BioNet), University of Minnesota, Minneapolis, Minnesota
| | - Timothy D. O'Brien
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
- Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota
- Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
| | - Ingrid Cornax
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
- Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
- Janssen Research and Development, LLC
| | - M. Gerard O'Sullivan
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
- Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
| | - Nuojin Cheng
- School of Mathematics, College of Science and Engineering, University of Minnesota, Minneapolis, Minnesota
- Applied Mathematics, University of Colorado Boulder, Boulder, Colorado
| | - Mitzi Lewellen
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - LeAnn Oseth
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Sunil Kumar
- Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
| | - Susan Bullman
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Chandra Sekhar Pedamallu
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Sagar M. Goyal
- Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
| | - Matthew Meyerson
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Troy C. Lund
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
- Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, Minnesota
| | - Matthew Breen
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, and Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina
- Cancer Genetics Program, University of North Carolina Lineberger Comprehensive Cancer Center, Raleigh, North Carolina
| | - Kerstin Lindblad-Toh
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Science of Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Erin B. Dickerson
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Dan S. Kaufman
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
- Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota
- Department of Medicine (Division of Hematology, Oncology, and Transplantation), Medical School, University of Minnesota, Minneapolis, Minnesota
- Center for Immunology, University of Minnesota, Minneapolis, Minnesota
- Division of Regenerative Medicine, Department of Medicine, University of California-San Diego, La Jolla, California
| | - Jaime F. Modiano
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
- Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota
- Center for Immunology, University of Minnesota, Minneapolis, Minnesota
- Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota
- Center for Engineering in Medicine, University of Minnesota, Minneapolis, Minnesota
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15
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Kaviani M, Soleimanian S, Keshtkar S, Azarpira N, Asvar Z, Pakbaz S. Molecular Prospective on Malignant Transformation of Mesenchymal Stem Cells: An Issue in Cell Therapy. Cell Reprogram 2024; 26:96-106. [PMID: 38917438 DOI: 10.1089/cell.2024.0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2024] Open
Abstract
Mesenchymal stem cell (MSCs) therapy, as a rapidly developing area of medicine, holds great promise for the treatment of a variety of medical conditions. MSCs are multipotent stem cells that can be isolated from various tissues and could self-renew and differentiate. They secrete cytokines and trophic factors that create a regenerative microenvironment and have immunomodulatory properties. Although clinical trials have been conducted with MSCs in various diseases, concerns regarding the possibility of malignant transformation of these cells have been raised. The studies showed a higher rate of hematological malignancy and carcinogenesis in experimental models after MSC transplantation. The mechanisms underlying malignant transformation of MSCs are complex and not fully understood, but they are believed to involve the presence of special signaling molecules and alterations in cell behavior regulation pathways. Possible pathways that lead to MSCs' oncogenic transformation occur through two mechanisms: spontaneous and stimulated malignant transformation, including cell fusion, fusion proteins, and the tumor microenvironment. MSC-based therapies have the potential to revolutionize medicine, and addressing the issue of malignancy is crucial to ensure their safety and efficacy. Therefore, the purpose of the present review is to summarize the potential mechanisms of the malignant transformation of MSCs. [Figure: see text].
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Affiliation(s)
- Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeede Soleimanian
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somayeh Keshtkar
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Asvar
- Nanotechnology School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Pakbaz
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine & Pathobiology, Mount Sinai Hospital, Toronto, ON, Canada
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16
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Chen D, Zhao Z, Zhang S, Chen S, Wu X, Shi J, Liu N, Pan C, Tang Y, Meng C, Zhao X, Tao B, Liu W, Chen D, Ding H, Zhang P, Tang Z. Evolving Therapeutic Landscape of Intracerebral Hemorrhage: Emerging Cutting-Edge Advancements in Surgical Robots, Regenerative Medicine, and Neurorehabilitation Techniques. Transl Stroke Res 2024:10.1007/s12975-024-01244-x. [PMID: 38558011 DOI: 10.1007/s12975-024-01244-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/06/2024] [Accepted: 03/19/2024] [Indexed: 04/04/2024]
Abstract
Intracerebral hemorrhage (ICH) is the most serious form of stroke and has limited available therapeutic options. As knowledge on ICH rapidly develops, cutting-edge techniques in the fields of surgical robots, regenerative medicine, and neurorehabilitation may revolutionize ICH treatment. However, these new advances still must be translated into clinical practice. In this review, we examined several emerging therapeutic strategies and their major challenges in managing ICH, with a particular focus on innovative therapies involving robot-assisted minimally invasive surgery, stem cell transplantation, in situ neuronal reprogramming, and brain-computer interfaces. Despite the limited expansion of the drug armamentarium for ICH over the past few decades, the judicious selection of more efficacious therapeutic modalities and the exploration of multimodal combination therapies represent opportunities to improve patient prognoses after ICH.
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Affiliation(s)
- Danyang Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhixian Zhao
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shenglun Zhang
- School of Mechanical Science and Engineering, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shiling Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xuan Wu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jian Shi
- School of Mechanical Science and Engineering, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Na Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chao Pan
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yingxin Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Cai Meng
- School of Astronautics, Beihang University, Beijing, China
| | - Xingwei Zhao
- School of Mechanical Science and Engineering, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bo Tao
- School of Mechanical Science and Engineering, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenjie Liu
- Beijing WanTeFu Medical Instrument Co., Ltd., Beijing, China
| | - Diansheng Chen
- Institute of Robotics, School of Mechanical Engineering and Automation, Beihang University, Beijing, China
| | - Han Ding
- School of Mechanical Science and Engineering, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ping Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Zhouping Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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17
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He YC, Yuan GD, Li N, Ren MF, Qian-Zhang, Deng KN, Wang LC, Xiao WL, Ma N, Stamm C, Felthaus O, Prantl L, Nie J, Wang G. Recent advances in mesenchymal stem cell therapy for myocardial infarction. Clin Hemorheol Microcirc 2024; 87:383-398. [PMID: 38578884 DOI: 10.3233/ch-249101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2024]
Abstract
Myocardial infarction refers to the ischemic necrosis of myocardium, characterized by a sharp reduction or interruption of blood flow in the coronary arteries due to the coronary artery occlusion, resulting in severe and prolonged ischemia in the corresponding myocardium and ultimately leading to ischemic necrosis of the myocardium. Given its high risk, it is considered as one of the most serious health threats today. In current clinical practice, multiple approaches have been explored to diminish myocardial oxygen consumption and alleviate symptoms, but notable success remains elusive. Accumulated clinical evidence has showed that the implantation of mesenchymal stem cell for treating myocardial infarction is both effective and safe. Nevertheless, there persists controversy and variability regarding the standardizing MSC transplantation protocols, optimizing dosage, and determining the most effective routes of administration. Addressing these remaining issues will pave the way of integration of MSCs as a feasible mainstream cardiac treatment.
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Affiliation(s)
- Yu-Chuan He
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Guo-Dong Yuan
- Hebei Provincial Hospital of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Nan Li
- Shijiazhuang Obstetrics and Gynecology Hospital, Shijiazhuang, Hebei, China
| | - Mei-Fang Ren
- Hebei Provincial Hospital of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Qian-Zhang
- Hebei Provincial Hospital of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Kai-Ning Deng
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Le-Chuan Wang
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Wei-Ling Xiao
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Nan Ma
- Helmholtz-Zentrum Hereon, Institute of Active Polymers, Teltow, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | | | - Oliver Felthaus
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Lukas Prantl
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Jia Nie
- Hebei Provincial Hospital of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Gang Wang
- Hebei Provincial Hospital of Chinese Medicine, Shijiazhuang, Hebei, China
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18
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Merino JJ, Cabaña-Muñoz ME. Nanoparticles and Mesenchymal Stem Cell (MSC) Therapy for Cancer Treatment: Focus on Nanocarriers and a si-RNA CXCR4 Chemokine Blocker as Strategies for Tumor Eradication In Vitro and In Vivo. MICROMACHINES 2023; 14:2068. [PMID: 38004925 PMCID: PMC10673568 DOI: 10.3390/mi14112068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 10/07/2023] [Accepted: 10/13/2023] [Indexed: 11/26/2023]
Abstract
Mesenchymal stem cells (MSCs) have a high tropism for the hypoxic microenvironment of tumors. The combination of nanoparticles in MSCs decreases tumor growth in vitro as well as in rodent models of cancers in vivo. Covalent conjugation of nanoparticles with the surface of MSCs can significantly increase the drug load delivery in tumor sites. Nanoparticle-based anti-angiogenic systems (gold, silica and silicates, diamond, silver, and copper) prevented tumor growth in vitro. For example, glycolic acid polyconjugates enhance nanoparticle drug delivery and have been reported in human MSCs. Labeling with fluorescent particles (coumarin-6 dye) identified tumor cells using fluorescence emission in tissues; the conjugation of different types of nanoparticles in MSCs ensured success and feasibility by tracking the migration and its intratumor detection using non-invasive imaging techniques. However, the biosafety and efficacy; long-term stability of nanoparticles, and the capacity for drug release must be improved for clinical implementation. In fact, MSCs are vehicles for drug delivery with nanoparticles and also show low toxicity but inefficient accumulation in tumor sites by clearance of reticuloendothelial organs. To solve these problems, the internalization or conjugation of drug-loaded nanoparticles should be improved in MSCs. Finally, CXCR4 may prove to be a promising target for immunotherapy and cancer treatment since the delivery of siRNA to knock down this alpha chemokine receptor or CXCR4 antagonism has been shown to disrupt tumor-stromal interactions.
