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1
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Saeedi P, Nilchiani LS, Zand B, Hajimirghasemi M, Halabian R. An overview of stem cells and cell products involved in trauma injury. Regen Ther 2025; 29:60-76. [PMID: 40143930 PMCID: PMC11938091 DOI: 10.1016/j.reth.2025.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/01/2025] [Accepted: 02/20/2025] [Indexed: 03/28/2025] Open
Abstract
Trauma injuries represent a significant public health burden worldwide, often leading to long-term disability and reduced quality of life. This review provides a comprehensive overview of the therapeutic potential of stem cells and cell products for traumatic injuries. The extraordinary characteristics of stem cells, such as self-renewal and transdifferentiation, make them definitive candidates for tissue regeneration. Mesenchymal stem cells (MSCs), neural stem cells (NSCs), and hematopoietic stem cells (HSCs) have been tested in preclinical studies for treating distinct traumatic injuries. Stem cell mechanisms of action are addressed through paracrine signaling, immunomodulation, differentiation, and neuroprotection. Cell products such as conditioned media, exosomes, and secretomes offer cell-free resources, thereby avoiding the risks of live cell transplantation. Clinical trials have reported many effective outcomes; however, variability exists across trauma types. Some challenges include tumorigenicity, standardized protocols, and regulatory issues. Collaboration and interdisciplinary research are being conducted to harness stem cells and products for trauma treatment. This emerging field is promising for improving patient recovery and quality of life after traumatic injuries.
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Affiliation(s)
- Pardis Saeedi
- Research Center for Health Management in Mass Gathering, Red Crescent Society of the Islamic Republic of Iran, Tehran, Iran
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Leila Sadat Nilchiani
- Department of Molecular and Cell Biology, Faculty of Advanced Sciences and Technology, Islamic Azad University Tehran Medical Sciences, Tehran, Iran
| | - Bita Zand
- Department of Molecular and Cell Biology, Faculty of Advanced Sciences and Technology, Islamic Azad University Tehran Medical Sciences, Tehran, Iran
| | - Maryam Hajimirghasemi
- Department of Internal Medicine, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Raheleh Halabian
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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2
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Li J, Liu L, Chen Y, Huang Y, Yang L. Exosomes derived from human umbilical cord mesenchymal stem cells attenuate senescence of peritoneal mesothelial cells by inhibiting oxidative stress. Int Immunopharmacol 2025; 158:114813. [PMID: 40354711 DOI: 10.1016/j.intimp.2025.114813] [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: 11/01/2024] [Revised: 05/04/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
OBJECTIVE Aging is a natural process that affects cellular function. In peritoneal dialysis (PD), chronic exposure to dialysate induces oxidative stress (OS) in peritoneal mesothelial cells (PMCs), leading to cellular aging, fibrosis, and reduced dialysis efficacy. Mesenchymal stem cells (MSCs) have shown potential in alleviating cellular aging. This study investigates the role of exosomes (hUMSC-Exos) derived from human umbilical cord MSCs (hUMSCs) in mitigating PMC senescence and explores the underlying mechanisms. METHODS Human peritoneal mesothelial cells (HMrSV5) were cultured with 2.5 % glucose to induce senescence. Aging markers were assessed via Western blotting, β-galactosidase staining, and cell cycle analysis. hUMSC-Exos were characterized using Western blot, electron microscopy, and nanoparticle tracking analysis. Their uptake by HMrSV5 cells was confirmed through fluorescence microscopy. Various concentrations of hUMSC-Exos were tested, and OS levels were evaluated using reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) assays. The impact of the OS inhibitor N-acetyl-L-cysteine (NAC) on aging markers was also examined. RESULTS HMrSV5 cells treated with 2.5 % glucose exhibited increased expression of P53, P21, and P16, along with G0/G1 cell cycle arrest. Treatment with 150 μg/mL hUMSC-Exos reduced aging markers, decreased ROS and MDA levels, and increased SOD activity. Similar effects were observed with NAC treatment. CONCLUSION hUMSC-Exos alleviate PMCs aging by inhibiting OS, highlighting their potential to improve PD outcomes.
