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Lan D, Zhang D, Dai X, Cai J, Zhou H, Song T, Wang X, Kong Q, Tang Z, Tan J, Zhang J. Mesenchymal stem cells and exosomes: A novel therapeutic approach for aging. Exp Gerontol 2025; 206:112781. [PMID: 40349806 DOI: 10.1016/j.exger.2025.112781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 05/05/2025] [Accepted: 05/07/2025] [Indexed: 05/14/2025]
Abstract
Mesenchymal stem cells (MSCs), a vital component of the adult stem cell repertoire, are distinguished by their dual capacity for self-renewal and multilineage differentiation. The therapeutic effects of MSCs are primarily mediated through mechanisms such as homing, paracrine signaling, and cellular differentiation. Exosomes (Exos), a type of extracellular vesicles (EVs) secreted by MSCs via the paracrine pathway, play a pivotal role in conveying the biological functions of MSCs. Accumulating evidence from extensive research underscores the remarkable anti-aging potential of both MSCs and their Exos. This review comprehensively explores the impact of MSCs and their Exos on key hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Furthermore, this paper highlights emerging strategies and novel approaches for modulating the aging process, offering insights into potential therapeutic interventions.
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Affiliation(s)
- Dongfeng Lan
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi 563000, China
| | - Dan Zhang
- Zunyi Medical University Library, Zunyi 563000, China
| | - Xiaofang Dai
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi 563000, China
| | - Ji Cai
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi 563000, China
| | - He Zhou
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi 563000, China
| | - Tao Song
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi 563000, China
| | - Xianyao Wang
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi 563000, China
| | - Qinghong Kong
- Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines, Zunyi Medical University, Zunyi 563000, China
| | - Zhengzhen Tang
- Department of Pediatrics, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi 563000, China.
| | - Jun Tan
- Department of Histology and Embryology, Zunyi Medical University, Zunyi 563000, China.
| | - Jidong Zhang
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi 563000, China; Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China.
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Hoang VT, Nguyen QT, Phan TTK, Pham TH, Dinh NTH, Anh LPH, Dao LTM, Bui VD, Dao H, Le DS, Ngo ATL, Le Q, Nguyen Thanh L. Tissue Engineering and Regenerative Medicine: Perspectives and Challenges. MedComm (Beijing) 2025; 6:e70192. [PMID: 40290901 PMCID: PMC12022429 DOI: 10.1002/mco2.70192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 12/30/2024] [Accepted: 03/04/2025] [Indexed: 04/30/2025] Open
Abstract
From the pioneering days of cell therapy to the achievement of bioprinting organs, tissue engineering, and regenerative medicine have seen tremendous technological advancements, offering solutions for restoring damaged tissues and organs. However, only a few products and technologies have received United States Food and Drug Administration approval. This review highlights significant progress in cell therapy, extracellular vesicle-based therapy, and tissue engineering. Hematopoietic stem cell transplantation is a powerful tool for treating many diseases, especially hematological malignancies. Mesenchymal stem cells have been extensively studied. The discovery of induced pluripotent stem cells has revolutionized disease modeling and regenerative applications, paving the way for personalized medicine. Gene therapy represents an innovative approach to the treatment of genetic disorders. Additionally, extracellular vesicle-based therapies have emerged as rising stars, offering promising solutions in diagnostics, cell-free therapeutics, drug delivery, and targeted therapy. Advances in tissue engineering enable complex tissue constructs, further transforming the field. Despite these advancements, many technical, ethical, and regulatory challenges remain. This review addresses the current bottlenecks, emphasizing novel technologies and interdisciplinary research to overcome these hurdles. Standardizing practices and conducting clinical trials will balance innovation and regulation, improving patient outcomes and quality of life.
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Affiliation(s)
- Van T. Hoang
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Quyen Thi Nguyen
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Trang Thi Kieu Phan
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Trang H. Pham
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Nhung Thi Hong Dinh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Le Phuong Hoang Anh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Lan Thi Mai Dao
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Van Dat Bui
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- School of Chemical EngineeringCollege of EngineeringSungkyunkwan University (SKKU)SuwonRepublic of Korea
| | - Hong‐Nhung Dao
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Duc Son Le
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Anh Thi Lan Ngo
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Quang‐Duong Le
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
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Xu K, Yang M, Guan L, Yang C, Qiao L, Li Y, Lin J, Li X. Therapeutic Potential of Mesenchymal Stem Cells in Niemann-Pick Disease. Mol Biotechnol 2025:10.1007/s12033-025-01435-3. [PMID: 40281376 DOI: 10.1007/s12033-025-01435-3] [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: 07/17/2024] [Accepted: 04/03/2025] [Indexed: 04/29/2025]
Abstract
Niemann-Pick disease (NPD) is a rare autosomal recessive neurodegenerative disease characterized by hepatosplenomegaly, neuropathy, and a significantly shortened lifespan. Lipid metabolism disorder is the main pathological feature of NPD. Currently, the exact pathogenesis of NPD remains unclear, and drug therapy is largely palliative, focusing on symptom management, but it has side effects. Mesenchymal stem cells (MSCs) possess several advantageous properties, including their differentiation potential, wide availability, low immunogenicity, and the ability to secrete regulatory factors, which have led to their extensive application in basic research targeting neurodegenerative diseases. Studies have demonstrated that transplantation of MSCs from different sources into animal models of NPD can delay the loss of Purkinje cells in the cerebellum, reduce lipid deposition, improve motor coordination, slow the rate of weight loss, and extend lifespan. This review explores the therapeutic potential of MSCs in the treatment of NPD, highlighting their emerging role in addressing this challenging condition.
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Affiliation(s)
- Keli Xu
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Minlin Yang
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Lihong Guan
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Ciqing Yang
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Liang Qiao
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Yonghai Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Juntang Lin
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Henan International Joint Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
| | - Xiaoying Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
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Ramalingam M, Jang S, Hwang J, Cho HH, Kim BC, Jeong HS. Neural-induced human adipose tissue-derived stem cell secretome exerts neuroprotection against rotenone-induced Parkinson's disease in rats. Stem Cell Res Ther 2025; 16:193. [PMID: 40254594 PMCID: PMC12010609 DOI: 10.1186/s13287-025-04306-5] [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: 09/09/2024] [Accepted: 04/01/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Parkinson's disease (PD) is a multifactorial disease that involves genetic and environmental factors, which play an essential role in the pathogenesis of PD. Mesenchymal stem cells release a set of bioactive molecules called "secretome" that regulates intercellular communication and cargo transfer in signaling pathways for PD treatment. Thus, this study aimed to evaluate the neuroprotective effects of neural-induced human adipose tissue-derived stem cell (NI-hADSC)-conditioned medium (NI-hADSC-CM) and its exosomes (NI-hADSC-Exo) in a rotenone (ROT)-induced model of PD in rats. METHODS The NI-hADSC-CM was collected from NI-hADSC after 14 days of neural differentiation, and its NI-hADSC-Exo were isolated using a tangential flow filtration system. ROT (1 mg/kg) was subcutaneously administered for 28 days to establish a model of PD in rats. The treatment of NI-hADSC-CM or NI-hADSC-Exo was intravenously injected on days 15, 18, 21, 24, and 27. Animal behavioral effects were explored via a rotarod test. After 28 days, histological and western blot analyses were performed to investigate the tyrosine hydroxylase (TH), α-synuclein (α-syn) aggregation, and downstream signaling pathways for experimental validation. RESULTS NI-hADSC-Exo improved the motor balance and coordination skills against ROT toxicity. ROT reproduced the pathological features of PD, such as a decrease in TH-positive dopaminergic neurons and an increase in α-syn aggregation and glial fibrillary acidic protein (GFAP)-positive cells. NI-hADSC-CM and NI-hADSC-Exo improved the TH expression, decreased the Triton X-100 soluble and insoluble oligomeric p-S129 α-syn, and influenced the differential reactivity to astrocytes and microglia. Secretome treatment could reverse the ROT-induced damages in the neuronal structural and functional proteins, mitochondrial apoptosis, and caspase cascade. The treatment of NI-hADSC-CM and NI-hADSC-Exo ameliorated the ROT toxicity-induced serine-threonine protein kinase dysregulation and autophagy impairment to clear the aggregated α-syn. CONCLUSIONS NI-hADSC-CM and NI-hADSC-Exo significantly exerted neuroprotection by decreasing α-syn toxicity, inhibiting neuroinflammation and apoptosis, restoring autophagic flux properties, and promoting the neuronal function in ROT-injected rats; however, the influence of these treatments on signaling pathways differed slightly between the midbrain and striatum regions. Targeting α-syn degradation pathways provides a novel strategy to elucidate the beneficial effects of MSC secretome and future safe cell-free treatments for PD.
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Affiliation(s)
- Mahesh Ramalingam
- Department of Physiology, Chonnam National University Medical School, Hwasun, 58128, Republic of Korea.
| | - Sujeong Jang
- Department of Physiology, Chonnam National University Medical School, Hwasun, 58128, Republic of Korea.
| | - Jinsu Hwang
- Department of Physiology, Chonnam National University Medical School, Hwasun, 58128, Republic of Korea
| | - Hyong-Ho Cho
- Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea
| | - Byeong C Kim
- Department of Neurology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea
| | - Han-Seong Jeong
- Department of Physiology, Chonnam National University Medical School, Hwasun, 58128, Republic of Korea.
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Volarevic A, Harrell CR, Arsenijevic A, Djonov V, Volarevic V. Therapeutic Potential of Mesenchymal Stem Cell-Derived Extracellular Vesicles in the Treatment of Parkinson's Disease. Cells 2025; 14:600. [PMID: 40277925 PMCID: PMC12025905 DOI: 10.3390/cells14080600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/11/2025] [Accepted: 04/12/2025] [Indexed: 04/26/2025] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the gradual loss of dopamine-producing neurons. Oxidative stress, mitochondrial dysfunction, detrimental immune response, and neuroinflammation are mainly responsible for the injury and degeneration of dopaminergic neurons in the brains of patients suffering from PD. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic approach for treating PD due to their ability to suppress the activation of inflammatory immune cells and enhance the viability and function of dopamine-producing neurons. MSC-EVs can easily bypass the blood-brain barrier and deliver their cargo (neuroprotective factors, immunosuppressive proteins, and microRNAs) to injured dopamine-producing neurons and brain-infiltrated inflammatory immune cells. A large number of recently published experimental studies demonstrated that MSC-EVs efficiently alleviated PD-related motor and behavioral deficits in animal models, indicating that MSC-EVs should be considered as potentially new therapeutic agents for the treatment of PD. Accordingly, in this review article, we summarized current knowledge about the therapeutic potential of MSCs-EVs in the treatment of PD, paving the way for their future clinical use in the treatment of neurodegenerative and neuroinflammatory disorders.