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Affiliation(s)
- José Joaquín Merino
- Departamento de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense de Madrid (U.C.M.), 28040 Madrid, Spain
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19
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Liu R, Wu S, Liu W, Wang L, Dong M, Niu W. microRNAs delivered by small extracellular vesicles in MSCs as an emerging tool for bone regeneration. Front Bioeng Biotechnol 2023; 11:1249860. [PMID: 37720323 PMCID: PMC10501734 DOI: 10.3389/fbioe.2023.1249860] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 08/21/2023] [Indexed: 09/19/2023] Open
Abstract
Bone regeneration is a dynamic process that involves angiogenesis and the balance of osteogenesis and osteoclastogenesis. In bone tissue engineering, the transplantation of mesenchymal stem cells (MSCs) is a promising approach to restore bone homeostasis. MSCs, particularly their small extracellular vesicles (sEVs), exert therapeutic effects due to their paracrine capability. Increasing evidence indicates that microRNAs (miRNAs) delivered by sEVs from MSCs (MSCs-sEVs) can alter gene expression in recipient cells and enhance bone regeneration. As an ideal delivery vehicle of miRNAs, MSCs-sEVs combine the high bioavailability and stability of sEVs with osteogenic ability of miRNAs, which can effectively overcome the challenge of low delivery efficiency in miRNA therapy. In this review, we focus on the recent advancements in the use of miRNAs delivered by MSCs-sEVs for bone regeneration and disorders. Additionally, we summarize the changes in miRNA expression in osteogenic-related MSCs-sEVs under different microenvironments.
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Affiliation(s)
| | | | | | | | - Ming Dong
- School of Stomatology, Dalian Medical University, Dalian, China
| | - Weidong Niu
- School of Stomatology, Dalian Medical University, Dalian, China
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20
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Khan S, Mahgoub S, Fallatah N, Lalor PF, Newsome PN. Liver Disease and Cell Therapy: Advances Made and Remaining Challenges. Stem Cells 2023; 41:739-761. [PMID: 37052348 PMCID: PMC10809282 DOI: 10.1093/stmcls/sxad029] [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: 04/12/2022] [Accepted: 02/27/2023] [Indexed: 04/14/2023]
Abstract
The limited availability of organs for liver transplantation, the ultimate curative treatment for end stage liver disease, has resulted in a growing and unmet need for alternative therapies. Mesenchymal stromal cells (MSCs) with their broad ranging anti-inflammatory and immunomodulatory properties have therefore emerged as a promising therapeutic agent in treating inflammatory liver disease. Significant strides have been made in exploring their biological activity. Clinical application of MSC has shifted the paradigm from using their regenerative potential to one which harnesses their immunomodulatory properties. Reassuringly, MSCs have been extensively investigated for over 30 years with encouraging efficacy and safety data from translational and early phase clinical studies, but questions remain about their utility. Therefore, in this review, we examine the translational and clinical studies using MSCs in various liver diseases and their impact on dampening immune-mediated liver damage. Our key observations include progress made thus far with use of MSCs for clinical use, inconsistency in the literature to allow meaningful comparison between different studies and need for standardized protocols for MSC manufacture and administration. In addition, the emerging role of MSC-derived extracellular vesicles as an alternative to MSC has been reviewed. We have also highlighted some of the remaining clinical challenges that should be addressed before MSC can progress to be considered as therapy for patients with liver disease.
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Affiliation(s)
- Sheeba Khan
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
| | - Sara Mahgoub
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
| | - Nada Fallatah
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Patricia F Lalor
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
| | - Philip N Newsome
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
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21
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Pan Y, Wu W, Jiang X, Liu Y. Mesenchymal stem cell-derived exosomes in cardiovascular and cerebrovascular diseases: From mechanisms to therapy. Biomed Pharmacother 2023; 163:114817. [PMID: 37141733 DOI: 10.1016/j.biopha.2023.114817] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/24/2023] [Accepted: 04/30/2023] [Indexed: 05/06/2023] Open
Abstract
Cardiovascular and cerebrovascular diseases (CVDs) remain an intractable problem and have high morbidity and mortality worldwide, as well as substantial health and economic burdens, representing an urgent clinical need. In recent years, the focus of research has shifted from the use of mesenchymal stem cells (MSCs) for transplantation to the use of their secretory exosomes (MSC-exosomes) for the treatment of numerous CVDs, including atherosclerosis, myocardial infarction (MI), heart failure (HF), ischemia/reperfusion (I/R), aneurysm, and stroke. MSCs are pluripotent stem cells with multiple differentiation pathways that exert pleiotropic effects by producing soluble factors, the most effective components of which are exosomes. MSC-exosomes are considered to be an excellent and promising cell-free therapy for CVDs due to their higher circulating stability, improved biocompatibility, reduced toxicity, and immunogenicity. In addition, exosomes play critical roles in repairing CVDs by inhibiting apoptosis, regulating inflammation, ameliorating cardiac remodeling, and promoting angiogenesis. Herein, we describe knowledge about the biological characteristics of MSC-exosomes, investigate the mechanism by which MSC-exosomes mediate therapeutic repair, and summarize recent advances in the efficacy of MSC-exosomes in CVDs, with a view toward future clinical applications.
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Affiliation(s)
- Yanhong Pan
- Department of Clinical Laboratory, The People's Hospital of Longhua Shenzhen, Shenzhen, Guangdong 518109, China.
| | - Weipeng Wu
- Department of Clinical Laboratory, Shenzhen Hospital of Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
| | - Xiaoxin Jiang
- Department of Clinical Laboratory, The People's Hospital of Longhua Shenzhen, Shenzhen, Guangdong 518109, China
| | - Yunhong Liu
- Department of Clinical Laboratory, The People's Hospital of Longhua Shenzhen, Shenzhen, Guangdong 518109, China
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22
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Zheng SP, Deng AJ, Zhou JJ, Yuan LZ, Shi X, Wang F. Endoscopic ultrasound-guided intraportal injection of autologous bone marrow in patients with decompensated liver cirrhosis: A case series. World J Gastrointest Surg 2023; 15:655-663. [PMID: 37206071 PMCID: PMC10190720 DOI: 10.4240/wjgs.v15.i4.655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 01/31/2023] [Accepted: 03/21/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Recently, stem cell therapy has been extensively studied as a promising treatment for decompensated liver cirrhosis (DLC). Technological advances in endoscopic ultrasonography (EUS) have facilitated EUS-guided portal vein (PV) access, through which stem cells can be precisely infused.
AIM To investigate the feasibility and safety of fresh autologous bone marrow injection into the PV under EUS guidance in patients with DLC.
METHODS Five patients with DLC were enrolled in this study after they provided written informed consent. EUS-guided intraportal bone marrow injection with a 22G FNA needle was performed using a transgastric, transhepatic approach. Several parameters were assessed before and after the procedure for a follow-up period of 12 mo.
RESULTS Four males and one female with a mean age of 51 years old participated in this study. All patients had hepatitis B virus-related DLC. EUS-guided intraportal bone marrow injection was performed in all patients successfully without any complications such as hemorrhage. The clinical outcomes of the patients revealed improvements in clinical symptoms, serum albumin, ascites, and Child-Pugh scores throughout the 12-mo follow-up.
CONCLUSION The use of EUS-guided fine needle injection for intraportal delivery of bone marrow was feasible and safe and appeared effective in patients with DLC. This treatment may thus be a safe, effective, non-radioactive, and minimally invasive treatment for DLC.
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Affiliation(s)
- Shao-Peng Zheng
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
- Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Central South University, Changsha 410000, Hunan Province, China
| | - Ao-Jian Deng
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
- Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Central South University, Changsha 410000, Hunan Province, China
| | - Jing-Jing Zhou
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Ling-Zhi Yuan
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
- Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Central South University, Changsha 410000, Hunan Province, China
| | - Xiao Shi
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Fen Wang
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
- Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Central South University, Changsha 410000, Hunan Province, China
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23
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Pellicer N, Cozzolino M, Diaz-García C, Galliano D, Cobo A, Pellicer A, Herraiz S. Ovarian rescue in women with premature ovarian insufficiency: facts and fiction. Reprod Biomed Online 2023; 46:543-565. [PMID: 36710157 DOI: 10.1016/j.rbmo.2022.12.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 11/16/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022]
Abstract
The ovary has a comparatively short functional lifespan compared with other organs, and genetic and pathological injuries can further shorten its functional life. Thus, preserving ovarian function should be considered in the context of women with threats to ovarian reserve, such as ageing, premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR). Indeed, one-third of women with POI retain resting follicles that can be reactivated to produce competent oocytes, as proved by the in-vitro activation of dormant follicles. This paper discusses mechanisms and clinical data relating to new therapeutic strategies using ovarian fragmentation, stem cells or platelet-rich plasma to regain ovarian function in women of older age (>38 years) or with POI or DOR. Follicle reactivation techniques show promising experimental outcomes and have been successful in some cases, when POI is established or DOR diagnosed; however, there is scarce clinical evidence to warrant their widespread clinical use. Beyond these contexts, also discussed is how new insights into the biological mechanisms governing follicular dynamics and oocyte competence may play a role in reversing ovarian damage, as no technique modifies oocyte quality. Additional studies should focus on increasing follicle number and quality. Finally, there is a small but important subgroup of women lacking residual follicles and requiring oocyte generation from stem cells.