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Affiliation(s)
- Jia Li
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Lixin Liu
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Yiman Chen
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Yuling Huang
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China
| | - Lina Yang
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR China; Department of International Physical Examination Center, The First Hospital of China Medical University, Shenyang, Liaoning 110001, PR 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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4
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Belousova E, Salikhova D, Maksimov Y, Nebogatikov V, Sudina A, Goldshtein D, Ustyugov A. Proposed Mechanisms of Cell Therapy for Alzheimer's Disease. Int J Mol Sci 2024; 25:12378. [PMID: 39596443 PMCID: PMC11595163 DOI: 10.3390/ijms252212378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/08/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Alzheimer's disease is a progressive neurodegenerative disorder characterized by mitochondria dysfunction, accumulation of beta-amyloid plaques, and hyperphosphorylated tau tangles in the brain leading to memory loss and cognitive deficits. There is currently no cure for this condition, but the potential of stem cells for the therapy of neurodegenerative pathologies is actively being researched. This review discusses preclinical and clinical studies that have used mouse models and human patients to investigate the use of novel types of stem cell treatment approaches. The findings provide valuable insights into the applications of stem cell-based therapies and include the use of neural, glial, mesenchymal, embryonic, and induced pluripotent stem cells. We cover current studies on stem cell replacement therapy where cells can functionally integrate into neural networks, replace damaged neurons, and strengthen impaired synaptic circuits in the brain. We address the paracrine action of stem cells acting via secreted factors to induce neuroregeneration and modify inflammatory responses. We focus on the neuroprotective functions of exosomes as well as their neurogenic and synaptogenic effects. We look into the shuttling of mitochondria through tunneling nanotubes that enables the transfer of healthy mitochondria by restoring the normal functioning of damaged cells, improving their metabolism, and reducing the level of apoptosis.
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Affiliation(s)
- Ekaterina Belousova
- Research Centre for Medical Genetics, Moscow 115522, Russia; (E.B.); (D.S.); (Y.M.); (A.S.); (D.G.)
| | - Diana Salikhova
- Research Centre for Medical Genetics, Moscow 115522, Russia; (E.B.); (D.S.); (Y.M.); (A.S.); (D.G.)
- Research Institute of Molecular and Cellular Medicine of the Medical Institute Peoples’ Friendship, University of Russia, Moscow 117198, Russia
| | - Yaroslav Maksimov
- Research Centre for Medical Genetics, Moscow 115522, Russia; (E.B.); (D.S.); (Y.M.); (A.S.); (D.G.)
- Research Institute of Molecular and Cellular Medicine of the Medical Institute Peoples’ Friendship, University of Russia, Moscow 117198, Russia
| | - Vladimir Nebogatikov
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry of the Russian Academy of Sciences, Chernogolovka 142432, Russia;
| | - Anastasiya Sudina
- Research Centre for Medical Genetics, Moscow 115522, Russia; (E.B.); (D.S.); (Y.M.); (A.S.); (D.G.)
- Research Institute of Molecular and Cellular Medicine of the Medical Institute Peoples’ Friendship, University of Russia, Moscow 117198, Russia
| | - Dmitry Goldshtein
- Research Centre for Medical Genetics, Moscow 115522, Russia; (E.B.); (D.S.); (Y.M.); (A.S.); (D.G.)
| | - Aleksey Ustyugov
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry of the Russian Academy of Sciences, Chernogolovka 142432, Russia;
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Jamshidi V, Nobakht BF, Bagheri H, Saeedi P, Ghanei M, Halabian R. Metabolomics to investigate the effect of preconditioned mesenchymal stem cells with crocin on pulmonary epithelial cells exposed to 2-chloroethyl ethyl sulfide. J Proteomics 2024; 308:105280. [PMID: 39147238 DOI: 10.1016/j.jprot.2024.105280] [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: 06/13/2024] [Revised: 08/11/2024] [Accepted: 08/11/2024] [Indexed: 08/17/2024]
Abstract
Metabolomics significantly impacts drug discovery and precise disease management. This study meticulously assesses the metabolite profiles of cells treated with Crocin, Dexamethasone, and mesenchymal stem cells (MSCs) under oxidative stress induced by 2-chloroethyl ethyl sulfide (CEES). Gas chromatography/mass spectrometry (GC/MS) analysis unequivocally identified substantial changes in 37 metabolites across the treated groups. Notably, pronounced alterations were observed in pathways associated with aminoacyl-tRNA biosynthesis and the metabolism of aspartate, serine, proline, and glutamate. These findings demonstrate the potent capacity of the analyzed treatments to effectively reduce inflammation, mitigate reactive oxygen species production, and enhance cell survival rates. SIGNIFICANCE.