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Affiliation(s)
- Ana Volarevic
- Departments of Psychology, Center for Research on Harmful Effects of Biological and Chemical Hazards, Faculty of Medical Sciences University of Kragujevac, 69 Svetozara Markovica Street, 34000 Kragujevac, Serbia;
| | - Carl Randall Harrell
- Regenerative Processing Plant, LLC, 34176 US Highway 19 N, Palm Harbor, FL 34684, USA
| | - Aleksandar Arsenijevic
- Departments of Genetics, Microbiology and Immunology, Center for Research on Harmful Effects of Biological and Chemical Hazards, Faculty of Medical Sciences University of Kragujevac, 69 Svetozara Markovica Street, 34000 Kragujevac, Serbia;
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012 Bern, Switzerland;
| | - Vladislav Volarevic
- Departments of Genetics, Microbiology and Immunology, Center for Research on Harmful Effects of Biological and Chemical Hazards, Faculty of Medical Sciences University of Kragujevac, 69 Svetozara Markovica Street, 34000 Kragujevac, Serbia;
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Tew VK, Barathan M, Nordin F, Law JX, Ng MH. Emerging Role of Mesenchymal Stromal Cell and Exosome Therapies in Treating Cognitive Impairment. Pharmaceutics 2025; 17:284. [PMID: 40142948 PMCID: PMC11945939 DOI: 10.3390/pharmaceutics17030284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/27/2024] [Accepted: 01/09/2025] [Indexed: 03/28/2025] Open
Abstract
Cognitive aging, characterized by the gradual decline in cognitive functions such as memory, attention, and problem-solving, significantly impacts daily life. This decline is often accelerated by neurodegenerative diseases, particularly Alzheimer's Disease (AD) and Parkinson's Disease (PD). AD is marked by the accumulation of amyloid-beta plaques and tau tangles, whereas PD involves the degeneration of dopaminergic neurons. Both conditions lead to severe cognitive impairment, greatly diminishing the quality of life for affected individuals. Recent advancements in regenerative medicine have highlighted mesenchymal stromal cells (MSCs) and their derived exosomes as promising therapeutic options. MSCs possess regenerative, neuroprotective, and immunomodulatory properties, which can promote neurogenesis, reduce inflammation, and support neuronal health. Exosomes, nanosized vesicles derived from MSCs, provide an efficient means for delivering bioactive molecules across the blood-brain barrier, targeting the underlying pathologies of AD and PD. While these therapies hold great promise, challenges such as variability in MSC sources, optimal dosing, and effective delivery methods need to be addressed for clinical application. The development of robust protocols, along with rigorous clinical trials, is crucial for validating the safety and efficacy of MSC and exosome therapies. Future research should focus on overcoming these barriers, optimizing treatment strategies, and exploring the integration of MSC and exosome therapies with lifestyle interventions. By addressing these challenges, MSC- and exosome-based therapies could offer transformative solutions for improving outcomes and enhancing the quality of life for individuals affected by cognitive aging and neurodegenerative diseases.
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Affiliation(s)
| | | | | | | | - Min Hwei Ng
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia (F.N.); (J.X.L.)
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Kumar R, Mahajan S, Gupta U, Madan J, Godugu C, Guru SK, Singh PK, Parvatikar P, Maji I. Stem cell therapy as a novel concept to combat CNS disorders. TARGETED THERAPY FOR THE CENTRAL NERVOUS SYSTEM 2025:175-206. [DOI: 10.1016/b978-0-443-23841-3.00009-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Yang Q, Zhou Y, Farooq W, Liu Q, Duan J, Xing L, Wu C, Dong L. The immunomodulatory effects of Mesenchymal stem cells on THP-1-derived macrophages against Mycobacterium tuberculosis H37Ra infection. Tuberculosis (Edinb) 2025; 150:102593. [PMID: 39709721 DOI: 10.1016/j.tube.2024.102593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND Immune imbalance is crucial in tuberculosis pathogenesis and may be modulated by mesenchymal stem cells (MSCs). However, how MSCs regulate the host's response to Mycobacterium tuberculosis (Mtb) is unclear. METHODS Human umbilical cord-derived MSCs were co-cultured with Mtb-infected THP-1 macrophages. The intracellular release of ROS in macrophages was measured by DCFH-DA. Cytokine expression was measured by RT-qPCR, apoptosis by Annexin V/PI assay, and pyroptosis markers by Western blotting. Differentially expressed genes (DEGs) in Mtb-infected THP-1 co-cultured with or without MSCs were identified by RNA-seq and potential signaling pathways were analyzed through bioinformatics. RESULTS The fibroblastic morphology of MSCs exhibited 95 % positivity for CD73, CD90, and CD105, while the positivity rate for negative marker HLA-DR was less than 2 %. In Mtb-infected THP-1 macrophages, co-culturing with MSCs increased ROS release, cytokines expression (IL-1β, IL-6, TNF-α), apoptosis, and pyroptosis markers (NLRP3, Caspase-1, and GSDMD). Comparative transcriptome analysis identified 347 up-regulated and 291 down-regulated DEGs, primarily associated with receptor-ligand interactions and enriched in cytokine signaling pathways including JAK-STAT, TNF, ferroptosis, and autophagy. CONCLUSION MSCs could enhance the macrophages' immune response to Mtb by activating immune receptors and inflammatory signaling pathways.
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Affiliation(s)
- Qianwei Yang
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Yiqun Zhou
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Waqas Farooq
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Qimiao Liu
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Jinhui Duan
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Li Xing
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Changxin Wu
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
| | - Li Dong
- Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, and Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
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Liu H, Cui D, Huangfu S, Wang X, Yu X, Yang H, Zheng X, Li Y, Bi J, Zhang L, Wang P. VCAM-1 + Mesenchymal Stem/Stromal Cells Reveal Preferable Efficacy Upon an Experimental Autoimmune Encephalomyelitis Mouse Model of Multiple Sclerosis Over the VCAM-1 - Counterpart. Neurochem Res 2024; 50:40. [PMID: 39613932 PMCID: PMC11607028 DOI: 10.1007/s11064-024-04267-w] [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: 04/05/2024] [Revised: 09/07/2024] [Accepted: 09/24/2024] [Indexed: 12/01/2024]
Abstract
Despite the considerable progress in mesenchymal stem/stromal cells (MSCs)-based novel intervention of multiple sclerosis (MS), yet the disease-modifying effect of VCAM-1- MSCs and novel VCAM-1+ counterpart is largely obscure. In this study, we took advantage of the EAE mouse model and VCAM-1+ human umbilical cord-derived MSCs (hUC-MSCs) for the evaluation of the therapeutic effect of systematic MSCs infusion. On the one hand, we compared the protective effect of VCAM-1- and VCAM-1+ hUC-MSCs against the clinical symptoms, demyelination, active glia cells and neuroinflammation in EAE mice by conducting multifaceted detections upon spinal cord and brain tissues. On the other hand, we conducted RNA-sequencing (RNA-SEQ) and multidimensional bioinformatics analyses for the evaluation of the transcriptomic features of spinal cord tissue in EAE mice after systematic hUC-MSCs infusion. Compared to those with VCAM-1- hUC-MSCs injection, VCAM-1+ mice showed further remission in clinical manifestations, and in particular, the inflammatory infiltration and active glial cells. Mice in all groups revealed conservations in overall gene expression profiling and somatic mutation spectrum. The differentially expressed genes (DEGs) between EAE mice and those with hUC-MSCs infusion were mainly involved in neuroinflammation and inflammatory response. Our findings indicated the feasibility of VCAM-1+ hUC-MSCs for multiple sclerosis treatment, which would supply new references for the development of novel VCAM-1+ MSCs-based cytotherapy in future.
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Affiliation(s)
- Haixia Liu
- Department of Neurology, The Second Hospital of Shandong University, 247 Beiyuan Road, Jinan, China
- Department of Neurology, Weihai Municipal Hospital, Weihai, China
| | - Dongqing Cui
- Department of Neurology, The Second Hospital of Shandong University, 247 Beiyuan Road, Jinan, China
| | - Shasha Huangfu
- Department of Neurology, The Second Hospital of Shandong University, 247 Beiyuan Road, Jinan, China
| | - Xiaojun Wang
- Universal Biomedical Research Institute, Zibo, China
| | - Xiao Yu
- Department of Neurology, The Second Hospital of Shandong University, 247 Beiyuan Road, Jinan, China
| | - Hui Yang
- Department of Neurology, The Second Hospital of Shandong University, 247 Beiyuan Road, Jinan, China
| | - Xiaolei Zheng
- Department of Neurology, The Second Hospital of Shandong University, 247 Beiyuan Road, Jinan, China
| | - Yan Li
- Universal Biomedical Research Institute, Zibo, China
| | - Jianzhong Bi
- Department of Neurology, The Second Hospital of Shandong University, 247 Beiyuan Road, Jinan, China
| | - Leisheng Zhang
- Science and Technology Innovation Center, Shandong Provincial Key Medical and Health Laboratory of Blood Ecology and Biointelligence, Jinan Key Laboratory of Medical Cell Bioengineering, The Fourth People's Hospital of Jinan, The Teaching Hospital of Shandong First Medical University, 50 Shifan Road, Jinan, China.
- National Health Commission (NHC) Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, 204 Donggang West Road, Lanzhou, China.
| | - Ping Wang
- Department of Neurology, The Second Hospital of Shandong University, 247 Beiyuan Road, Jinan, China.
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Lee GB, Park SM, Jung UJ, Kim SR. The Potential of Mesenchymal Stem Cells in Treating Spinocerebellar Ataxia: Advances and Future Directions. Biomedicines 2024; 12:2507. [PMID: 39595073 PMCID: PMC11591855 DOI: 10.3390/biomedicines12112507] [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: 10/01/2024] [Revised: 10/28/2024] [Accepted: 10/31/2024] [Indexed: 11/28/2024] Open
Abstract
Spinocerebellar ataxia (SCA) is a heterogeneous disorder characterized by impaired balance and coordination caused by cerebellar dysfunction. The absence of treatments approved by the U.S. Food and Drug Administration for SCA has driven the investigation of alternative therapeutic strategies, including stem cell therapy. Mesenchymal stem cells (MSCs), known for their multipotent capabilities, have demonstrated significant potential in treating SCA. This review examines how MSCs may promote neuronal growth, enhance synaptic connectivity, and modulate brain inflammation. Recent findings from preclinical and clinical studies are also reviewed, emphasizing the promise of MSC therapy in addressing the unmet needs of SCA patients. Furthermore, ongoing clinical trials and future directions are proposed to address the limitations of the current approaches.
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Affiliation(s)
- Gi Beom Lee
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; (G.B.L.); (S.M.P.)
| | - Se Min Park
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; (G.B.L.); (S.M.P.)
| | - Un Ju Jung
- Department of Food Science and Nutrition, Pukyong National University, Busan 48513, Republic of Korea;
| | - Sang Ryong Kim
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; (G.B.L.); (S.M.P.)
- Brain Science and Engineering Institute, Kyungpook National University, Daegu 41404, Republic of Korea
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11
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Wang P, Chen W, li B, Yang S, Li W, Zhao S, Ning J, Zhou X, Cheng F. Exosomes on the development and progression of renal fibrosis. Cell Prolif 2024; 57:e13677. [PMID: 38898750 PMCID: PMC11533081 DOI: 10.1111/cpr.13677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 04/09/2024] [Accepted: 05/14/2024] [Indexed: 06/21/2024] Open
Abstract
Renal fibrosis is a prevalent pathological alteration that occurs throughout the progression of primary and secondary renal disorders towards end-stage renal disease. As a complex and irreversible pathophysiological phenomenon, it includes a sequence of intricate regulatory processes at the molecular and cellular levels. Exosomes are a distinct category of extracellular vesicles that play a crucial role in facilitating intercellular communication. Multiple pathways are regulated by exosomes produced by various cell types, including tubular epithelial cells and mesenchymal stem cells, in the context of renal fibrosis. Furthermore, research has shown that exosomes present in bodily fluids, including urine and blood, may be indicators of renal fibrosis. However, the regulatory mechanism of exosomes in renal fibrosis has not been fully elucidated. This article reviewed and analysed the various mechanisms by which exosomes regulate renal fibrosis, which may provide new ideas for further study of the pathophysiological process of renal fibrosis and targeted treatment of renal fibrosis with exosomes.