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Affiliation(s)
| | | | - César Diaz-García
- IVI London, EGA Institute for Women's Health, UCL, London, UK; IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | | | - Ana Cobo
- IVI RMA Valencia, Valencia, Spain
| | - Antonio Pellicer
- IVI RMA Rome, Rome, Italy; IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Sonia Herraiz
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain.
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24
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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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25
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Hohenwallner K, Troppmair N, Panzenboeck L, Kasper C, El Abiead Y, Koellensperger G, Lamp LM, Hartler J, Egger D, Rampler E. Decoding Distinct Ganglioside Patterns of Native and Differentiated Mesenchymal Stem Cells by a Novel Glycolipidomics Profiling Strategy. JACS AU 2022; 2:2466-2480. [PMID: 36465531 PMCID: PMC9709940 DOI: 10.1021/jacsau.2c00230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 10/01/2022] [Accepted: 10/03/2022] [Indexed: 06/17/2023]
Abstract
Gangliosides are an indispensable glycolipid class concentrated on cell surfaces with a critical role in stem cell differentiation. Nonetheless, owing to the lack of suitable methods for scalable analysis covering the full scope of ganglioside molecular diversity, their mechanistic properties in signaling and differentiation remain undiscovered to a large extent. This work introduces a sensitive and comprehensive ganglioside assay based on liquid chromatography, high-resolution mass spectrometry, and multistage fragmentation. Complemented by an open-source data evaluation workflow, we provide automated in-depth lipid species-level and molecular species-level annotation based on decision rule sets for all major ganglioside classes. Compared to conventional state-of-the-art methods, the presented ganglioside assay offers (1) increased sensitivity, (2) superior structural elucidation, and (3) the possibility to detect novel ganglioside species. A major reason for the highly improved sensitivity is the optimized spectral readout based on the unique capability of two parallelizable mass analyzers for multistage fragmentation. We demonstrated the high-throughput universal capability of our novel analytical strategy by identifying 254 ganglioside species. As a proof of concept, 137 unique gangliosides were annotated in native and differentiated human mesenchymal stem cells including 78 potential cell-state-specific markers and 38 previously unreported gangliosides. A general increase of the ganglioside numbers upon differentiation was observed as well as cell-state-specific clustering based on the ganglioside species patterns. The combination of the developed glycolipidomics assay with the extended automated annotation tool enables comprehensive in-depth ganglioside characterization as shown on biological samples of interest. Our results suggest ganglioside patterns as a promising quality control tool for stem cells and their differentiation products. Additionally, we believe that our analytical workflow paves the way for probing glycolipid-based biochemical processes shedding light on the enigmatic processes of gangliosides and glycolipids in general.
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Affiliation(s)
- Katharina Hohenwallner
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
- Vienna
Doctoral School in Chemistry (DoSChem), University of Vienna, Vienna 1090, Austria
| | - Nina Troppmair
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
- Vienna
Doctoral School in Chemistry (DoSChem), University of Vienna, Vienna 1090, Austria
| | - Lisa Panzenboeck
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
- Vienna
Doctoral School in Chemistry (DoSChem), University of Vienna, Vienna 1090, Austria
| | - Cornelia Kasper
- Institute
of Cell and Tissue Culture Technologies, University of Natural Resources and Life Sciences, Vienna 1190, Austria
| | - Yasin El Abiead
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
| | - Gunda Koellensperger
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
| | - Leonida M. Lamp
- Institute
of Pharmaceutical Sciences, University of
Graz, Graz 8010, Austria
| | - Jürgen Hartler
- Institute
of Pharmaceutical Sciences, University of
Graz, Graz 8010, Austria
- Field
of Excellence BioHealth − University
of Graz, Graz 8010, Austria
| | - Dominik Egger
- Institute
of Cell and Tissue Culture Technologies, University of Natural Resources and Life Sciences, Vienna 1190, Austria
| | - Evelyn Rampler
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
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26
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Jafari A, Ajji Z, Mousavi A, Naghieh S, Bencherif SA, Savoji H. Latest Advances in 3D Bioprinting of Cardiac Tissues. ADVANCED MATERIALS TECHNOLOGIES 2022; 7:2101636. [PMID: 38044954 PMCID: PMC10691862 DOI: 10.1002/admt.202101636] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Indexed: 12/05/2023]
Abstract
Cardiovascular diseases (CVDs) are known as the major cause of death worldwide. In spite of tremendous advancements in medical therapy, the gold standard for CVD treatment is still transplantation. Tissue engineering, on the other hand, has emerged as a pioneering field of study with promising results in tissue regeneration using cells, biological cues, and scaffolds. Three-dimensional (3D) bioprinting is a rapidly growing technique in tissue engineering because of its ability to create complex scaffold structures, encapsulate cells, and perform these tasks with precision. More recently, 3D bioprinting has made its debut in cardiac tissue engineering, and scientists are investigating this technique for development of new strategies for cardiac tissue regeneration. In this review, the fundamentals of cardiac tissue biology, available 3D bioprinting techniques and bioinks, and cells implemented for cardiac regeneration are briefly summarized and presented. Afterwards, the pioneering and state-of-the-art works that have utilized 3D bioprinting for cardiac tissue engineering are thoroughly reviewed. Finally, regulatory pathways and their contemporary limitations and challenges for clinical translation are discussed.
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Affiliation(s)
- Arman Jafari
- Institute of Biomedical Engineering, Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, H3T 1J4, Canada
- Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, H3T 1C5, Canada
- Montreal TransMedTech Institute, Montreal, QC, H3T 1J4, Canada
| | - Zineb Ajji
- Institute of Biomedical Engineering, Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, H3T 1J4, Canada
- Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, H3T 1C5, Canada
- Montreal TransMedTech Institute, Montreal, QC, H3T 1J4, Canada
| | - Ali Mousavi
- Institute of Biomedical Engineering, Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, H3T 1J4, Canada
- Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, H3T 1C5, Canada
- Montreal TransMedTech Institute, Montreal, QC, H3T 1J4, Canada
| | - Saman Naghieh
- Division of Biomedical Engineering, College of Engineering, University of Saskatchewan, Saskatoon, SK, S7N 5A9, Canada
| | - Sidi A. Bencherif
- Department of Chemical Engineering, Northeastern University, Boston, MA 02115, United States
- Department of Bioengineering, Northeastern University, Boston, MA 02115, United States
- Sorbonne University, UTC CNRS UMR 7338, Biomechanics and Bioengineering (BMBI), University of Technology of Compiègne, 60203 Compiègne, France
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02128, United States
| | - Houman Savoji
- Institute of Biomedical Engineering, Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, H3T 1J4, Canada
- Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, H3T 1C5, Canada
- Montreal TransMedTech Institute, Montreal, QC, H3T 1J4, Canada
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27
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Micropattern-based nerve guidance conduit with hundreds of microchannels and stem cell recruitment for nerve regeneration. NPJ Regen Med 2022; 7:62. [PMID: 36261427 PMCID: PMC9582221 DOI: 10.1038/s41536-022-00257-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 10/05/2022] [Indexed: 11/12/2022] Open
Abstract
Guiding the regrowth of thousands of nerve fibers within a regeneration-friendly environment enhances the regeneration capacity in the case of peripheral nerve injury (PNI) and spinal cord injury (SCI). Although clinical treatments are available and several studies have been conducted, the development of nerve guidance conduits (NGCs) with desirable properties, including controllable size, hundreds of nerve bundle-sized microchannels, and host stem-cell recruitment, remains challenging. In this study, the micropattern-based fabrication method was combined with stem-cell recruitment factor (substance P, SP) immobilization onto the main material to produce a size-tunable NGC with hundreds of microchannels with stem-cell recruitment capability. The SP-immobilized multiple microchannels aligned the regrowth of nerve fibers and recruited the host stem cells, which enhanced the functional regeneration capacity. This method has wide applicability in the modification and augmentation of NGCs, such as bifurcated morphology or directional topographies on microchannels. Additional improvements in fabrication will advance the regeneration technology and improve the treatment of PNI/SCI.