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Affiliation(s)
- Vahid Jamshidi
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - B Fatemeh Nobakht
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Hasan Bagheri
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Pardis Saeedi
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mostafa Ghanei
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Raheleh Halabian
- Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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6
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Jiang Y, Yusoff NM, Du J, Moses EJ, Lin JT. Current perspectives on mesenchymal stem cells as a potential therapeutic strategy for non-alcoholic fatty liver disease. World J Stem Cells 2024; 16:760-772. [PMID: 39086561 PMCID: PMC11287429 DOI: 10.4252/wjsc.v16.i7.760] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/18/2024] [Accepted: 06/14/2024] [Indexed: 07/25/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant health challenge, characterized by its widespread prevalence, intricate natural progression and multifaceted pathogenesis. Although NAFLD initially presents as benign fat accumulation, it may progress to steatosis, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Mesenchymal stem cells (MSCs) are recognized for their intrinsic self-renewal, superior biocompatibility, and minimal immunogenicity, positioning them as a therapeutic innovation for liver diseases. Therefore, this review aims to elucidate the potential roles of MSCs in alleviating the progression of NAFLD by alteration of underlying molecular pathways, including glycolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. The insights are expected to provide further understanding of the potential of MSCs in NAFLD therapeutics, and support the development of MSC-based therapy in the treatment of NAFLD.
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Affiliation(s)
- Yan Jiang
- School of Nursing, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
| | - Narazah Mohd Yusoff
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
| | - Jiang Du
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
- 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 Province, China
| | - Emmanuel Jairaj Moses
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
| | - Jun-Tang 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 Province, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453000, Henan Province, China.
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7
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Larey AM, Spoerer TM, Daga KR, Morfin MG, Hynds HM, Carpenter J, Hines KM, Marklein RA. High throughput screening of mesenchymal stromal cell morphological response to inflammatory signals for bioreactor-based manufacturing of extracellular vesicles that modulate microglia. Bioact Mater 2024; 37:153-171. [PMID: 38549769 PMCID: PMC10972802 DOI: 10.1016/j.bioactmat.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 02/14/2024] [Accepted: 03/07/2024] [Indexed: 04/09/2024] Open
Abstract
Due to their immunomodulatory function, mesenchymal stromal cells (MSCs) are a promising therapeutic with the potential to treat neuroinflammation associated with neurodegenerative diseases. This function is mediated by secreted extracellular vesicles (MSC-EVs). Despite established safety, MSC clinical translation has been unsuccessful due to inconsistent clinical outcomes resulting from functional heterogeneity. Current approaches to mitigate functional heterogeneity include 'priming' MSCs with inflammatory signals to enhance function. However, comprehensive evaluation of priming and its effects on MSC-EV function has not been performed. Furthermore, clinical translation of MSC-EV therapies requires significant manufacturing scale-up, yet few studies have investigated the effects of priming in bioreactors. As MSC morphology has been shown to predict their immunomodulatory function, we screened MSC morphological response to an array of priming signals and evaluated MSC-EV identity and potency in response to priming in flasks and bioreactors. We identified unique priming conditions corresponding to distinct morphologies. These conditions demonstrated a range of MSC-EV preparation quality and lipidome, allowing us to discover a novel MSC-EV manufacturing condition, as well as gain insight into potential mechanisms of MSC-EV microglia modulation. Our novel screening approach and application of priming to MSC-EV bioreactor manufacturing informs refinement of larger-scale manufacturing and enhancement of MSC-EV function.
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Affiliation(s)
- Andrew M. Larey
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Thomas M. Spoerer
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Kanupriya R. Daga
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Maria G. Morfin
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Hannah M. Hynds
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Jana Carpenter
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Kelly M. Hines
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Ross A. Marklein
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
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8
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Marquez-Curtis LA, Elliott JAW. Mesenchymal stromal cells derived from various tissues: Biological, clinical and cryopreservation aspects: Update from 2015 review. Cryobiology 2024; 115:104856. [PMID: 38340887 DOI: 10.1016/j.cryobiol.2024.104856] [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: 11/28/2023] [Revised: 01/26/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024]
Abstract
Mesenchymal stromal cells (MSCs) have become one of the most investigated and applied cells for cellular therapy and regenerative medicine. In this update of our review published in 2015, we show that studies continue to abound regarding the characterization of MSCs to distinguish them from other similar cell types, the discovery of new tissue sources of MSCs, and the confirmation of their properties and functions that render them suitable as a therapeutic. Because cryopreservation is widely recognized as the only technology that would enable the on-demand availability of MSCs, here we show that although the traditional method of cryopreserving cells by slow cooling in the presence of 10% dimethyl sulfoxide (Me2SO) continues to be used by many, several novel MSC cryopreservation approaches have emerged. As in our previous review, we conclude from these recent reports that viable and functional MSCs from diverse tissues can be recovered after cryopreservation using a variety of cryoprotectants, freezing protocols, storage temperatures, and periods of storage. We also show that for logistical reasons there are now more studies devoted to the cryopreservation of tissues from which MSCs are derived. A new topic included in this review covers the application in COVID-19 of MSCs arising from their immunomodulatory and antiviral properties. Due to the inherent heterogeneity in MSC populations from different sources there is still no standardized procedure for their isolation, identification, functional characterization, cryopreservation, and route of administration, and not likely to be a "one-size-fits-all" approach in their applications in cell-based therapy and regenerative medicine.