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Affiliation(s)
- Peihan Wang
- Department of UrologyRenmin Hospital of Wuhan UniversityWuhanHubeiP.R. China
| | - Wu Chen
- Department of UrologyRenmin Hospital of Wuhan UniversityWuhanHubeiP.R. China
| | - Bojun li
- Department of UrologyRenmin Hospital of Wuhan UniversityWuhanHubeiP.R. China
| | - Songyuan Yang
- Department of UrologyRenmin Hospital of Wuhan UniversityWuhanHubeiP.R. China
| | - Wei Li
- Department of AnesthesiologyRenmin Hospital of Wuhan UniversityWuhanHubeiP.R. China
| | - Sheng Zhao
- Department of UrologyRenmin Hospital of Wuhan UniversityWuhanHubeiP.R. China
| | - Jinzhuo Ning
- Department of UrologyRenmin Hospital of Wuhan UniversityWuhanHubeiP.R. China
| | - Xiangjun Zhou
- Department of UrologyRenmin Hospital of Wuhan UniversityWuhanHubeiP.R. China
| | - Fan Cheng
- Department of UrologyRenmin Hospital of Wuhan UniversityWuhanHubeiP.R. China
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12
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Huang M, Liu Y, Zhang L, Wang S, Wang X, He Z. Advancements in Research on Mesenchymal Stem-Cell-Derived Exosomal miRNAs: A Pivotal Insight into Aging and Age-Related Diseases. Biomolecules 2024; 14:1354. [PMID: 39595531 PMCID: PMC11592330 DOI: 10.3390/biom14111354] [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: 09/12/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 11/28/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are capable of differentiating into various cell types and play a crucial role in repairing aging tissues and diseased organs. Aging manifests as a gradual loss of cellular, tissue, and organ function, leading to the progression of pathologies. Exosomes (Exos) are extracellular vesicles secreted by cells, which maintain cellular homeostasis, clear cellular debris, and facilitate communication between cells and organs. This review provides a comprehensive summary of the mechanisms for the synthesis and sorting of MSC-Exo miRNAs and summarizes the current research status of MSCs-Exos in mitigating aging and age-related diseases. It delves into the underlying molecular mechanisms, which encompass antioxidative stress, anti-inflammatory response, and the promotion of angiogenesis. Additionally, this review also discusses potential challenges in and future strategies for advancing MSC-Exo miRNA-based therapies in the treatment of aging and age-related diseases.
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Affiliation(s)
- Minglei Huang
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; (M.H.); (Y.L.); (S.W.)
| | - Ye Liu
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; (M.H.); (Y.L.); (S.W.)
| | - Longze Zhang
- Scientific Research Center, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi 563000, China;
| | - Shuangmin Wang
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; (M.H.); (Y.L.); (S.W.)
| | - Xianyao Wang
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; (M.H.); (Y.L.); (S.W.)
| | - Zhixu He
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
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13
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Tambe P, Undale V, Sanap A, Bhonde R, Mante N. The prospective role of mesenchymal stem cells in Parkinson's disease. Parkinsonism Relat Disord 2024; 127:107087. [PMID: 39142905 DOI: 10.1016/j.parkreldis.2024.107087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/14/2024] [Accepted: 08/01/2024] [Indexed: 08/16/2024]
Abstract
Parkinson's disease (PD) is a stressful neurodegenerative disorder affecting millions worldwide. PD leads to debilitating motor and cognitive symptoms such as tremors, rigidity, and difficulty walking. Current therapies for PD are symptomatic and don't address the root cause. Therefore, there is an urgent need for better management and intensive research into alternative therapies. Mesenchymal stem cell (MSC) therapy is among the leading contenders among these promising avenues. We examined preclinical and clinical evidence demonstrating the neuroprotective, anti-inflammatory, and regenerative properties of the MSCs. This review focuses on the complex pathophysiological mechanisms of PD, as well as the perspectives of MSCs and their derivatives, such as secretomes and exosomes, in the clinical management of PD. We also analyzed the challenges and limitations of each approach, including delivery methods, timing of administration, and long-term safety considerations.
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Affiliation(s)
- Pratima Tambe
- Department of Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, 411018, India
| | - Vaishali Undale
- Department of Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, 411018, India.
| | - Avinash Sanap
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, 411018, India.
| | - Ramesh Bhonde
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, 411018, India
| | - Nishant Mante
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, 411018, India
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14
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Akbari-Gharalari N, Ghahremani-Nasab M, Naderi R, Chodari L, Nezhadshahmohammad F. The potential of exosomal biomarkers: Revolutionizing Parkinson's disease: How do they influence pathogenesis, diagnosis, and therapeutic strategies? AIMS Neurosci 2024; 11:374-397. [PMID: 39431275 PMCID: PMC11486621 DOI: 10.3934/neuroscience.2024023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/10/2024] [Accepted: 09/18/2024] [Indexed: 10/22/2024] Open
Abstract
Parkinson's disease (PD) is characterized by the pathological accumulation of α-synuclein, which has driven extensive research into the role of exosomes in disease mechanisms. Exosomes are nanoscale vesicles enriched with proteins, RNA, and lipids that facilitate critical intercellular communication processes. Recent studies have elucidated the role of exosomes in transmitting misfolded proteins among neurons, which significantly impacts the progression of PD. The presence of disease-associated exosomes in cerebrospinal fluid and blood highlights their substantial diagnostic potential for PD. Specifically, exosomes derived from the central nervous system (CNS) have emerged as promising biomarkers because of their ability to accurately reflect pathological states. Furthermore, the isolation of exosomes from distinct brain cell types allows the identification of precise biomarkers, increasing diagnostic specificity and accuracy. In addition to being useful for diagnostics, exosomes hold therapeutic promise given their ability to cross the blood-brain barrier (BBB) and selectively modulate their cargo. These findings suggest that these materials could be used as delivery systems for therapeutic drugs for the treatment of neurodegenerative diseases. This review comprehensively examines the multifaceted roles of exosomes in PD pathogenesis, diagnosis, and treatment. It also addresses the associated clinical challenges and underscores the urgent need for further research and development to fully leverage exosome-based strategies in PD management.
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Affiliation(s)
- Naeimeh Akbari-Gharalari
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Maryam Ghahremani-Nasab
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roya Naderi
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Leila Chodari
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
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15
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Zhou R, Guo J, Jin Z. Advancing osteoarthritis therapy with GMOCS hydrogel-loaded BMSCs-exos. J Nanobiotechnology 2024; 22:493. [PMID: 39160590 PMCID: PMC11334447 DOI: 10.1186/s12951-024-02713-z] [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: 03/05/2024] [Accepted: 07/08/2024] [Indexed: 08/21/2024] Open
Abstract
This study investigated the mechanism of the extracellular matrix-mimicking hydrogel-mediated TGFB1/Nrf2 signaling pathway in osteoarthritis using bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos). A GMOCS-Exos hydrogel was synthesized and evaluated for its impact on chondrocyte viability and neutrophil extracellular traps (NETs) formation. In an OA rat model, GMOCS-Exos promoted cartilage regeneration and inhibited NETs formation. Transcriptome sequencing identified TGFB1 as a key gene, with GMOCS-Exos activating Nrf2 signaling through TGFB1. Depletion of TGFB1 hindered the cartilage-protective effect of GMOCS-Exos. This study sheds light on a promising therapeutic strategy for osteoarthritis through GMOCS-Exos-mediated TGFB1/Nrf2 pathway modulation.
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Affiliation(s)
- Renyi Zhou
- Department of Orthopedics, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China
| | - Jiarong Guo
- Department of Orthopedics, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China
| | - Zhe Jin
- Department of Orthopedics, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China.
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16
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Przywara D, Petniak A, Gil-Kulik P. Optimizing Mesenchymal Stem Cells for Regenerative Medicine: Influence of Diabetes, Obesity, Autoimmune, and Inflammatory Conditions on Therapeutic Efficacy: A Review. Med Sci Monit 2024; 30:e945331. [PMID: 39154207 PMCID: PMC11340262 DOI: 10.12659/msm.945331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 06/28/2024] [Indexed: 08/19/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are a promising tool that may be used in regenerative medicine. Thanks to their ability to differentiate and paracrine signaling, they can be used in the treatment of many diseases. Undifferentiated MSCs can support the regeneration of surrounding tissues through secreted substances and exosomes. This is possible thanks to the production of growth factors. These factors stimulate the growth of neighboring cells, have an anti-apoptotic effect, and support angiogenesis, and MSCs also have an immunomodulatory effect. The level of secreted factors may vary depending on many factors. Apart from the donor's health condition, it is also influenced by the source of MSCs, methods of harvesting, and even the banking of cells. This work is a review of research on how the patient's health condition affects the properties of obtained MSCs. The review discusses the impact of the patient's diabetes, obesity, autoimmune diseases, and inflammation, as well as the impact of the source of MSCs and methods of harvesting and banking cells on the phenotype, differentiation capacity, anti-inflammatory, angiogenic effects, and proliferation potential of MSCs. Knowledge about specific clinical factors allows for better use of the potential of stem cells and more appropriate targeting of procedures for collecting, multiplying, and banking these cells, as well as for their subsequent use. This article aims to review the characteristics, harvesting, banking, and paracrine signaling of MSCs and their role in diabetes, obesity, autoimmune and inflammatory diseases, and potential role in regenerative medicine.
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17
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Din MAU, Wan A, Chu Y, Zhou J, Yan Y, Xu Z. Therapeutic role of extracellular vesicles from human umbilical cord mesenchymal stem cells and their wide therapeutic implications in inflammatory bowel disease and other inflammatory disorder. Front Med (Lausanne) 2024; 11:1406547. [PMID: 39139783 PMCID: PMC11319305 DOI: 10.3389/fmed.2024.1406547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 07/18/2024] [Indexed: 08/15/2024] Open
Abstract
The chronic immune-mediated inflammatory condition known as inflammatory bowel disease (IBD) significantly affects the gastrointestinal system. While the precise etiology of IBD remains elusive, extensive research suggests that a range of pathophysiological pathways and immunopathological mechanisms may significantly contribute as potential factors. Mesenchymal stem cells (MSCs) have shown significant potential in the development of novel therapeutic approaches for various medical conditions. However, some MSCs have been found to exhibit tumorigenic characteristics, which limit their potential for medical treatments. The extracellular vesicles (EVs), paracrine factors play a crucial role in the therapeutic benefits conferred by MSCs. The EVs consist of proteins, microRNAs, and lipids, and are instrumental in facilitating intercellular communication. Due to the ease of maintenance, and decreased immunogenicity, tumorigenicity the EVs have become a new and exciting option for whole cell treatment. This review comprehensively assesses recent preclinical research on human umbilical cord mesenchymal stem cell (hUC-MSC)-derived EVs as a potential IBD therapy. It comprehensively addresses key aspects of various conditions, including diabetes, cancer, dermal injuries, neurological disorders, cardiovascular issues, liver and kidney diseases, and bone-related afflictions.
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Affiliation(s)
- Muhammad Azhar Ud Din
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine Jiangsu University, Zhenjiang, China
| | | | - Ying Chu
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
| | - Jing Zhou
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
| | - Yongmin Yan
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
| | - Zhiliang Xu
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
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18
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Mei R, Wan Z, Yang C, Shen X, Wang R, Zhang H, Yang R, Li J, Song Y, Su H. Advances and clinical challenges of mesenchymal stem cell therapy. Front Immunol 2024; 15:1421854. [PMID: 39100671 PMCID: PMC11294097 DOI: 10.3389/fimmu.2024.1421854] [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: 04/23/2024] [Accepted: 07/02/2024] [Indexed: 08/06/2024] Open
Abstract
In recent years, cell therapy has provided desirable properties for promising new drugs. Mesenchymal stem cells are promising candidates for developing genetic engineering and drug delivery strategies due to their inherent properties, including immune regulation, homing ability and tumor tropism. The therapeutic potential of mesenchymal stem cells is being investigated for cancer therapy, inflammatory and fibrotic diseases, among others. Mesenchymal stem cells are attractive cellular carriers for synthetic nanoparticles for drug delivery due to their inherent homing ability. In this review, we comprehensively discuss the various genetic and non-genetic strategies of mesenchymal stem cells and their derivatives in drug delivery, tumor therapy, immune regulation, tissue regeneration and other fields. In addition, we discuss the current limitations of stem cell therapy and the challenges in clinical translation, aiming to identify important development areas and potential future directions.