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28
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Park KS, Bergqvist M, Lässer C, Lötvall J. Targeting Myd88 using peptide-loaded mesenchymal stem cell membrane-derived synthetic vesicles to treat systemic inflammation. J Nanobiotechnology 2022; 20:451. [PMID: 36243859 PMCID: PMC9571445 DOI: 10.1186/s12951-022-01660-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 10/07/2022] [Indexed: 11/10/2022] Open
Abstract
Mesenchymal stem cells (MSC) secrete extracellular vesicles (EV) with a regenerative profile, and an increasing number of studies have focused on the utilization of MSC-EV for therapeutic drug delivery. However, EV are usually produced by cells in low quantities and are packed with numerous cytoplasmic components, which may be unfavorable for further drug loading. In this study, we developed a simple process for generating membrane vesicles directly from the cells, which we refer to as synthetic eukaryotic vesicles (SyEV). We hypothesized that MSC-derived SyEV can be efficiently loaded with an anti-inflammatory drug and the loaded vesicles can strongly suppress the systemic inflammation induced by bacterial outer membrane vesicles (OMV). SyEV were generated from MSC membranes through serial extrusion of the cells, ionic stress, and subsequent vesiculation of the membrane sheets, leading to high yield and purity of the SyEV with few cytosolic components remaining. When these SyEV were given to macrophages or mice exposed to OMV, the release of pro-inflammatory cytokines was similarly attenuated comparable to treatment with natural EV. We then loaded the SyEV with large numbers of peptides targeting Myd88 and observed enhanced therapeutic potential of the loaded vesicles in OMV-induced macrophages. Further, in vivo experiments showed that the peptide-encapsulated MSC-SyEV suppressed cytokine production synergistically. Taken together, these findings suggest that SyEV-based therapeutics is a highly interesting platform for delivering an advanced therapeutic drug for the treatment of systemic inflammation without severe side effects.
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Affiliation(s)
- Kyong-Su Park
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | - Markus Bergqvist
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Cecilia Lässer
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jan Lötvall
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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29
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Zhang X, Ren Z, Jiang Z. EndMT-derived mesenchymal stem cells: a new therapeutic target to atherosclerosis treatment. Mol Cell Biochem 2022; 478:755-765. [PMID: 36083511 DOI: 10.1007/s11010-022-04544-8] [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: 04/22/2022] [Accepted: 08/12/2022] [Indexed: 11/28/2022]
Abstract
Cardiovascular diseases, such as coronary artery disease and stroke, are the main threats to human health worldwide. Atherosclerosis, a chronic inflammatory disorder, plays a role as an initiator of all of the above-mentioned diseases. Cell therapy for diseases has attracted widespread attention. Mesenchymal stem cells (MSCs) are a type of stem cell that still exist in adults and have the characteristics of self-renewal ability, pluripotent differentiation potential, immunomodulation, tissue regeneration, anti-inflammation and low immunogenicity. In light of the properties of MSCs, some researchers have begun to target MSCs to create a possible way to alleviate atherosclerosis. Most of these studies are focused on MSC transplantation, injecting MSCs to modulate macrophages, the key inflammatory cell in atherosclerosis plaque. According to recent studies, researchers found that endothelial-to-mesenchymal transition (EndMT) has something to do with atherosclerosis development. A new cell type MSC might also appear during the EndMT process. In this article, we summarize the characteristics of MSCs, the latest progress of MSC research and its application prospects, and in view of the process of EndMT occurring in atherosclerosis, we propose some new ideas for the treatment of atherosclerosis by targeting MSCs.
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Affiliation(s)
- Xiaofan Zhang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Zhong Ren
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Zhisheng Jiang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, China.
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30
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The secretome obtained under hypoxic preconditioning from human adipose-derived stem cells exerts promoted anti-apoptotic potentials through upregulated autophagic process. Mol Biol Rep 2022; 49:8859-8870. [PMID: 35941418 DOI: 10.1007/s11033-022-07736-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 06/14/2022] [Accepted: 06/22/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Hypoxic preconditioning (HP) is a stem cell preconditioning modality designed to augment the therapeutic effects of mesenchymal stem cells (MSCs). Although autophagy is expected to play a role in HP, very little is known regarding the relationship between HP and autophagy. METHODS AND RESULTS The adipose-derived stem cell (ASC)-secretome obtained under normoxia (NCM) and ASC-secretome obtained under HP (HCM) were obtained by culturing ASCs for 24 h under normoxic (21% partial pressure of O2) and hypoxic (1% partial pressure of O2) conditions, respectively. Subsequently, to determine the in vivo effects of HCM, each secretome was injected into 70% partially hepatectomized mice, and liver specimens were obtained. HCM significantly reduced the apoptosis of thioacetamide-treated AML12 hepatocytes and promoted the autophagic processes of the cells (P < 0.05). Autophagy blockage by either bafilomycin A1 or ATG5 siRNA significantly abrogated the anti-apoptotic effect of HCM (P < 0.05), demonstrating that HCM exerts its anti-apoptotic effect by promoting autophagy. The effect of HCM - reduction of cell apoptosis and promotion of autophagic process - was also demonstrated in a mouse model. CONCLUSIONS HP appears to induce ASCs to release a secretome with enhanced anti-apoptotic effects by promoting the autophagic process of ASCs.
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31
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Zhou JF, Xiong Y, Kang X, Pan Z, Zhu Q, Goldbrunner R, Stavrinou L, Lin S, Hu W, Zheng F, Stavrinou P. Application of stem cells and exosomes in the treatment of intracerebral hemorrhage: an update. Stem Cell Res Ther 2022; 13:281. [PMID: 35765072 PMCID: PMC9241288 DOI: 10.1186/s13287-022-02965-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 06/19/2022] [Indexed: 12/14/2022] Open
Abstract
Non-traumatic intracerebral hemorrhage is a highly destructive intracranial disease with high mortality and morbidity rates. The main risk factors for cerebral hemorrhage include hypertension, amyloidosis, vasculitis, drug abuse, coagulation dysfunction, and genetic factors. Clinically, surviving patients with intracerebral hemorrhage exhibit different degrees of neurological deficits after discharge. In recent years, with the development of regenerative medicine, an increasing number of researchers have begun to pay attention to stem cell and exosome therapy as a new method for the treatment of intracerebral hemorrhage, owing to their intrinsic potential in neuroprotection and neurorestoration. Many animal studies have shown that stem cells can directly or indirectly participate in the treatment of intracerebral hemorrhage through regeneration, differentiation, or secretion. However, considering the uncertainty of its safety and efficacy, clinical studies are still lacking. This article reviews the treatment of intracerebral hemorrhage using stem cells and exosomes from both preclinical and clinical studies and summarizes the possible mechanisms of stem cell therapy. This review aims to provide a reference for future research and new strategies for clinical treatment.
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Affiliation(s)
- Jian-Feng Zhou
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Yu Xiong
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Xiaodong Kang
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Zhigang Pan
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Qiangbin Zhu
- Department of Neurosurgery, Hui'an County Hospital of Fujian Province, Quanzhou, Fujian, China
| | - Roland Goldbrunner
- Department of Neurosurgery, Faculty of Medicine and University Hospital, Center for Neurosurgery, University of Cologne, Cologne, Germany
| | - Lampis Stavrinou
- 2nd Department of Neurosurgery, Athens Medical School, "Attikon" University Hospital, National and Kapodistrian University, Athens, Greece
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China. .,Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia.
| | - Weipeng Hu
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China.
| | - Feng Zheng
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China.
| | - Pantelis Stavrinou
- Department of Neurosurgery, Faculty of Medicine and University Hospital, Center for Neurosurgery, University of Cologne, Cologne, Germany.,Neurosurgery, Metropolitan Hospital, Athens, Greece
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Pan Y, Tan WF, Yang MQ, Li JY, Geller DA. The therapeutic potential of exosomes derived from different cell sources in liver diseases. Am J Physiol Gastrointest Liver Physiol 2022; 322:G397-G404. [PMID: 35107032 PMCID: PMC8917924 DOI: 10.1152/ajpgi.00054.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Exosomes are small nanovesicles with a size of approximately 40-120 nm that are secreted from cells. They are involved in the regulation of cell homeostasis and mediate intercellular communication. In addition, they carry proteins, nucleic acids, and lipids that regulate the biological activity of receptor cells. Recent studies have shown that exosomes perform important functions in liver diseases. This review will focus on liver diseases (drug-induced liver injury, hepatic ischemia-reperfusion injury, liver fibrosis, acute liver failure, and hepatocellular carcinoma) and summarize the therapeutic potential of exosomes from different cell sources in liver disease.
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Affiliation(s)
- Yun Pan
- 1Colorectal Cancer Center, Tenth People’s Hospital of Tongji University, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Wei-Feng Tan
- 2Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Mu-Qing Yang
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - Ji-Yu Li
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - David A. Geller
- 4Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Recent Advances in the Application of Mesenchymal Stem Cell-Derived Exosomes for Cardiovascular and Neurodegenerative Disease Therapies. Pharmaceutics 2022; 14:pharmaceutics14030618. [PMID: 35335993 PMCID: PMC8949563 DOI: 10.3390/pharmaceutics14030618] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/02/2022] [Accepted: 03/09/2022] [Indexed: 12/17/2022] Open
Abstract
Exosomes are naturally occurring nanoscale vesicles that are released and received by almost all cells in the body. Exosomes can be transferred between cells and contain various molecular constitutes closely related to their origin and function, including proteins, lipids, and RNAs. The importance of exosomes in cellular communication makes them important vectors for delivering a variety of drugs throughout the body. Exosomes are ubiquitous in the circulatory system and can reach the site of injury or disease through a variety of biological barriers. Due to its unique structure and rich inclusions, it can be used for the diagnosis and treatment of diseases. Mesenchymal stem-cell-derived exosomes (MSCs-Exo) inherit the physiological functions of MSCs, including repairing and regenerating tissues, suppressing inflammatory responses, and regulating the body’s immunity; therefore, MSCs-Exo can be used as a natural drug delivery carrier with therapeutic effects, and has been increasingly used in the treatment of cardiovascular diseases and neurodegenerative diseases. Here, we summarize the research progress of MSCs-Exo as drug delivery vectors and their application for various drug deliveries, providing ideas and references for the study of MSCs-Exo in recent years.
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Berlet R, Galang Cabantan DA, Gonzales-Portillo D, Borlongan CV. Enriched Environment and Exercise Enhance Stem Cell Therapy for Stroke, Parkinson’s Disease, and Huntington’s Disease. Front Cell Dev Biol 2022; 10:798826. [PMID: 35309929 PMCID: PMC8927702 DOI: 10.3389/fcell.2022.798826] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 02/01/2022] [Indexed: 12/12/2022] Open
Abstract
Stem cells, specifically embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (IPSCs), and neural progenitor stem cells (NSCs), are a possible treatment for stroke, Parkinson’s disease (PD), and Huntington’s disease (HD). Current preclinical data suggest stem cell transplantation is a potential treatment for these chronic conditions that lack effective long-term treatment options. Finding treatments with a wider therapeutic window and harnessing a disease-modifying approach will likely improve clinical outcomes. The overarching concept of stem cell therapy entails the use of immature cells, while key in recapitulating brain development and presents the challenge of young grafted cells forming neural circuitry with the mature host brain cells. To this end, exploring strategies designed to nurture graft-host integration will likely enhance the reconstruction of the elusive neural circuitry. Enriched environment (EE) and exercise facilitate stem cell graft-host reconstruction of neural circuitry. It may involve at least a two-pronged mechanism whereby EE and exercise create a conducive microenvironment in the host brain, allowing the newly transplanted cells to survive, proliferate, and differentiate into neural cells; vice versa, EE and exercise may also train the transplanted immature cells to learn the neurochemical, physiological, and anatomical signals in the brain towards better functional graft-host connectivity.
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Affiliation(s)
- Reed Berlet
- Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | | | | | - Cesar V. Borlongan
- Center of Excellence for Aging and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- *Correspondence: Cesar V. Borlongan,
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Egger D, Lavrentieva A, Kugelmeier P, Kasper C. Physiologic isolation and expansion of human mesenchymal stem/stromal cells for manufacturing of cell-based therapy products. Eng Life Sci 2022; 22:361-372. [PMID: 35382547 PMCID: PMC8961040 DOI: 10.1002/elsc.202100097] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 10/13/2021] [Accepted: 10/15/2021] [Indexed: 01/04/2023] Open
Abstract
The utilization of mesenchymal stem/stromal cells raises new hopes in treatment of diseases and pathological conditions, while at the same time bringing immense challenges for researchers, manufacturers and physicians. It is essential to consider all steps along the in vitro fabrication of cell-based products in order to reach efficient and reproducible treatment outcomes. Here, the optimal protocols for isolation, cultivation and differentiation of mesenchymal stem cells are required. In this review we discuss these aspects and their influence on the final cell-based product quality. We demonstrate that physiological in vitro cell cultivation conditions play a crucial role in therapeutic functionalities of cultivated cells. We show that three-dimensional cell culture, dynamic culture conditions and physiologically relevant in vitro oxygen concentrations during isolation and expansion make a decisive contribution towards the improvement of cell-based products in regenerative medicine.
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Affiliation(s)
- Dominik Egger
- Department of BiotechnologyUniversity of Natural Resources and Life ScienceViennaAustria
| | | | | | - Cornelia Kasper
- Department of BiotechnologyUniversity of Natural Resources and Life ScienceViennaAustria
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Damerell V, Ambele MA, Salisbury S, Neumann-Mufweba A, Durandt C, Pepper MS, Prince S. The c-Myc/TBX3 Axis Promotes Cellular Transformation of Sarcoma-Initiating Cells. Front Oncol 2022; 11:801691. [PMID: 35145908 PMCID: PMC8821881 DOI: 10.3389/fonc.2021.801691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/30/2021] [Indexed: 11/23/2022] Open
Abstract
Sarcomas are highly aggressive cancers of mesenchymal origin whose clinical management is highly complex. This is partly due to a lack of understanding of the molecular mechanisms underpinning the transformation of mesenchymal stromal/stem cells (MSCs) which are presumed to be the sarcoma-initiating cells. c-Myc is amplified/overexpressed in a range of sarcomas where it has an established oncogenic role and there is evidence that it contributes to the malignant transformation of MSCs. T-box transcription factor 3 (TBX3) is upregulated by c-Myc in a host of sarcoma subtypes where it promotes proliferation, tumor formation, migration, and invasion. This study investigated whether TBX3 is a c-Myc target in human MSCs (hMSCs) and whether overexpressing TBX3 in hMSCs can phenocopy c-Myc overexpression to promote malignant transformation. Using siRNA, qRT-PCR, luciferase reporter and chromatin-immunoprecipitation assays, we show that c-Myc binds and directly activates TBX3 transcription in hMSCs at a conserved E-box motif. When hMSCs were engineered to stably overexpress TBX3 using lentiviral gene transfer and the resulting cells characterised in 2D and 3D, the overexpression of TBX3 was shown to promote self-renewal, bypass senescence, and enhance proliferation which corresponded with increased levels of cell cycle progression markers (cyclin A, cyclin B1, CDK2) and downregulation of the p14ARF/MDM2/p53 tumor suppressor pathway. Furthermore, TBX3 promoted the migratory and invasive ability of hMSCs which associated with increased levels of markers of migration (Vimentin, SLUG, SNAIL, TWIST1) and invasion (MMP2, MMP9). Transcriptomic analysis revealed that genes upregulated upon TBX3 overexpression overlapped with c-myc targets, were involved in cell cycle progression, and were associated with sarcomagenesis. Together, the data described indicate that the c-Myc/TBX3 oncogenic molecular pathway may be a key mechanism that transforms hMSCs into sarcomas.
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Affiliation(s)
- Victoria Damerell
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Melvin Anyasi Ambele
- Department of Immunology and SAMRC Extramural Unit for Stem Research and Therapy, Faculty of Health Sciences, Institute for Cellular and Molecular Medicine, University of Pretoria, Pretoria, South Africa
- Department of Oral Pathology and Oral Biology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Shanel Salisbury
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Alexis Neumann-Mufweba
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Chrisna Durandt
- Department of Immunology and SAMRC Extramural Unit for Stem Research and Therapy, Faculty of Health Sciences, Institute for Cellular and Molecular Medicine, University of Pretoria, Pretoria, South Africa
| | - Michael Sean Pepper
- Department of Immunology and SAMRC Extramural Unit for Stem Research and Therapy, Faculty of Health Sciences, Institute for Cellular and Molecular Medicine, University of Pretoria, Pretoria, South Africa
| | - Sharon Prince
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- *Correspondence: Sharon Prince,
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Mesenchymal Stem Cell-Based Therapy as a New Approach for the Treatment of Systemic Sclerosis. Clin Rev Allergy Immunol 2022; 64:284-320. [PMID: 35031958 DOI: 10.1007/s12016-021-08892-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2021] [Indexed: 12/13/2022]
Abstract
Systemic sclerosis (SSc) is an intractable autoimmune disease with unmet medical needs. Conventional immunosuppressive therapies have modest efficacy and obvious side effects. Targeted therapies with small molecules and antibodies remain under investigation in small pilot studies. The major breakthrough was the development of autologous haematopoietic stem cell transplantation (AHSCT) to treat refractory SSc with rapidly progressive internal organ involvement. However, AHSCT is contraindicated in patients with advanced visceral involvement. Mesenchymal stem cells (MSCs) which are characterized by immunosuppressive, antifibrotic and proangiogenic capabilities may be a promising alternative option for the treatment of SSc. Multiple preclinical and clinical studies on the use of MSCs to treat SSc are underway. However, there are several unresolved limitations and safety concerns of MSC transplantation, such as immune rejections and risks of tumour formation, respectively. Since the major therapeutic potential of MSCs has been ascribed to their paracrine signalling, the use of MSC-derived extracellular vesicles (EVs)/secretomes/exosomes as a "cell-free" therapy might be an alternative option to circumvent the limitations of MSC-based therapies. In the present review, we overview the current knowledge regarding the therapeutic efficacy of MSCs in SSc, focusing on progresses reported in preclinical and clinical studies using MSCs, as well as challenges and future directions of MSC transplantation as a treatment option for patients with SSc.