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Affiliation(s)
- Ruiyan Mei
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Zhuo Wan
- Department of Hematology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Cheng Yang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Xiangjing Shen
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Ronglin Wang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Haihua Zhang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Rui Yang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Junqiang Li
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Yang Song
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Haichuan Su
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
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Liang X, Miao Y, Tong X, Chen J, Liu H, He Z, Liu A, Hu Z. Dental pulp mesenchymal stem cell-derived exosomes inhibit neuroinflammation and microglial pyroptosis in subarachnoid hemorrhage via the miRNA-197-3p/FOXO3 axis. J Nanobiotechnology 2024; 22:426. [PMID: 39030593 PMCID: PMC11264715 DOI: 10.1186/s12951-024-02708-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 07/05/2024] [Indexed: 07/21/2024] Open
Abstract
BACKGROUND Subarachnoid hemorrhage (SAH) is a severe stroke subtype that lacks effective treatment. Exosomes derived from human dental pulp stem cells (DPSCs) are a promising acellular therapeutic strategy for neurological diseases. However, the therapeutic effects of DPSC-derived exosomes (DPSC-Exos) on SAH remain unknown. In this study, we investigated the therapeutic effects and mechanisms of action of DPSC-Exos in SAH. MATERIALS AND METHODS SAH was established using 120 male Sprague-Dawley rats. One hour after SAH induction, DPSC-Exos were administered via tail vein injection. To investigate the effect of DPSC-Exos, SAH grading, short-term and long-term neurobehavioral assessments, brain water content, western blot (WB), immunofluorescence staining, Nissl staining, and HE staining were performed. The role of miR-197-3p/FOXO3 in regulating pyroptosis was demonstrated through miRNA sequencing, bioinformatics analysis, and rescue experiments. The SAH model in vitro was established by stimulating BV2 cells with hemoglobin (Hb) and the underlying mechanism of DPSC-Exos was investigated through WB and Hoechst/PI staining. RESULTS The expressions of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were increased after SAH. DPSC-Exos alleviated brain edema and neuroinflammation by inhibiting the expression of FOXO3 and reducing NLRP3 inflammasome activation, leading to improved neurobehavioral functions at 24 h after SAH. In vitro, the expression of the NLRP3 inflammasome components (NLRP3 and caspase1-p20), GSDMD-N, and IL-18 was inhibited in BV2 cells pretreated with DPSC-Exos. Importantly, DPSC-Exos overexpressing miR-197-3p had a more obvious protective effect than those from NC-transfected DPSCs, while those from DPSCs transfected with the miR-197-3p inhibitor had a weaker protective effect. Functional studies indicated that miR-197-3p bound to the 3'-untranslated region of FOXO3, inhibiting its transcription. Furthermore, the overexpression of FOXO3 reversed the protective effects of miR-197-3p. CONCLUSIONS DPSC-Exos inhibited activation of the NLRP3 inflammasome and related cytokine release via the miR-197-3p/FOXO3 pathway, alleviated neuroinflammation, and inhibited microglial pyroptosis. These findings suggest that using DPSC-Exos is a promising therapeutic strategy for SAH.
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Affiliation(s)
- Xin Liang
- Department of Neurosurgery, Affiliated Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
- Department of Neurosurgery, Affiliated Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - Yan Miao
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Xin Tong
- Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- Cerebrovascular Disease Department, Neurological Disease Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jigang Chen
- Department of burn and plastic surgery, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
| | - Hongyi Liu
- Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- School of Biomedical Engineering, Capital Medical University, Beijing, 100069, China
| | - Zilong He
- Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Aihua Liu
- Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
- Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
- Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
- China National Clinical Research Centre for Neurological Diseases, Beijing, 100070, China.
| | - Zhiqiang Hu
- Department of Neurosurgery, Affiliated Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
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20
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Chen KS, Koubek EJ, Sakowski SA, Feldman EL. Stem cell therapeutics and gene therapy for neurologic disorders. Neurotherapeutics 2024; 21:e00427. [PMID: 39096590 PMCID: PMC11345629 DOI: 10.1016/j.neurot.2024.e00427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 07/22/2024] [Accepted: 07/22/2024] [Indexed: 08/05/2024] Open
Abstract
Rapid advances in biological knowledge and technological innovation have greatly advanced the fields of stem cell and gene therapies to combat a broad spectrum of neurologic disorders. Researchers are currently exploring a variety of stem cell types (e.g., embryonic, progenitor, induced pluripotent) and various transplantation strategies, each with its own advantages and drawbacks. Similarly, various gene modification techniques (zinc finger, TALENs, CRISPR-Cas9) are employed with various delivery vectors to modify underlying genetic contributors to neurologic disorders. While these two individual fields continue to blaze new trails, it is the combination of these technologies which enables genetically engineered stem cells and vastly increases investigational and therapeutic opportunities. The capability to culture and expand stem cells outside the body, along with their potential to correct genetic abnormalities in patient-derived cells or enhance cells with extra gene products, unleashes the full biological potential for innovative, multifaceted approaches to treat complex neurological disorders. In this review, we provide an overview of stem cell and gene therapies in the context of neurologic disorders, highlighting recent advances and current shortcomings, and discuss prospects for future therapies in clinical settings.
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Affiliation(s)
- Kevin S Chen
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Emily J Koubek
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA
| | - Stacey A Sakowski
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eva L Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA.
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21
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Kwon M, Kim BS, Yoon S, Oh SO, Lee D. Hematopoietic Stem Cells and Their Niche in Bone Marrow. Int J Mol Sci 2024; 25:6837. [PMID: 38999948 PMCID: PMC11241602 DOI: 10.3390/ijms25136837] [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: 05/09/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 07/14/2024] Open
Abstract
Extensive research has explored the functional correlation between stem cells and progenitor cells, particularly in blood. Hematopoietic stem cells (HSCs) can self-renew and regenerate tissues within the bone marrow, while stromal cells regulate tissue function. Recent studies have validated the role of mammalian stem cells within specific environments, providing initial empirical proof of this functional phenomenon. The interaction between bone and blood has always been vital to the function of the human body. It was initially proposed that during evolution, mammalian stem cells formed a complex relationship with the surrounding microenvironment, known as the niche. Researchers are currently debating the significance of molecular-level data to identify individual stromal cell types due to incomplete stromal cell mapping. Obtaining these data can help determine the specific activities of HSCs in bone marrow. This review summarizes key topics from previous studies on HSCs and their environment, discussing current and developing concepts related to HSCs and their niche in the bone marrow.
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Affiliation(s)
- Munju Kwon
- Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Byoung Soo Kim
- School of Biomedical Convergence Engineering, Pusan National University, Yangsan 50612, Republic of Korea
| | - Sik Yoon
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Sae-Ock Oh
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Dongjun Lee
- Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
- Transplantation Research Center, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
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22
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Yuan D, Bao Y, El-Hashash A. Mesenchymal stromal cell-based therapy in lung diseases; from research to clinic. AMERICAN JOURNAL OF STEM CELLS 2024; 13:37-58. [PMID: 38765802 PMCID: PMC11101986 DOI: 10.62347/jawm2040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 03/02/2024] [Indexed: 05/22/2024]
Abstract
Recent studies demonstrated that mesenchymal stem cells (MSCs) are important for the cell-based therapy of diseased or injured lung due to their immunomodulatory and regenerative properties as well as limited side effects in experimental animal models. Preclinical studies have shown that MSCs have also a remarkable effect on the immune cells, which play major roles in the pathogenesis of multiple lung diseases, by modulating their activity, proliferation, and functions. In addition, MSCs can inhibit both the infiltrated immune cells and detrimental immune responses in the lung and can be used in treating lung diseases caused by a virus infection such as Tuberculosis and SARS-COV-2. Moreover, MSCs are a source for alveolar epithelial cells such as type 2 (AT2) cells. These MSC-derived functional AT2-like cells can be used to treat and diminish serious lung disorders, including acute lung injury, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis in animal models. As an alternative MSC-based therapy, extracellular vesicles that are derived from MSC-derived can be employed in regenerative medicine. Herein, we discussed the key research findings from recent clinical and preclinical studies on the functions of MSCs in treating some common and well-studied lung diseases. We also discussed the mechanisms underlying MSC-based therapy of well-studied lung diseases, and the recent employment of MSCs in both the attenuation of lung injury/inflammation and promotion of the regeneration of lung alveolar cells after injury. Finally, we described the role of MSC-based therapy in treating major pulmonary diseases such as pneumonia, COPD, asthma, and idiopathic pulmonary fibrosis (IPF).
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Affiliation(s)
- Dailin Yuan
- Zhejiang UniversityHangzhou 310058, Zhejiang, PR China
| | - Yufei Bao
- School of Biomedical Engineering, University of SydneyDarlington, NSW 2008, Australia
| | - Ahmed El-Hashash
- Texas A&M University, 3258 TAMU, College StationTX 77843-3258, USA
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23
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Alzahrani FA, Riza YM, Eid TM, Almotairi R, Scherschinski L, Contreras J, Nadeem M, Perez SE, Raikwar SP, Jha RM, Preul MC, Ducruet AF, Lawton MT, Bhatia K, Akhter N, Ahmad S. Exosomes in Vascular/Neurological Disorders and the Road Ahead. Cells 2024; 13:670. [PMID: 38667285 PMCID: PMC11049650 DOI: 10.3390/cells13080670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/05/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aneurysms, are characterized by the abnormal accumulation and aggregation of disease-causing proteins in the brain and spinal cord. Recent research suggests that proteins linked to these conditions can be secreted and transferred among cells using exosomes. The transmission of abnormal protein buildup and the gradual degeneration in the brains of impacted individuals might be supported by these exosomes. Furthermore, it has been reported that neuroprotective functions can also be attributed to exosomes in neurodegenerative diseases. The potential neuroprotective functions may play a role in preventing the formation of aggregates and abnormal accumulation of proteins associated with the disease. The present review summarizes the roles of exosomes in neurodegenerative diseases as well as elucidating their therapeutic potential in AD, PD, ALS, HD, stroke, and aneurysms. By elucidating these two aspects of exosomes, valuable insights into potential therapeutic targets for treating neurodegenerative diseases may be provided.
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Affiliation(s)
- Faisal A. Alzahrani
- Department of Biochemistry, King Fahad Center for Medical Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Yasir M. Riza
- Department of Biochemistry, King Fahad Center for Medical Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Thamir M. Eid
- Department of Biochemistry, King Fahad Center for Medical Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Reema Almotairi
- Department of Medical Laboratory Technology, Prince Fahad bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Lea Scherschinski
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
| | - Jessica Contreras
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
| | - Muhammed Nadeem
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
| | - Sylvia E. Perez
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
| | - Sudhanshu P. Raikwar
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
| | - Ruchira M. Jha
- Department of Neurology, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Mark C. Preul
- Department of Neurosurgery, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Andrew F. Ducruet
- Department of Neurosurgery, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Michael T. Lawton
- Department of Neurosurgery, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Kanchan Bhatia
- School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA
| | - Naseem Akhter
- Department of Biology, Arizona State University, Lake Havasu City, AZ 86403, USA
| | - Saif Ahmad
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
- Department of Neurosurgery, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
- Phoenix Veterans Affairs (VA) Health Care System, Phoenix, AZ 85012, USA
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24
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Yang L, Liu SC, Liu YY, Zhu FQ, Xiong MJ, Hu DX, Zhang WJ. Therapeutic role of neural stem cells in neurological diseases. Front Bioeng Biotechnol 2024; 12:1329712. [PMID: 38515621 PMCID: PMC10955145 DOI: 10.3389/fbioe.2024.1329712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 02/12/2024] [Indexed: 03/23/2024] Open
Abstract
The failure of endogenous repair is the main feature of neurological diseases that cannot recover the damaged tissue and the resulting dysfunction. Currently, the range of treatment options for neurological diseases is limited, and the approved drugs are used to treat neurological diseases, but the therapeutic effect is still not ideal. In recent years, different studies have revealed that neural stem cells (NSCs) have made exciting achievements in the treatment of neurological diseases. NSCs have the potential of self-renewal and differentiation, which shows great foreground as the replacement therapy of endogenous cells in neurological diseases, which broadens a new way of cell therapy. The biological functions of NSCs in the repair of nerve injury include neuroprotection, promoting axonal regeneration and remyelination, secretion of neurotrophic factors, immune regulation, and improve the inflammatory microenvironment of nerve injury. All these reveal that NSCs play an important role in improving the progression of neurological diseases. Therefore, it is of great significance to better understand the functional role of NSCs in the treatment of neurological diseases. In view of this, we comprehensively discussed the application and value of NSCs in neurological diseases as well as the existing problems and challenges.