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Zhang W, Wei L, Weng J, Yu F, Qin H, Wang D, Zeng H. Advances in the Research of Osteosarcoma Stem Cells and its Related Genes. Cell Biol Int 2021; 46:336-343. [PMID: 34941001 DOI: 10.1002/cbin.11752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 11/29/2021] [Accepted: 12/12/2021] [Indexed: 11/07/2022]
Abstract
Osteosarcoma is a malignant tumor that often occurs in adolescents. There is an urgent need of new treatment options for osteosarcoma due to its poor prognosis after metastasis. Cancer stem cell theory states that cancer stem cells represent a small proportion of cancer cells. These cancer stem cells have self-renewal ability and are closely associated with cancer growth and metastasis as well as chemotherapy resistance. Similarly, osteosarcoma stem cells (OSCs) play an important role in the growth, metastasis, and chemotherapy resistance of osteosarcoma cells. Targeting OSCs may represent a future treatment of osteosarcoma. Furthermore, some genes have shown to regulate the growth, metastasis, and chemotherapy resistance of osteosarcoma cells by altering the stemness of OSCs. Targeting these genes may help in the treatment of osteosarcoma. This review mainly discusses recent advances in the research of OSCs and its related genes. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Weifei Zhang
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Liangchen Wei
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Jian Weng
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Fei Yu
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Haotian Qin
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Deli Wang
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
| | - Hui Zeng
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036.,National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, PR China, 518036
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Muthu S, Kartheek RR, Jeyaraman N, Rajendran RL, Khanna M, Jeyaraman M, Packkyarathinam RP, Gangadaran P, Ahn BC. Is Culture Expansion Necessary in Autologous Mesenchymal Stromal Cell Therapy to Obtain Superior Results in the Management of Knee Osteoarthritis?-Meta-Analysis of Randomized Controlled Trials. Bioengineering (Basel) 2021; 8:bioengineering8120220. [PMID: 34940373 PMCID: PMC8698637 DOI: 10.3390/bioengineering8120220] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/10/2021] [Accepted: 12/15/2021] [Indexed: 02/05/2023] Open
Abstract
Study Design: Meta-analysis. Objectives: We aimed to analyze the impact of cultured expansion of autologous mesenchymal stromal cells (MSCs) in the management of osteoarthritis of the knee from randomized controlled trials (RCTs) available in the literature. Materials and Methods: We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library until August 2021 for RCTs analyzing the efficacy and safety of culture-expanded compared to non-cultured autologous MSCs in the management of knee osteoarthritis. The Visual Analog Score (VAS) for pain, Western Ontario McMaster University's Osteoarthritis Index (WOMAC), Lysholm score, Knee Osteoarthritis Outcome Score (KOOS), and adverse events were the analyzed outcomes. Analysis was performed in R-platform using OpenMeta [Analyst] software. Results: Overall, 17 studies involving 767 patients were included for analysis. None of the studies made a direct comparison of the culture expanded and non-cultured MSCs, hence we pooled the results of all the included studies of non-cultured and cultured types of MSC sources and made a comparative analysis of the outcomes. At six months, culture expanded MSCs showed significantly better improvement (p < 0.001) in VAS outcome. Uncultured MSCs, on the other hand, demonstrated significant VAS improvement in the long term (12 months) in VAS (p < 0.001), WOMAC (p = 0.025), KOOS score (p = 0.016) where cultured-expanded MSCs failed to demonstrate a significant change. Culturing of MSCs did not significantly increase the complications noted (p = 0.485). On sub-group analysis, adipose-derived uncultured MSCs outperformed culture-expanded MSCs at both short term (six months) and long term (12 months) in functional outcome parameters such as WOMAC (p < 0.001, p = 0.025), Lysholm (p < 0.006), and KOOS (p < 0.003) scores, respectively, compared to their controls. Conclusions: We identified a void in literature evaluating the impact of culture expansion of MSCs for use in knee osteoarthritis. Our indirect analysis of literature showed that culture expansion of autologous MSCs is not a necessary factor to obtain superior results in the management of knee osteoarthritis. Moreover, while using uncultured autologous MSCs, we recommend MSCs of adipose origin to obtain superior functional outcomes. However, we urge future trials of sufficient quality to validate our findings to arrive at a consensus on the need for culture expansion of MSCs for use in cellular therapy of knee osteoarthritis.
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Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624001, Tamil Nadu, India;
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
| | - Randhi Rama Kartheek
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226010, Uttar Pradesh, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, Atlas Hospitals, Tiruchirappalli 620002, Tamil Nadu, India
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Department of Orthopaedics, Prasad Institute of Medical Sciences, Lucknow 226401, Uttar Pradesh, India
| | - Madhan Jeyaraman
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Department of Orthopaedics, Faculty of Medicine—Sri Lalithambigai Medical College and Hospital, Dr. MGR Educational and Research Institute, Chennai 600095, Tamil Nadu, India
- Correspondence: (M.J.); (R.P.P.); (P.G.); (B.-C.A.)
| | - Rathinavelpandian Perunchezhian Packkyarathinam
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India; (R.R.K.); (N.J.); (M.K.)
- Department of Orthopaedics, Government Medical College, Omandurar Government Estate, Chennai 600002, Tamil Nadu, India
- Correspondence: (M.J.); (R.P.P.); (P.G.); (B.-C.A.)
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Korea
- Correspondence: (M.J.); (R.P.P.); (P.G.); (B.-C.A.)
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Korea
- Correspondence: (M.J.); (R.P.P.); (P.G.); (B.-C.A.)
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Palmer MCL, Neudorf NM, Farrell AC, Razi T, Lichtensztejn Z, McManus KJ. The F-box protein, FBXO7 is required to maintain chromosome stability in humans. Hum Mol Genet 2021; 31:1471-1486. [PMID: 34791250 PMCID: PMC9071473 DOI: 10.1093/hmg/ddab330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/06/2021] [Accepted: 11/08/2021] [Indexed: 11/19/2022] Open
Abstract
Despite the high morbidity and mortality rates associated with colorectal cancer (CRC), the aberrant genes and mechanisms driving CRC pathogenesis remain poorly understood. Chromosome instability (CIN), or ongoing changes in chromosome numbers, is a predominant form of genome instability associated with ~85% of CRCs, suggesting it may be a key mechanism driving CRC oncogenesis. CIN enables the acquisition of copy number alterations conferring selective growth, proliferation and survival advantages that promote cellular transformation. Despite these associations, the aberrant genes underlying CIN remain largely unknown. Candidate CIN gene FBXO7 encodes an F-box protein, a subunit of the SKP1-CUL1-FBOX (SCF) complex that confers substrate specificity to the complex and targets proteins for subsequent degradation by the 26S proteasome. Recently, the genes encoding the three core SCF complex members were identified as CIN genes; however, it is unknown whether F-box proteins exhibit similar integral roles in maintaining chromosome stability. Using short- small interfering RNA (siRNA) and long- (CRISPR/Cas9) term approaches, we show that reduced FBXO7 expression induces CIN in various colonic epithelial cell contexts, whereas FBXO7 knockout clones also exhibit hallmarks associated with cellular transformation, namely increased clonogenic and anchorage-independent growth. Collectively, these data demonstrate that FBXO7 is required to maintain genome stability identifying FBXO7 a novel CIN gene whose reduced expression may contribute to CRC development and progression.
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Affiliation(s)
- Michaela C L Palmer
- CancerCare Manitoba Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada.,Department of Biochemistry & Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Nicole M Neudorf
- CancerCare Manitoba Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada.,Department of Biochemistry & Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Ally C Farrell
- CancerCare Manitoba Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada.,Department of Biochemistry & Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Tooba Razi
- CancerCare Manitoba Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada.,Department of Biochemistry & Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Zelda Lichtensztejn
- CancerCare Manitoba Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada.,Department of Biochemistry & Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Kirk J McManus
- CancerCare Manitoba Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada.,Department of Biochemistry & Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
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Zhang DY, Monteiro MJ, Liu JP, Gu WY. Mechanisms of cancer stem cell senescence: Current understanding and future perspectives. Clin Exp Pharmacol Physiol 2021; 48:1185-1202. [PMID: 34046925 DOI: 10.1111/1440-1681.13528] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 05/24/2021] [Indexed: 12/13/2022]
Abstract
Cancer stem cells (CSCs) are a small population of heterogeneous tumor cells with the capacity of self-renewal and aberrant differentiation for immortality and divergent lineages of cancer cells. In contrast to bulky tumor cells, CSCs remain less differentiated and resistant to therapy even when targeted with tissue-specific antigenic markers. This makes CSCs responsible for not only tumor initiation, development, but also tumor recurrence. Emerging evidence suggests that CSCs can undergo cell senescence, a non-proliferative state of cells in response to stress. While cell senescence attenuates tumor cell proliferation, it is commonly regarded as a tumor suppressive mechanism. However, mounting research indicates that CSC senescence also provides these cells with the capacity to evade cytotoxic effects from cancer therapy, exacerbating cancer relapse and metastasis. Recent studies demonstrate that senescence drives reprogramming of cancer cell toward stemness and promotes CSC generation. In this review, we highlight the origin, heterogeneity and senescence regulatory mechanisms of CSCs, the complex relationship between CSC senescence and tumor therapy, and the recent beneficial effects of senotherapy on eliminating senescent tumor cells.