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Affiliation(s)
- Ling Yang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
- Department of Physical Examination, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Si-Cheng Liu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Yi-Yi Liu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Fu-Qi Zhu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Mei-Juan Xiong
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Dong-Xia Hu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
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25
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Tashima T. Mesenchymal Stem Cell (MSC)-Based Drug Delivery into the Brain across the Blood-Brain Barrier. Pharmaceutics 2024; 16:289. [PMID: 38399342 PMCID: PMC10891589 DOI: 10.3390/pharmaceutics16020289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
At present, stem cell-based therapies using induced pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs) are being used to explore the potential for regenerative medicine in the treatment of various diseases, owing to their ability for multilineage differentiation. Interestingly, MSCs are employed not only in regenerative medicine, but also as carriers for drug delivery, homing to target sites in injured or damaged tissues including the brain by crossing the blood-brain barrier (BBB). In drug research and development, membrane impermeability is a serious problem. The development of central nervous system drugs for the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, remains difficult due to impermeability in capillary endothelial cells at the BBB, in addition to their complicated pathogenesis and pathology. Thus, intravenously or intraarterially administered MSC-mediated drug delivery in a non-invasive way is a solution to this transendothelial problem at the BBB. Substances delivered by MSCs are divided into artificially included materials in advance, such as low molecular weight compounds including doxorubicin, and expected protein expression products of genetic modification, such as interleukins. After internalizing into the brain through the fenestration between the capillary endothelial cells, MSCs release their cargos to the injured brain cells. In this review, I introduce the potential and advantages of drug delivery into the brain across the BBB using MSCs as a carrier that moves into the brain as if they acted of their own will.
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Affiliation(s)
- Toshihiko Tashima
- Tashima Laboratories of Arts and Sciences, 1239-5 Toriyama-cho, Kohoku-ku, Yokohama 222-0035, Japan
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26
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Onkar A, Khan F, Goenka A, Rajendran RL, Dmello C, Hong CM, Mubin N, Gangadaran P, Ahn BC. Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications. ACS APPLIED MATERIALS & INTERFACES 2024; 16:6709-6742. [PMID: 38315446 DOI: 10.1021/acsami.3c16839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
Information exchange is essential for the brain, where it communicates the physiological and pathological signals to the periphery and vice versa. Extracellular vesicles (EVs) are a heterogeneous group of membrane-bound cellular informants actively transferring informative calls to and from the brain via lipids, proteins, and nucleic acid cargos. In recent years, EVs have also been widely used to understand brain function, given their "cell-like" properties. On the one hand, the presence of neuron and astrocyte-derived EVs in biological fluids have been exploited as biomarkers to understand the mechanisms and progression of multiple neurological disorders; on the other, EVs have been used in designing targeted therapies due to their potential to cross the blood-brain-barrier (BBB). Despite the expanding literature on EVs in the context of central nervous system (CNS) physiology and related disorders, a comprehensive compilation of the existing knowledge still needs to be made available. In the current review, we provide a detailed insight into the multifaceted role of brain-derived extracellular vesicles (BDEVs) in the intricate regulation of brain physiology. Our focus extends to the significance of these EVs in a spectrum of disorders, including brain tumors, neurodegenerative conditions, neuropsychiatric diseases, autoimmune disorders, and others. Throughout the review, parallels are drawn for using EVs as biomarkers for various disorders, evaluating their utility in early detection and monitoring. Additionally, we discuss the promising prospects of utilizing EVs in targeted therapy while acknowledging the existing limitations and challenges associated with their applications in clinical scenarios. A foundational comprehension of the current state-of-the-art in EV research is essential for informing the design of future studies.
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Affiliation(s)
- Akanksha Onkar
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, United States
| | - Fatima Khan
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States
| | - Anshika Goenka
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, United States
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Crismita Dmello
- Department of Neurological Surgery and Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States
| | - Chae Moon Hong
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
| | - Nida Mubin
- Department of Medicine, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
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27
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Hashemi A, Ezati M, Nasr MP, Zumberg I, Provaznik V. Extracellular Vesicles and Hydrogels: An Innovative Approach to Tissue Regeneration. ACS OMEGA 2024; 9:6184-6218. [PMID: 38371801 PMCID: PMC10870307 DOI: 10.1021/acsomega.3c08280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/27/2023] [Accepted: 12/19/2023] [Indexed: 02/20/2024]
Abstract
Extracellular vesicles have emerged as promising tools in regenerative medicine due to their inherent ability to facilitate intercellular communication and modulate cellular functions. These nanosized vesicles transport bioactive molecules, such as proteins, lipids, and nucleic acids, which can affect the behavior of recipient cells and promote tissue regeneration. However, the therapeutic application of these vesicles is frequently constrained by their rapid clearance from the body and inability to maintain a sustained presence at the injury site. In order to overcome these obstacles, hydrogels have been used as extracellular vesicle delivery vehicles, providing a localized and controlled release system that improves their therapeutic efficacy. This Review will examine the role of extracellular vesicle-loaded hydrogels in tissue regeneration, discussing potential applications, current challenges, and future directions. We will investigate the origins, composition, and characterization techniques of extracellular vesicles, focusing on recent advances in exosome profiling and the role of machine learning in this field. In addition, we will investigate the properties of hydrogels that make them ideal extracellular vesicle carriers. Recent studies utilizing this combination for tissue regeneration will be highlighted, providing a comprehensive overview of the current research landscape and potential future directions.
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Affiliation(s)
- Amir Hashemi
- Department
of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology, Technicka 3082/12, 61600 Brno, Czech Republic
| | - Masoumeh Ezati
- Department
of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology, Technicka 3082/12, 61600 Brno, Czech Republic
| | - Minoo Partovi Nasr
- Department
of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology, Technicka 3082/12, 61600 Brno, Czech Republic
| | - Inna Zumberg
- Department
of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology, Technicka 3082/12, 61600 Brno, Czech Republic
| | - Valentine Provaznik
- Department
of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology, Technicka 3082/12, 61600 Brno, Czech Republic
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28
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Zhang X, Che X, Zhang S, Wang R, Li M, Jin Y, Wang T, Song Y. Mesenchymal stem cell-derived extracellular vesicles for human diseases. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2024; 5:64-82. [PMID: 39698413 PMCID: PMC11648454 DOI: 10.20517/evcna.2023.47] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 01/26/2024] [Accepted: 02/01/2024] [Indexed: 12/20/2024]
Abstract
Stem cell therapy is a novel approach for treating various severe and intractable diseases, including autoimmune disorders, organ transplants, tumors, and neurodegenerative diseases. Nevertheless, the extensive utilization of stem cells is constrained by potential tumorigenicity, challenges in precise differentiation, rejection concerns, and ethical considerations. Extracellular vesicles possess the ability to carry diverse bioactive factors from stem cells and deliver them to specific target cells or tissues. Moreover, they offer the advantage of low immunogenicity. Consequently, they have the potential to facilitate the therapeutic potential of stem cells, mitigating the risks associated with direct stem cell application. Therefore, the use of stem cell extracellular vesicles in clinical diseases has received increasing attention. This review summarizes advances in the use of extracellular vesicles from mesenchymal stem cells (MSC). MSC extracellular vesicles are used in the treatment of inflammatory diseases such as rheumatoid arthritis, liver injury, COVID-19, and allergies; in the repair of tissue damage in heart disease, kidney injury, and osteoarthritic diseases; as a carrier in the treatment of tumors; and as a regenerative agent in neurodegenerative disorders such as Alzheimer's and Parkinson's.
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Affiliation(s)
- Xiaofang Zhang
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
- Authors contributed equally
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China
- Authors contributed equally
| | - Sibo Zhang
- The Fourth Hospital of China Medical University, Shenyang 110032, Liaoning, China
- Authors contributed equally
| | - Runze Wang
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
| | - Mo Li
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
| | - Yi Jin
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
| | - Tianlu Wang
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
| | - Yingqiu Song
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
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29
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Jiang N, Tian X, Wang Q, Hao J, Jiang J, Wang H. Regulation Mechanisms and Maintenance Strategies of Stemness in Mesenchymal Stem Cells. Stem Cell Rev Rep 2024; 20:455-483. [PMID: 38010581 DOI: 10.1007/s12015-023-10658-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2023] [Indexed: 11/29/2023]
Abstract
Stemness pertains to the intrinsic ability of mesenchymal stem cells (MSCs) to undergo self-renewal and differentiate into multiple lineages, while simultaneously impeding their differentiation and preserving crucial differentiating genes in a state of quiescence and equilibrium. Owing to their favorable attributes, including uncomplicated isolation protocols, ethical compliance, and ease of procurement, MSCs have become a focal point of inquiry in the domains of regenerative medicine and tissue engineering. As age increases or ex vivo cultivation is prolonged, the functionality of MSCs decreases and their stemness gradually diminishes, thereby limiting their potential therapeutic applications. Despite the existence of several uncertainties surrounding the comprehension of MSC stemness, considerable advancements have been achieved in the clarification of the potential mechanisms that lead to stemness loss, as well as the associated strategies for stemness maintenance. This comprehensive review provides a systematic overview of the factors influencing the preservation of MSC stemness, the molecular mechanisms governing it, the strategies for its maintenance, and the therapeutic potential associated with stemness. Finally, we underscore the obstacles and prospective avenues in present investigations, providing innovative perspectives and opportunities for the preservation and therapeutic utilization of MSC stemness.
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Affiliation(s)
- Nizhou Jiang
- Central Hospital of Dalian University of Technology Department of Spine Surgery, Dalian, China
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiliang Tian
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Quanxiang Wang
- Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, China
| | - Jiayu Hao
- Central Hospital of Dalian University of Technology Department of Spine Surgery, Dalian, China
| | - Jian Jiang
- Central Hospital of Dalian University of Technology Department of Spine Surgery, Dalian, China.
| | - Hong Wang
- Central Hospital of Dalian University of Technology Department of Spine Surgery, Dalian, China.
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30
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Wu Y, Meng X, Cheng WY, Yan Z, Li K, Wang J, Jiang T, Zhou F, Wong KH, Zhong C, Dong Y, Gao S. Can pluripotent/multipotent stem cells reverse Parkinson's disease progression? Front Neurosci 2024; 18:1210447. [PMID: 38356648 PMCID: PMC10864507 DOI: 10.3389/fnins.2024.1210447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 01/02/2024] [Indexed: 02/16/2024] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by continuous and selective degeneration or death of dopamine neurons in the midbrain, leading to dysfunction of the nigrostriatal neural circuits. Current clinical treatments for PD include drug treatment and surgery, which provide short-term relief of symptoms but are associated with many side effects and cannot reverse the progression of PD. Pluripotent/multipotent stem cells possess a self-renewal capacity and the potential to differentiate into dopaminergic neurons. Transplantation of pluripotent/multipotent stem cells or dopaminergic neurons derived from these cells is a promising strategy for the complete repair of damaged neural circuits in PD. This article reviews and summarizes the current preclinical/clinical treatments for PD, their efficacies, and the advantages/disadvantages of various stem cells, including pluripotent and multipotent stem cells, to provide a detailed overview of how these cells can be applied in the treatment of PD, as well as the challenges and bottlenecks that need to be overcome in future translational studies.
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Affiliation(s)
- Yongkang Wu
- Key Laboratory of Adolescent Health Evaluation and Sports Intervention, Ministry of Education, East China Normal University, Shanghai, China
| | - Xiangtian Meng
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wai-Yin Cheng
- Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Zhichao Yan
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Keqin Li
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jian Wang
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tianfang Jiang
- Department of Neurology, Shanghai Eighth People’s Hospital Affiliated to Jiangsu University, Shanghai, China
| | - Fei Zhou
- Department of Neurology, Third Affiliated Hospital of Navy Military Medical University, Shanghai, China
| | - Ka-Hing Wong
- Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Chunlong Zhong
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yi Dong
- Key Laboratory of Adolescent Health Evaluation and Sports Intervention, Ministry of Education, East China Normal University, Shanghai, China
| | - Shane Gao
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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31
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Malekpour K, Hazrati A, Khosrojerdi A, Roshangar L, Ahmadi M. An overview to nanocellulose clinical application: Biocompatibility and opportunities in disease treatment. Regen Ther 2023; 24:630-641. [PMID: 38034858 PMCID: PMC10682839 DOI: 10.1016/j.reth.2023.10.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 10/13/2023] [Accepted: 10/26/2023] [Indexed: 12/02/2023] Open
Abstract
Recently, the demand for organ transplantation has promptly increased due to the enhanced incidence of body organ failure, the increasing efficiency of transplantation, and the improvement in post-transplant outcomes. However, due to a lack of suitable organs for transplantation to fulfill current demand, significant organ shortage problems have emerged. Developing efficient technologies in combination with tissue engineering (TE) has opened new ways of producing engineered tissue substitutes. The use of natural nanoparticles (NPs) such as nanocellulose (NC) and nano-lignin should be used as suitable candidates in TE due to their desirable properties. Many studies have used these components to form scaffolds and three-dimensional (3D) cultures of cells derived from different tissues for tissue repair. Interestingly, these natural NPs can afford scaffolds a degree of control over their characteristics, such as modifying their mechanical strength and distributing bioactive compounds in a controlled manner. These bionanomaterials are produced from various sources and are highly compatible with human-derived cells as they are derived from natural components. In this review, we discuss some new studies in this field. This review summarizes the scaffolds based on NC, counting nanocrystalline cellulose and nanofibrillated cellulose. Also, the efficient approaches that can extract cellulose with high purity and increased safety are discussed. We concentrate on the most recent research on the use of NC-based scaffolds for the restoration, enhancement, or replacement of injured organs and tissues, such as cartilage, skin, arteries, brain, and bone. Finally, we suggest the experiments and promises of NC-based TE scaffolds.
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Affiliation(s)
- Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Disease Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Leila Roshangar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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32
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Shelash Al-Hawary SI, Yahya Ali A, Mustafa YF, Margiana R, Maksuda Ilyasovna S, Ramadan MF, Almalki SG, Alwave M, Alkhayyat S, Alsalamy A. The microRNAs (miRs) overexpressing mesenchymal stem cells (MSCs) therapy in neurological disorders; hope or hype. Biotechnol Prog 2023; 39:e3383. [PMID: 37642165 DOI: 10.1002/btpr.3383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/30/2023] [Accepted: 08/09/2023] [Indexed: 08/31/2023]
Abstract
Altered expression of multiple miRNAs was found to be extensively involved in the pathogenesis of different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. One of the biggest concerns within gene-based therapy is the delivery of the therapeutic microRNAs to the intended place, which is obligated to surpass the biological barriers without undergoing degradation in the bloodstream or renal excretion. Hence, the delivery of modified and unmodified miRNA molecules using excellent vehicles is required. In this light, mesenchymal stem cells (MSCs) have attracted increasing attention. The MSCs can be genetically modified to express or overexpress a particular microRNA aimed with promote neurogenesis and neuroprotection. The current review has focused on the therapeutic capabilities of microRNAs-overexpressing MSCs to ameliorate functional deficits in neurological conditions.
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Affiliation(s)
| | - Anas Yahya Ali
- Department of Nursing, Al-maarif University College, Ramadi, Al-Anbar, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | | | | | - Sami G Almalki
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia
| | - Marim Alwave
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Safa Alkhayyat
- College of Pharmacy, The Islamic University, Najaf, Iraq
| | - Ali Alsalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, Iraq
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Zayed M, Kook SH, Jeong BH. Potential Therapeutic Use of Stem Cells for Prion Diseases. Cells 2023; 12:2413. [PMID: 37830627 PMCID: PMC10571911 DOI: 10.3390/cells12192413] [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: 08/30/2023] [Revised: 10/02/2023] [Accepted: 10/05/2023] [Indexed: 10/14/2023] Open
Abstract
Prion diseases are neurodegenerative disorders that are progressive, incurable, and deadly. The prion consists of PrPSc, the misfolded pathogenic isoform of the cellular prion protein (PrPC). PrPC is involved in a variety of physiological functions, including cellular proliferation, adhesion, differentiation, and neural development. Prion protein is expressed on the membrane surface of a variety of stem cells (SCs), where it plays an important role in the pluripotency and self-renewal matrix, as well as in SC differentiation. SCs have been found to multiply the pathogenic form of the prion protein, implying their potential as an in vitro model for prion diseases. Furthermore, due to their capability to self-renew, differentiate, immunomodulate, and regenerate tissue, SCs are prospective cell treatments in many neurodegenerative conditions, including prion diseases. Regenerative medicine has become a new revolution in disease treatment in recent years, particularly with the introduction of SC therapy. Here, we review the data demonstrating prion diseases' biology and molecular mechanism. SC biology, therapeutic potential, and its role in understanding prion disease mechanisms are highlighted. Moreover, we summarize preclinical studies that use SCs in prion diseases.
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Affiliation(s)
- Mohammed Zayed
- Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Republic of Korea;
- Department of Bioactive Material Sciences, Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju 54896, Republic of Korea
- Department of Surgery, College of Veterinary Medicine, South Valley University, Qena 83523, Egypt
| | - Sung-Ho Kook
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Byung-Hoon Jeong
- Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Republic of Korea;
- Department of Bioactive Material Sciences, Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju 54896, Republic of Korea
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Nazari S, Pourmand SM, Motevaseli E, Hassanzadeh G. Mesenchymal stem cells (MSCs) and MSC-derived exosomes in animal models of central nervous system diseases: Targeting the NLRP3 inflammasome. IUBMB Life 2023; 75:794-810. [PMID: 37278718 DOI: 10.1002/iub.2759] [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: 03/08/2023] [Accepted: 05/02/2023] [Indexed: 06/07/2023]
Abstract
The NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome is a multimeric protein complex that is engaged in the innate immune system and plays a vital role in inflammatory reactions. Activation of the NLRP3 inflammasome and subsequent release of proinflammatory cytokines can be triggered by microbial infection or cellular injury. The NLRP3 inflammasome has been implicated in the pathogenesis of many disorders affecting the central nervous system (CNS), ranging from stroke, traumatic brain injury, and spinal cord injury to Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, and depression. Furthermore, emerging evidence has suggested that mesenchymal stem cells (MSCs) and their exosomes may modulate NLRP3 inflammasome activation in a way that might be promising for the therapeutic management of CNS diseases. In the present review, particular focus is placed on highlighting and discussing recent scientific evidence regarding the regulatory effects of MSC-based therapies on the NLRP3 inflammasome activation and their potential to counteract proinflammatory responses and pyroptotic cell death in the CNS, thereby achieving neuroprotective impacts and improvement in behavioral impairments.
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Affiliation(s)
- Shahrzad Nazari
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mahmoud Pourmand
- School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elahe Motevaseli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Hassanzadeh
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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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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Kandeel M, Morsy MA, Alkhodair KM, Alhojaily S. Mesenchymal Stem Cell-Derived Extracellular Vesicles: An Emerging Diagnostic and Therapeutic Biomolecules for Neurodegenerative Disabilities. Biomolecules 2023; 13:1250. [PMID: 37627315 PMCID: PMC10452295 DOI: 10.3390/biom13081250] [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: 07/01/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a type of versatile adult stem cells present in various organs. These cells give rise to extracellular vesicles (EVs) containing a diverse array of biologically active elements, making them a promising approach for therapeutics and diagnostics. This article examines the potential therapeutic applications of MSC-derived EVs in addressing neurodegenerative disorders such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Furthermore, the present state-of-the-art for MSC-EV-based therapy in AD, HD, PD, ALS, and MS is discussed. Significant progress has been made in understanding the etiology and potential treatments for a range of neurodegenerative diseases (NDs) over the last few decades. The contents of EVs are carried across cells for intercellular contact, which often results in the control of the recipient cell's homeostasis. Since EVs represent the therapeutically beneficial cargo of parent cells and are devoid of many ethical problems connected with cell-based treatments, they offer a viable cell-free therapy alternative for tissue regeneration and repair. Developing innovative EV-dependent medicines has proven difficult due to the lack of standardized procedures in EV extraction processes as well as their pharmacological characteristics and mechanisms of action. However, recent biotechnology and engineering research has greatly enhanced the content and applicability of MSC-EVs.
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Affiliation(s)
- Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Mohamed A. Morsy
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
| | - Khalid M. Alkhodair
- Department of Anatomy, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
| | - Sameer Alhojaily
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
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He A, Wang M, Li X, Chen H, Lim K, Lu L, Zhang C. Role of Exosomes in the Pathogenesis and Theranostic of Alzheimer's Disease and Parkinson's Disease. Int J Mol Sci 2023; 24:11054. [PMID: 37446231 DOI: 10.3390/ijms241311054] [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: 05/22/2023] [Revised: 06/25/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases (NDDs) threatening the lives of millions of people worldwide, including especially elderly people. Currently, due to the lack of a timely diagnosis and proper intervention strategy, AD and PD largely remain incurable. Innovative diagnosis and therapy are highly desired. Exosomes are small vesicles that are present in various bodily fluids, which contain proteins, nucleic acids, and active biomolecules, and which play a crucial role especially in intercellular communication. In recent years, the role of exosomes in the pathogenesis, early diagnosis, and treatment of diseases has attracted ascending attention. However, the exact role of exosomes in the pathogenesis and theragnostic of AD and PD has not been fully illustrated. In the present review, we first introduce the biogenesis, components, uptake, and function of exosomes. Then we elaborate on the involvement of exosomes in the pathogenesis of AD and PD. Moreover, the application of exosomes in the diagnosis and therapeutics of AD and PD is also summarized and discussed. Additionally, exosomes serving as drug carriers to deliver medications to the central nervous system are specifically addressed. The potential role of exosomes in AD and PD is explored, discussing their applications in diagnosis and treatment, as well as their current limitations. Given the limitation in the application of exosomes, we also propose future perspectives for better utilizing exosomes in NDDs. Hopefully, it would pave ways for expanding the biological applications of exosomes in fundamental research as well as theranostics of NDDs.
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Affiliation(s)
- Aojie He
- School of Basic Medical Sciences, Shanxi Medical University, 56 Xinjiannan Road, Taiyuan 030001, China
| | - Meiling Wang
- School of Basic Medical Sciences, Shanxi Medical University, 56 Xinjiannan Road, Taiyuan 030001, China
| | - Xiaowan Li
- School of Basic Medical Sciences, Shanxi Medical University, 56 Xinjiannan Road, Taiyuan 030001, China
| | - Hong Chen
- School of Basic Medical Sciences, Shanxi Medical University, 56 Xinjiannan Road, Taiyuan 030001, China
| | - Kahleong Lim
- Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore
| | - Li Lu
- School of Basic Medical Sciences, Shanxi Medical University, 56 Xinjiannan Road, Taiyuan 030001, China
| | - Chengwu Zhang
- School of Basic Medical Sciences, Shanxi Medical University, 56 Xinjiannan Road, Taiyuan 030001, China
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Borkowska P, Morys J, Zielinska A, Kowalski J. Effects of the Co-Overexpression of the BCL and BDNF Genes on the Gamma-Aminobutyric Acid-Ergic Differentiation of Wharton's-Jelly-Derived Mesenchymal Stem Cells. Biomedicines 2023; 11:1751. [PMID: 37371846 DOI: 10.3390/biomedicines11061751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
One of the problems with using MSCs (mesenchymal stem cells) to treat different neurodegenerative diseases of the central nervous system is their low ability to spontaneously differentiate into functional neurons. The aim of this study was to investigate how the co-overexpression of the BCL and BDNF genes affects the ability of genetically modified MSCs to differentiate into GABA-ergic neurons. A co-overexpression of two genes was performed, one of which, BCL, was supposed to increase the resistance of the cells to the toxic agents in the brain environment. The second one, BDNF, was supposed to direct the cells onto the neuronal differentiation pathway. As a result, the co-overexpression of both BCL2 + BDNF and BCLXL + BDNF caused an increase in the MAP2 gene expression level (a marker of the neuronal pathway) and the SYP gene that is associated with synaptogenesis. In both cases, approximately 18% of the genetically modified and then differentiated cells exhibited the presence of the GAD protein, which is characteristic of GABA-ergic neurons. Despite the presence of GAD, after both modifications, only the BCL2 and BDNF co-overexpression correlated with the ability of the modified cells to release gamma-aminobutyric acid (GABA) after depolarization. Our study identified a novel model of genetically engineered MSCs that can be used as a tool to deliver the antiapoptotic proteins (BCL) and neurotrophic factor (BDNF) directly into the brain microenvironment. Additionally, in the investigated model, the genetically modified MSCs could easily differentiate into functional GABA-ergic neurons and, moreover, due to the secreted BCL and BDNF, promote endogenous neuronal growth and encourage synaptic connections between neurons.