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Affiliation(s)
- Da-Yong Zhang
- Department of Clinical Medicine, Zhejiang University City College, Hangzhou, China
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD, Australia
| | - Michael J Monteiro
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD, Australia
| | - Jun-Ping Liu
- Institute of Ageing Research, Hangzhou Normal University, Hangzhou, China
- Department of Immunology, Monash University Faculty of Medicine, Prahran, Vic, Australia
- Hudson Institute of Medical Research, and Department of Molecular and Translational Science, Monash University Faculty of Medicine, Clayton, Vic, Australia
| | - Wen-Yi Gu
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD, Australia
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Parathyroid hormone promotes the osteogenesis of lipopolysaccharide-induced human bone marrow mesenchymal stem cells through the JNK MAPK pathway. Biosci Rep 2021; 41:229448. [PMID: 34350461 PMCID: PMC8380916 DOI: 10.1042/bsr20210420] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 07/02/2021] [Accepted: 08/03/2021] [Indexed: 11/23/2022] Open
Abstract
Periodontitis is a series of inflammatory processes caused by bacterial infection. Parathyroid hormone (PTH) plays a critical role in bone remodeling. The present study aimed to investigate the influences of PTH on human bone marrow mesenchymal stem cells (HBMSCs) pretreated with lipopolysaccharide (LPS). The proliferative ability was measured using cell counting kit-8 (CCK-8) and flow cytometry. The optimal concentrations of PTH and LPS were determined using alkaline phosphatase (ALP) activity assay, ALP staining, and Alizarin Red staining. Osteogenic differentiation was further assessed by quantitative reverse-transcription polymerase chain reaction (RT-qPCR), Western blot analysis, and immunofluorescence staining. PTH had no effects on the proliferation of HBMSCs. Also, 100 ng/ml LPS significantly inhibited HBMSC osteogenesis, while 10−9 mol/l PTH was considered as the optimal concentration to reverse the adverse effects. Mechanistically, c-Jun N-terminal kinase (JNK) phosphorylation was activated by PTH in LPS-induced HBMSCs. SP600125, a selective inhibitor targeting JNK mitogen-activated protein kinase (MAPK) signaling, weakened the effects of PTH. Taken together, the findings revealed the role and mechanism of PTH and JNK pathway in promoting the osteogenic differentiation of LPS-induced HBMSCs, which offered an alternative for treating periodontal diseases.
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Kirwin T, Gomes A, Amin R, Sufi A, Goswami S, Wang B. Mechanisms underlying the therapeutic potential of mesenchymal stem cells in atherosclerosis. Regen Med 2021; 16:669-682. [PMID: 34189963 DOI: 10.2217/rme-2021-0024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory condition resulting in the formation of fibrofatty plaques within the intimal layer of arterial walls. The identification of resident stem cells in the vascular wall has led to significant investigation into their contributions to health and disease, as well as their therapeutic potential. Of these, mesenchymal stem cells (MSCs) are the most widely studied in human clinical trials, which have demonstrated a modulatory role in vascular physiology and disease. This review highlights the most recent knowledge surrounding the cell biology of MSCs, including their origin, identification markers and differentiation potential. The limitations concerning the implementation of MSC therapy are considered and novel solutions to overcome these are proposed.
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Affiliation(s)
- Thomas Kirwin
- Department of Medicine, Imperial College London, SW7 2BU, UK.,College of Medical & Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Ana Gomes
- Department of Medicine, Imperial College London, SW7 2BU, UK
| | - Ravi Amin
- Department of Medicine, Imperial College London, SW7 2BU, UK
| | - Annam Sufi
- Department of Medicine, Imperial College London, SW7 2BU, UK.,GKT School of Medical Education, King's College London, London, SE1 1UL, UK
| | - Sahil Goswami
- Department of Medicine, Imperial College London, SW7 2BU, UK.,Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, E1 2AD, UK
| | - Brian Wang
- Department of Medicine, Imperial College London, SW7 2BU, UK
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Metwally AM, Li H, Houghton JM. Alterations of epigenetic regulators and P53 mutations in murine mesenchymal stem cell cultures: A possible mechanism of spontaneous transformation. Cancer Biomark 2021; 32:327-337. [PMID: 34151835 DOI: 10.3233/cbm-203121] [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: 11/15/2022]
Abstract
BACKGROUND Recent studies demonstrated the involvement of mesenchymal stem/stromal cells (MSCs) in carcinogenesis, but the molecular mechanism behind this transformation is still obscured. OBJECTIVE To screen both the expression levels of polycomb and trithorax epigenetic regulators and TrP53 mutations in early and late MSC culture passages in an attempt to decipher the mechanism of spontaneous transformation. METHODS The study was conducted on early and late passages of MSC culture model from C57BL/6J mice. The expression profile of 84 epigenetic regulators was examined using RT2 profiler PCR array. TrP53 mutations in the DNA binding domain was screened. Codons, amino acids positions and the corresponding human variants were detected in P53 sequences. RESULTS Sixty-two epigenetic regulators were dysregulated. Abnormalities were detected starting the third passage. Nine regulators were dysregulated in all passages. (C>G) substitution P53 mutation was detected in passage 3 resulting in Ser152Arg substitution. Passages 6, 9, 12 and the last passage showed T>C substitution resulting in Cys235Arg substitution. The last passage had T deletion and A insertion resulting in frame shift mutations changing the p.Phe286Ser and p.Asn103Lys respectively. CONCLUSION In vitro expanded MSCs undergo transformation through alteration of epigenetic regulators which results in genomic instability and frequent P53 mutations.
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Affiliation(s)
- Ayman Mohamed Metwally
- Technology of Medical Laboratory Department, College of Applied Health Science Technology, Misr University for Science and Technology, Egypt.,Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Hanchen Li
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Jean Marie Houghton
- Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
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Sun J, Huang J, Bao G, Zheng H, Wang C, Wei J, Fu Y, Qiu J, Liao Y, Cai J. MRI detection of the malignant transformation of stem cells through reporter gene expression driven by a tumor-specific promoter. Stem Cell Res Ther 2021; 12:284. [PMID: 33980305 PMCID: PMC8117323 DOI: 10.1186/s13287-021-02359-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 04/27/2021] [Indexed: 01/10/2023] Open
Abstract
Background Existing evidence has shown that mesenchymal stem cells (MSCs) can undergo malignant transformation, which is a serious limitation of MSC-based therapies. Therefore, it is necessary to monitor malignant transformation of MSCs via a noninvasive imaging method. Although reporter gene-based magnetic resonance imaging (MRI) has been successfully applied to longitudinally monitor MSCs, this technique cannot distinguish the cells before and after malignant transformation. Herein, we investigated the feasibility of using a tumor-specific promoter to drive reporter gene expression for MRI detection of the malignant transformation of MSCs. Methods The reporter gene ferritin heavy chain (FTH1) was modified by adding a promoter from the tumor-specific gene progression elevated gene-3 (PEG3) and transduced into MSCs to obtain MSCs-PEG3-FTH1. Cells were induced to undergo malignant transformation via indirect coculture with C6 glioma cells, and these transformed cells were named MTMSCs-PEG3-FTH1. Western blot analysis of FTH1 expression, Prussian blue staining and transmission electron microscopy (TEM) to detect intracellular iron, and MRI to detect signal changes were performed before and after malignant transformation. Then, the cells before and after malignant transformation were inoculated subcutaneously into nude mice, and MRI was performed to observe the signal changes in the xenografts. Results After induction of malignant transformation, MTMSCs demonstrated tumor-like features in morphology, proliferation, migration, and invasion. FTH1 expression was significantly increased in MTMSCs-PEG3-FTH1 compared with MSCs-PEG3-FTH1. Prussian blue staining and TEM showed a large amount of iron particles in MTMSCs-PEG3-FTH1 but a minimal amount in MSCs-PEG3-FTH1. MRI demonstrated that the T2 value was significantly decreased in MTMSCs-PEG3-FTH1 compared with MSCs-PEG3-FTH1. In vivo, mass formation was observed in the MTMSCs-PEG3-FTH1 group but not the MSCs-PEG3-FTH1 group. T2-weighted MRI showed a significant signal decrease, which was correlated with iron accumulation in the tissue mass. Conclusions We developed a novel MRI model based on FTH1 reporter gene expression driven by the tumor-specific PEG3 promoter. This approach could be applied to sensitively detect the occurrence of MSC malignant transformation.
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Affiliation(s)
- Jun Sun
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China.,Department of Radiology, Chongqing University Central Hospital, Chongqing, 400014, China
| | - Jie Huang
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China
| | - Guangcheng Bao
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China
| | - Helin Zheng
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Cui Wang
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Jie Wei
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China
| | - Yuanqiao Fu
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China
| | - Jiawen Qiu
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China
| | - Yifan Liao
- Department of Nuclear Medicine, Xinqiao Hospital affiliated with Third Military Medical University, Chongqing, 400037, China
| | - Jinhua Cai
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. .,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China. .,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China. .,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China.