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Affiliation(s)
- Paulina Borkowska
- Department of Medical Genetics, Medical University of Silesia, 41-200 Sosnowiec, Poland
| | - Julia Morys
- Department of Medical Genetics, Medical University of Silesia, 41-200 Sosnowiec, Poland
| | - Aleksandra Zielinska
- Department of Medical Genetics, Medical University of Silesia, 41-200 Sosnowiec, Poland
| | - Jan Kowalski
- Department of Medical Genetics, Medical University of Silesia, 41-200 Sosnowiec, Poland
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Hazrati A, Mirsanei Z, Heidari N, Malekpour K, Rahmani-Kukia N, Abbasi A, Soudi S. The potential application of encapsulated exosomes: A new approach to increase exosomes therapeutic efficacy. Biomed Pharmacother 2023; 162:114615. [PMID: 37011484 DOI: 10.1016/j.biopha.2023.114615] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
Cell therapy is one of the methods that have shown promising results in treating diseases in recent decades. However, the use of different types of cells comes with limitations. The application of immune cells in cell therapy can lead to cytokine storms and inappropriate responses to self-antigens. Also, the use of stem cells has the potential to create tumors. Also, cells may not migrate to the injury site after intravenous injection. Therefore, using exosomes from different cells as therapeutic candidates were proposed. Due to their small size and favorable characteristics, such as biocompatibility and immunocompatibility, the easy storage and isolation, exosomes have attracted much attention. They are used in treating many diseases, including cardiovascular diseases, orthopedic diseases, autoimmune diseases, and cancer. However, the results of various studies have shown that the therapeutic efficiency of exosomes (Exo) can be increased by loading different drugs and microRNAs inside them (encapsulated exosomes). Therefore, analyzing studies investigating encapsulated exosomes' therapeutic ability is critical. In this study, we have examined the studies related to the use of encapsulated exosomes in treating diseases such as cancer and infectious diseases and their use in regenerative medicine. Compared to intact exosomes, the results show that the application of encapsulated exosomes has a higher therapeutic ability. Therefore it is suggested to use this method depending on the treatment type to increase the treatment's efficiency.
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40
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Fang X, Lan H, Jin K, Qian J. Pancreatic cancer and exosomes: role in progression, diagnosis, monitoring, and treatment. Front Oncol 2023; 13:1149551. [PMID: 37287924 PMCID: PMC10242099 DOI: 10.3389/fonc.2023.1149551] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 05/05/2023] [Indexed: 06/09/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most dangerous diseases that threaten human life, and investigating the details affecting its progression or regression is particularly important. Exosomes are one of the derivatives produced from different cells, including tumor cells and other cells such as Tregs, M2 macrophages, and MDSCs, and can help tumor growth. These exosomes perform their actions by affecting the cells in the tumor microenvironment, such as pancreatic stellate cells (PSCs) that produce extracellular matrix (ECM) components and immune cells that are responsible for killing tumor cells. It has also been shown that pancreatic cancer cell (PCC)-derived exosomes at different stages carry molecules. Checking the presence of these molecules in the blood and other body fluids can help us in the early stage diagnosis and monitoring of PC. However, immune system cell-derived exosomes (IEXs) and mesenchymal stem cell (MSC)-derived exosomes can contribute to PC treatment. Immune cells produce exosomes as part of the mechanisms involved in the immune surveillance and tumor cell-killing phenomenon. Exosomes can be modified in such a way that their antitumor properties are enhanced. One of these methods is drug loading in exosomes, which can significantly increase the effectiveness of chemotherapy drugs. In general, exosomes form a complex intercellular communication network that plays a role in developing, progressing, diagnosing, monitoring, and treating pancreatic cancer.
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Affiliation(s)
- Xingliang Fang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Jun Qian
- Department of Colorectal Surgery, Xinchang People’s Hospital, Affiliated Xinchang Hospital, Wenzhou Medical University, Xinchang, Zhejiang, China
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41
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Kim SG, George NP, Hwang JS, Park S, Kim MO, Lee SH, Lee G. Human Bone Marrow-Derived Mesenchymal Stem Cell Applications in Neurodegenerative Disease Treatment and Integrated Omics Analysis for Successful Stem Cell Therapy. Bioengineering (Basel) 2023; 10:bioengineering10050621. [PMID: 37237691 DOI: 10.3390/bioengineering10050621] [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: 04/27/2023] [Revised: 05/16/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Neurodegenerative diseases (NDDs), which are chronic and progressive diseases, are a growing health concern. Among the therapeutic methods, stem-cell-based therapy is an attractive approach to NDD treatment owing to stem cells' characteristics such as their angiogenic ability, anti-inflammatory, paracrine, and anti-apoptotic effects, and homing ability to the damaged brain region. Human bone-marrow-derived mesenchymal stem cells (hBM-MSCs) are attractive NDD therapeutic agents owing to their widespread availability, easy attainability and in vitro manipulation and the lack of ethical issues. Ex vivo hBM-MSC expansion before transplantation is essential because of the low cell numbers in bone marrow aspirates. However, hBM-MSC quality decreases over time after detachment from culture dishes, and the ability of hBM-MSCs to differentiate after detachment from culture dishes remains poorly understood. Conventional analysis of hBM-MSCs characteristics before transplantation into the brain has several limitations. However, omics analyses provide more comprehensive molecular profiling of multifactorial biological systems. Omics and machine learning approaches can handle big data and provide more detailed characterization of hBM-MSCs. Here, we provide a brief review on the application of hBM-MSCs in the treatment of NDDs and an overview of integrated omics analysis of the quality and differentiation ability of hBM-MSCs detached from culture dishes for successful stem cell therapy.
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Affiliation(s)
- Seok Gi Kim
- Department of Molecular Science and Technology, Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
| | - Nimisha Pradeep George
- Department of Molecular Science and Technology, Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
| | - Ji Su Hwang
- Department of Molecular Science and Technology, Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
| | - Seokho Park
- Department of Physiology, Ajou University School of Medicine, 206 World Cup-ro, Suwon 16499, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
| | - Myeong Ok Kim
- Division of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Soo Hwan Lee
- Department of Physiology, Ajou University School of Medicine, 206 World Cup-ro, Suwon 16499, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
| | - Gwang Lee
- Department of Molecular Science and Technology, Ajou University, 206 World Cup-ro, Suwon 16499, Republic of Korea
- Department of Physiology, Ajou University School of Medicine, 206 World Cup-ro, Suwon 16499, Republic of Korea
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Mirsanei Z, Heidari N, Hazrati A, Asemani Y, Niknam B, Yousefi Z, Jafari R. Oleuropein reduces LPS-induced inflammation via stimulating M2 macrophage polarization. Biomed Pharmacother 2023; 163:114857. [PMID: 37178576 DOI: 10.1016/j.biopha.2023.114857] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/04/2023] [Accepted: 05/06/2023] [Indexed: 05/15/2023] Open
Abstract
Oleuropein (OLEU) is the most prevalent phenolic component in olive varieties, and it has been considered for its powerful antioxidant properties in therapeutic applications. OLEU has anti-inflammatory properties and performs this property by suppressing inflammatory cells' function and reducing oxidative stress caused by various factors. This study investigated the ability of OLEU to polarize LPS-stimulated murine macrophage (MQ) cell RAW 264.7 into M1/M2 macrophages. As a first step, the cytotoxicity effects of OLEU were evaluated on LPS-stimulated RAW 264.7 cells using the thiazolyl blue (MTT) colorimetric test. Then, cytokines production, gene expression (Real-Time PCR), and functions (Nitrite oxide assay and phagocytosis assay) of OLEU-treated LPS-stimulated RAW 264.7 cells were evaluated. Our findings demonstrated that OLEU could reduce nitrite oxide (NO) production in LPS-stimulated RAW 264.7 cells by downregulating the inducible nitric oxide synthase gene expression. Furthermore, OLEU therapy decreases the expression of M1-associated pro-inflammatory cytokines production (IL-12, IFN-γ, and TNF-α) and genes expression (iNOS, TNF-α) while increasing the M2-associated anti-inflammatory gene expression and cytokines production (IL-10, and TGF-β). Based on the result, OLEU may be considered a potential therapeutic approach for inflammatory diseases due to its possible effects on oxidative stress-related factors, cytokine expression and production, and phagocytosis.
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Affiliation(s)
- Zahra Mirsanei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Yahya Asemani
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bahare Niknam
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Yousefi
- School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Reza Jafari
- School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran.
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Malekpour K, Hazrati A, Soudi S, Roshangar L, Pourfathollah AA, Ahmadi M. Combinational administration of mesenchymal stem cell-derived exosomes and metformin reduces inflammatory responses in an in vitro model of insulin resistance in HepG2 cells. Heliyon 2023; 9:e15489. [PMID: 37153436 PMCID: PMC10160701 DOI: 10.1016/j.heliyon.2023.e15489] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 03/30/2023] [Accepted: 04/11/2023] [Indexed: 05/09/2023] Open
Abstract
Diabetes is a highly common metabolic disorder in advanced societies. One of the causes of diabetes is insulin resistance, which is associated with a loss of sensitivity to insulin-sensitive cells. Insulin resistance develops in the body of a person prone to diabetes many years before diabetes development. Insulin resistance is associated with complications such as hyperglycemia, hyperlipidemia, and compensatory hyperinsulinemia and causes liver inflammation, which, if left untreated, can lead to cirrhosis, fibrosis, and even liver cancer. Metformin is the first line of treatment for patients with diabetes, which lowers blood sugar and increases insulin sensitivity by inhibiting gluconeogenesis in liver cells. The use of metformin has side effects, including a metallic taste in the mouth, vomiting, nausea, diarrhea, and upset stomach. For this reason, other treatments, along with metformin, are being developed. Considering the anti-inflammatory role of mesenchymal stem cells (MSCs) derived exosomes, their use seems to help improve liver tissue function and prevent damage caused by inflammation. This study investigated the anti-inflammatory effect of Wharton's jelly MSCs derived exosomes in combination with metformin in the HepG2 cells insulin resistance model induced by high glucose. This study showed that MSCs derived exosomes as an anti-inflammatory agent in combination with metformin could increase the therapeutic efficacy of metformin without needing to change metformin doses by decreasing inflammatory cytokines production, including IL-1, IL-6, and TNF-α and apoptosis in HepG2 cells.
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Affiliation(s)
- Kosar Malekpour
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Leila Roshangar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Pourfathollah
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- Corresponding author.
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Corresponding author.
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Chenari A, Hazrati A, Hosseini AZ, Motiee M, Soudi S. The effect of mesenchymal stem cell-derived supernatant nasal administration on lung inflammation and immune response in BCG-vaccinated BALB/c mice. Life Sci 2023; 317:121465. [PMID: 36731650 DOI: 10.1016/j.lfs.2023.121465] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023]
Abstract
Mesenchymal stem cells (MSCs) are among the known cells that can control and modulate immune responses in different circumstances, including autoimmune diseases. Also, various studies have shown that they can prevent and reduces the pulmonary inflammation caused by infectious agents. In the case of tuberculosis and inflammation caused by BCG, the granuloma has destructive effects and improper orientation of the immune response. Therefore, it is possible to prevent airway damage by preventing harmful inflammatory responses and guiding the immune system responses. This study investigates the role of nasal administration of MSCs supernatant by designing an inflammatory model in the BALB/c mice lung with BCG. MSCs are isolated from mice adipose tissue in this study and evaluated for their phenotypic and differentiation properties. After the third passage, these cells' condition medium (CM) was collected. 20 mice were divided into four groups. Group 1 receive BCG (107 CFU in 5 ml volume for 15 min) nasal administration. Group 2 treated with CM, and group 3 initially were treated with CM (in 5 ml volume for 15 min) and, after 24 h, treated with BCG nasal administration. CM treatment was continued every five days for one month. The fourth group of mice was treated with PBS nasal administration of CM and BCG. One week after the last administration, the lung tissue of mice in each group was pathologically examined. In addition, secretion of IL1-β, IL-6, TNF-α, TGF-β, and IL-10 in the alveolar fluid and secretion of IL-4 and IFN-γ cytokines in the supernatant of splenocytes was evaluated by ELISA. The TNF-α/IL-10 ratio in the alveolar lung fluid of the BCG received group is 2/9 and decreased to 0.58 after successive CM treatment. Therefore, it can be concluded that inflammatory responses to BCG infection in the presence of CM are balanced and pave the way for the induction of effective immune responses by reducing lung tissue damage.
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Affiliation(s)
- Abolfazl Chenari
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Zavaran Hosseini
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Mahdieh Motiee
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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45
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Hashemi B, Abdollahi M, Abbaspour-Aghdam S, Hazrati A, Malekpour K, Meshgi S, Kafil HS, Ghazi F, Yousefi M, Roshangar L, Ahmadi M. The effect of probiotics on immune responses and their therapeutic application: A new treatment option for multiple sclerosis. Biomed Pharmacother 2023; 159:114195. [PMID: 36630847 DOI: 10.1016/j.biopha.2022.114195] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/10/2022] [Accepted: 12/28/2022] [Indexed: 01/12/2023] Open
Abstract
Multiple sclerosis (MS) is known as a chronic inflammatory disease (CID) that affects the central nervous system and leads to nerve demyelination. However, the exact cause of MS is unknown, but immune system regulation and inhibiting the function of inflammatory pathways may have a beneficial effect on controlling and improving the disease. Studies show that probiotics can alter the gut microbiome, thereby improving and affecting the immune system and inflammatory responses in patients with MS. The results show that probiotics have a good effect on the recovery of patients with MS in humans and animals. The present study investigated the effect of probiotics and possible therapeutic mechanisms of probiotics on immune cells and inflammatory cytokines. This review article showed that probiotics could improve immune cells and inflammatory cytokines in patients with MS and can play an effective role in disease management and control.
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Affiliation(s)
- Behnam Hashemi
- Department of Bacteriology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Maryam Abdollahi
- Department of Bacteriology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Sanaz Abbaspour-Aghdam
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shahla Meshgi
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Samadi Kafil
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhood Ghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Roshangar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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46
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Malekpour K, Hazrati A, Soudi S, Hashemi SM. Mechanisms behind therapeutic potentials of mesenchymal stem cell mitochondria transfer/delivery. J Control Release 2023; 354:755-769. [PMID: 36706838 DOI: 10.1016/j.jconrel.2023.01.059] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/21/2023] [Accepted: 01/22/2023] [Indexed: 01/29/2023]
Abstract
Mesenchymal stromal/stem cells (MSCs) perform their therapeutic effects through various mechanisms, including their ability to differentiate, producing different growth factors, immunomodulatory factors, and extracellular vesicles (EVs). In addition to the mentioned mechanisms, a new aspect of the therapeutic potential of MSCs has recently been noticed, which occurs through mitochondrial transfer. Various methods of MSCs mitochondria transfer have been used in studies to benefit from their therapeutic potential. Among these methods, mitochondrial transfer after MSCs transplantation in cell-to-cell contact, EVs-mediated transfer of mitochondria, and the use of MSCs isolated mitochondria (MSCs-mt) are well studied. Pathological conditions can affect the cells in the damaged microenvironment and lead to cells mitochondrial damage. Since the defect in the mitochondrial function of the cell leads to a decrease in ATP production and the subsequent cell death, restoring the mitochondrial content, functions, and hemostasis can affect the functions of the damaged cell. Various studies show that the transfer of MSCs mitochondria to other cells can affect vital processes such as proliferation, differentiation, cell metabolism, inflammatory responses, cell senescence, cell stress, and cell migration. These changes in cell attributes and behavior are very important for therapeutic purposes. For this reason, their investigation can play a significant role in the direction of the researchers'.
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Affiliation(s)
- Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Seyed Mahmoud Hashemi
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran..
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Lafuente JV, Sharma A, Feng L, Muresanu DF, Nozari A, Tian ZR, Buzoianu AD, Sjöquist PO, Wiklund L, Sharma HS. Nanowired Delivery of Mesenchymal Stem Cells with Antioxidant Compound H-290/51 Reduces Exacerbation of Methamphetamine Neurotoxicity in Hot Environment. ADVANCES IN NEUROBIOLOGY 2023; 32:317-352. [PMID: 37480465 DOI: 10.1007/978-3-031-32997-5_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/24/2023]
Abstract
Military personnel are often exposed to hot environments either for combat operations or peacekeeping missions. Hot environment is a severe stressful situation leading to profound hyperthermia, fatigue and neurological impairments. To avoid stressful environment, some people frequently use methamphetamine (METH) or other psychostimulants to feel comfortable under adverse situations. Our studies show that heat stress alone induces breakdown of the blood-brain barrier (BBB) and edema formation associated with reduced cerebral blood flow (CBF). On the other hand, METH alone induces hyperthermia and neurotoxicity. These effects of METH are exacerbated at high ambient temperatures as seen with greater breakdown of the BBB and brain pathology. Thus, a combination of METH use at hot environment may further enhance the brain damage-associated behavioral dysfunctions. METH is well known to induce severe oxidative stress leading to brain pathology. In this investigation, METH intoxication at hot environment was examined on brain pathology and to explore suitable strategies to induce neuroprotection. Accordingly, TiO2-nanowired delivery of H-290/51 (150 mg/kg, i.p.), a potent chain-breaking antioxidant in combination with mesenchymal stem cells (MSCs), is investigated in attenuating METH-induced brain damage at hot environment in model experiments. Our results show that nanodelivery of H-290/51 with MSCs significantly enhanced CBF and reduced BBB breakdown, edema formation and brain pathology following METH exposure at hot environment. These observations are the first to point out that METH exacerbated brain pathology at hot environment probably due to enhanced oxidative stress, and MSCs attenuate these adverse effects, not reported earlier.
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Affiliation(s)
- José Vicente Lafuente
- LaNCE, Department Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Lianyuan Feng
- Department of Neurology, Bethune International Peace Hospital, Zhongshan, Hebei Province, China
| | - Dafin F Muresanu
- Department Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania
- "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - Ala Nozari
- Anesthesiology & Intensive Care, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA
| | - Z Ryan Tian
- Department Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Per-Ove Sjöquist
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Lars Wiklund
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
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Feng L, Sharma A, Wang Z, Muresanu DF, Tian ZR, Lafuente JV, Buzoianu AD, Nozari A, Wiklund L, Sharma HS. Co-administration of Nanowired DL-3-n-Butylphthalide (DL-NBP) Together with Mesenchymal Stem Cells, Monoclonal Antibodies to Alpha Synuclein and TDP-43 (TAR DNA-Binding Protein 43) Enhance Superior Neuroprotection in Parkinson's Disease Following Concussive Head Injury. ADVANCES IN NEUROBIOLOGY 2023; 32:97-138. [PMID: 37480460 DOI: 10.1007/978-3-031-32997-5_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/24/2023]
Abstract
dl-3-n-butylphthalide (dl-NBP) is one of the potent antioxidant compounds that induces profound neuroprotection in stroke and traumatic brain injury. Our previous studies show that dl-NBP reduces brain pathology in Parkinson's disease (PD) following its nanowired delivery together with mesenchymal stem cells (MSCs) exacerbated by concussive head injury (CHI). CHI alone elevates alpha synuclein (ASNC) in brain or cerebrospinal fluid (CSF) associated with elevated TAR DNA-binding protein 43 (TDP-43). TDP-43 protein is also responsible for the pathologies of PD. Thus, it is likely that exacerbation of brain pathology in PD following brain injury may be thwarted using nanowired delivery of monoclonal antibodies (mAb) to ASNC and/or TDP-43. In this review, the co-administration of dl-NBP with MSCs and mAb to ASNC and/or TDP-43 using nanowired delivery in PD and CHI-induced brain pathology is discussed based on our own investigations. Our observations show that co-administration of TiO2 nanowired dl-NBP with MSCs and mAb to ASNC with TDP-43 induced superior neuroprotection in CHI induced exacerbation of brain pathology in PD, not reported earlier.
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Affiliation(s)
- Lianyuan Feng
- Department of Neurology, Bethune International Peace Hospital, Zhongshan Road (West), Shijiazhuang, Hebei Province, China
| | - Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Zhenguo Wang
- Shijiazhuang Pharma Group NBP Pharmaceutical Co., Ltd., Shijiazhuang, Hebei Province, China
| | - Dafin F Muresanu
- Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania
- "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA
| | - José Vicente Lafuente
- LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ala Nozari
- Anesthesiology & Intensive Care, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA
| | - Lars Wiklund
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
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49
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Isaković J, Šerer K, Barišić B, Mitrečić D. Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force? Front Bioeng Biotechnol 2023; 11:1139359. [PMID: 36926687 PMCID: PMC10011535 DOI: 10.3389/fbioe.2023.1139359] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Neurological disorders are recognized as major causes of death and disability worldwide. Because of this, they represent one of the largest public health challenges. With awareness of the massive burden associated with these disorders, came the recognition that treatment options were disproportionately scarce and, oftentimes, ineffective. To address these problems, modern research is increasingly looking into novel, more effective methods to treat neurological patients; one of which is cell-based therapies. In this review, we present a critical analysis of the features, challenges, and prospects of one of the stem cell types that can be employed to treat numerous neurological disorders-mesenchymal stem cells (MSCs). Despite the fact that several studies have already established the safety of MSC-based treatment approaches, there are still some reservations within the field regarding their immunocompatibility, heterogeneity, stemness stability, and a range of adverse effects-one of which is their tumor-promoting ability. We additionally examine MSCs' mechanisms of action with respect to in vitro and in vivo research as well as detail the findings of past and ongoing clinical trials for Parkinson's and Alzheimer's disease, ischemic stroke, glioblastoma multiforme, and multiple sclerosis. Finally, this review discusses prospects for MSC-based therapeutics in the form of biomaterials, as well as the use of electromagnetic fields to enhance MSCs' proliferation and differentiation into neuronal cells.
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Affiliation(s)
- Jasmina Isaković
- Omnion Research International, Zagreb, Croatia.,Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Klara Šerer
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Barbara Barišić
- University of Zagreb School of Dental Medicine, Zagreb, Croatia
| | - Dinko Mitrečić
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia.,Laboratory for Stem Cells, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
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50
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CRISPR/Cas9-engineered mesenchymal stromal/stem cells and their extracellular vesicles: A new approach to overcoming cell therapy limitations. Biomed Pharmacother 2022; 156:113943. [DOI: 10.1016/j.biopha.2022.113943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/21/2022] [Accepted: 10/26/2022] [Indexed: 11/11/2022] Open
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