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Kang SH, Kim MY, Eom YW, Baik SK. Mesenchymal Stem Cells for the Treatment of Liver Disease: Present and Perspectives. Gut Liver 2021; 14:306-315. [PMID: 31581387 PMCID: PMC7234888 DOI: 10.5009/gnl18412] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 12/14/2018] [Accepted: 12/23/2018] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cell transplantation is an emerging therapy for treating chronic liver diseases. The potential of this treatment has been evaluated in preclinical and clinical studies. Although the mechanisms of mesenchymal stem cell transplantation are still not completely understood, accumulating evidence has revealed that their immunomodulation, differentiation, and antifibrotic properties play a crucial role in liver regeneration. The safety and therapeutic effects of mesenchymal stem cells in patients with chronic liver disease have been observed in many clinical studies. However, only modest improvements have been seen, partly because of the limited feasibility of transplanted cells at present. Here, we discuss several strategies targeted at improving viable cell engraftment and the potential challenges in the use of extracellular vesicle-based therapies for liver disease in the future.
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Affiliation(s)
- Seong Hee Kang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Institute of Evidence Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Young Woo Eom
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Institute of Evidence Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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47
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Yang Q, Zhou Y, Wang T, Cai P, Fu W, Wang J, Li X. MiRNA-1271-5p regulates osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by targeting forkhead box O1 (FOXO1). Cell Biol Int 2021; 45:1468-1476. [PMID: 33675274 DOI: 10.1002/cbin.11585] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/03/2021] [Accepted: 02/27/2021] [Indexed: 12/13/2022]
Abstract
Forkhead box O1 (FOXO1) is a key regulator of osteogenesis. The aim of this study was to identify the mechanisms of microRNAs (miRNAs) targeting FOXO1 in osteogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs). Three miRNA target prediction programs were used to search for potential miRNAs that target FOXO1. Quantitative real-time polymerase chain reaction was conducted to detect the expression of miR-1271-5p and FOXO1 during osteogenic differentiation. Target gene prediction and screening, luciferase reporter assay was used to verify the downstream target gene of miR-1271-5p. The expression levels of FOXO1 and Runx2 were detected by RT-qPCR and Western blot analysis. Alkaline phosphatase (ALP) activity and matrix mineralization were detected by biochemical methods. The expression levels of Runx2, ALP, and osteocalcin were detected by RT-qPCR. Our results showed that miR-1271-5p was downregulated during osteogenic induction. And the expression levels of miR-1271-5p were higher in osteoporotic tissues than that in adjacent nonosteoporotic tissues. The expression levels of FOXO1 were lower in osteoporotic tissues than that in adjacent nonosteoporotic tissues. And a negative correlation was found between miR-1271-5p and FOXO1 in osteoporotic tissues. Overexpression of miR-1271-5p downregulated FOXO1 and inhibited osteogenic differentiation in hMSCs. Overexpression of miR-1271-5p downregulated the expression of osteogenic markers and reduced ALP activity. In addition, ectopic expression of FOXO1 reversed the effect of miR-1271-5p on osteogenic differentiation. In conclusion, miR-1271-5p functioned as a therapeutic target of osteogenic differentiation in hMSCs by inhibiting FOXO1, which provides valuable insights into the use of miR-1271-5p as a target in the treatment of osteoporosis and other bone metabolic diseases.
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Affiliation(s)
- Qining Yang
- Department of Joint surgery, The affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua City, Zhejiang Province, China
| | - Yongwei Zhou
- Department of Joint surgery, The affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua City, Zhejiang Province, China
| | - Tianbao Wang
- Department of Joint surgery, The affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua City, Zhejiang Province, China
| | - Pengfei Cai
- Department of Joint surgery, The affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua City, Zhejiang Province, China
| | - Weicong Fu
- Department of Joint surgery, The affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua City, Zhejiang Province, China
| | - Jinhua Wang
- Department of Joint surgery, The affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua City, Zhejiang Province, China
| | - Xiaofei Li
- Department of Joint surgery, The affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua City, Zhejiang Province, China
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Abstract
Being the second leading cause of death globally, cancer has been a long-standing and rapidly evolving focus of biomedical research and practice in the world. A tremendous effort has been made to understand the origin of cancer cells, the formation of cancerous tissues, and the mechanism by which they spread and relapse, but the disease still remains mysterious. Here, we made an attempt to scrutinize evidences that indicate the role of stem cells in tumorigenesis and metastasis, and cancer relapse. We also looked into the influence of cancers on stem cells, which in turn represent a major constituent of tumor microenvironment. Based on current understandings of the properties of (cancer) stem cells and their relation to cancers, we can foresee that novel therapeutic approaches would become the next wave of cancer treatment.
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Affiliation(s)
- Wen Yin
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Sichuan 610041, China
| | - Jialing Wang
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Sichuan 610041, China
| | - Linling Jiang
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Sichuan 610041, China
| | - Y James Kang
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Sichuan 610041, China.,Memphis Institute of Regenerative Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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49
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Mesenchymal stromal cells for corneal transplantation: Literature review and suggestions for successful clinical trials. Ocul Surf 2021; 20:185-194. [PMID: 33607323 PMCID: PMC9878990 DOI: 10.1016/j.jtos.2021.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 01/28/2023]
Abstract
Corneal transplantation is a routine procedure for patients with corneal blindness. Despite the streamlining of surgical techniques and deeper understanding of the cellular and molecular pathways mediating rejection, corticosteroids are still the main immunosuppressive regimen in corneal transplantation, and the 15-year survival of corneal transplants remains as low as 50%, which is poorer than that for most solid organ transplants. Recently, mesenchymal stromal cells (MSCs) with unique regenerative and immune-modulating properties have emerged as a promising cell therapy to promote transplant tolerance, minimize the use of immunosuppressants, and prevent chronic rejection. Here, we review the literature on preclinical studies of MSCs for corneal transplantation and summarize the key findings from clinical trials with MSCs in solid organ transplantation. Finally, we highlight current issues and challenges regarding MSC therapies and suggest strategies for safe and effective MSC-based therapies in clinical transplantation.
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50
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Zhang J, Qin X, Deng Y, Lu J, Li Z, Feng Y, Yan X, Chen M, Gao L, Xu Y, Shi D, Lu F. Transforming Growth Factor-β1 Enhances Mesenchymal Characteristics of Buffalo ( Bubalus bubalis) Bone Marrow-Derived Mesenchymal Stem Cells. Cell Reprogram 2021; 23:127-138. [PMID: 33861638 DOI: 10.1089/cell.2020.0093] [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] [Indexed: 11/13/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) from livestock are valuable resources for animal reproduction and veterinary therapeutics. Previous studies have shown that BMSCs were prone to malignant transformation of mesenchymal-to-epithelial transition in vitro, which can cause many barriers to further application of BMSCs. The transforming growth factor β (TGF-β) signaling pathway has been widely studied as the most important signaling pathway involved in regulating mesenchymal features of BMSCs. However, the effects of the TGF-β signaling pathway on mesenchymal characteristics of buffalo BMSCs (bBMSCs) remain unclear. In the present study, the impacts of the growth factor, TGF-β1, on cell proliferation, apoptosis, migration, and karyotype of bBMSCs were tested. Besides, the effects of TGF-β1 on pluripotency, mesenchymal markers, and epithelial-to-mesenchymal transition (EMT)-related gene expression of bBMSCs were also examined. Results showed that the suitable concentration and time of TGF-β1 treatment (2 ng/mL and 24 hours) promoted cell proliferation and significantly reduced cell apoptosis (p < 0.05) in bBMSCs. The cell migration capacity and normal karyotype rate of bBMSCs were significantly (p < 0.05) improved under TGF-β1 treatment. The expression levels of pluripotency-related genes (Sox2 and Nanog) and mesenchymal markers (N-cadherin and Fn1) were significantly (p < 0.05) up-regulated under TGF-β1 treatment. Furthermore, TGF-β1 activated the EMT process, thereby contributing to significantly enhancing the expression levels of EMT-related genes (Snail and Slug) (p < 0.05), which in turn improved maintenance of the mesenchymal nature in bBMSCs. Finally, bBMSCs underwent self-transformation more easily and efficiently and exhibited more characteristics of mesenchymal stem cells under TGF-β1 treatment. This study provides theoretical guidance for elucidating the detailed mechanism of the TGF-β signaling pathway in mesenchymal feature maintenance of bBMSCs and is of significance to establish a stable culture system of bBMSCs.
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Affiliation(s)
- Jun Zhang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Xiling Qin
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Yanfei Deng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Jiaka Lu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Zhengda Li
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Yun Feng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Xi Yan
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Mengjia Chen
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Lv Gao
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Ye Xu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Deshun Shi
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
| | - Fenghua Lu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning, China
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