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Affiliation(s)
- Leah A Marquez-Curtis
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, Canada, T6G 1H9; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada, T6G 1C9
| | - Janet A W Elliott
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, Canada, T6G 1H9; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada, T6G 1C9.
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9
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Sharma M, Pal P, Gupta SK. The neurotransmitter puzzle of Alzheimer's: Dissecting mechanisms and exploring therapeutic horizons. Brain Res 2024; 1829:148797. [PMID: 38342422 DOI: 10.1016/j.brainres.2024.148797] [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: 11/22/2023] [Revised: 01/10/2024] [Accepted: 02/06/2024] [Indexed: 02/13/2024]
Abstract
Alzheimer's Disease (AD) represents a complex interplay of neurological pathways and molecular mechanisms, with significant impacts on patients' lives. This review synthesizes the latest developments in AD research, focusing on both the scientific advancements and their clinical implications. We examine the role of microglia in AD, highlighting their contribution to the disease's inflammatory aspects. The cholinergic hypothesis, a cornerstone of AD research, is re-evaluated, including the role of Alpha-7 Nicotinic Acetylcholine Receptors in disease progression. This review places particular emphasis on the neurotransmission systems, exploring the therapeutic potential of GABAergic neurotransmitters and the role of NMDA inhibitors in the context of glutamatergic neurotransmission. By analyzing the interactions and implications of neurotransmitter pathways in AD, we aim to shed light on emerging therapeutic strategies. In addition to molecular insights, the review addresses the clinical and personal aspects of AD, underscoring the need for patient-centered approaches in treatment and care. The final section looks at the future directions of AD research and treatment, discussing the integration of scientific innovation with patient care. This review aims to provide a comprehensive update on AD, merging scientific insights with practical considerations, suitable for both specialists and those new to the field.
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Affiliation(s)
- Monika Sharma
- Faculty of Pharmacy, Department of Pharmacology, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India
| | - Pankaj Pal
- Department of Pharmacy, Banasthali Vidyapith, Rajasthan, India
| | - Sukesh Kumar Gupta
- Department of Anatomy and Neurobiology, School of Medicine, University of California, USA.
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10
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Larey AM, Spoerer TM, Daga KR, Morfin MG, Hynds HM, Carpenter J, Hines KM, Marklein RA. High throughput screening of mesenchymal stromal cell morphological response to inflammatory signals for bioreactor-based manufacturing of extracellular vesicles that modulate microglia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.19.567730. [PMID: 38014258 PMCID: PMC10680807 DOI: 10.1101/2023.11.19.567730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Due to their immunomodulatory function, mesenchymal stromal cells (MSCs) are a promising therapeutic with the potential to treat neuroinflammation associated with neurodegenerative diseases. This function can be mediated by secreted extracellular vesicles (MSC-EVs). Despite established safety, MSC clinical translation has been unsuccessful due to inconsistent clinical outcomes resulting from functional heterogeneity. Current approaches to mitigate functional heterogeneity include 'priming' MSCs with inflammatory signals to enhance function. However, comprehensive evaluation of priming and its effects on MSC-EV function has not been performed. Clinical translation of MSC-EV therapies requires significant manufacturing scale-up, yet few studies have investigated the effects of priming in bioreactors. As MSC morphology has been shown to predict their immunomodulatory function, we screened MSC morphological response to an array of priming signals and evaluated MSC-EV identity and potency in response to priming in flasks and bioreactors. We identified unique priming conditions corresponding to distinct morphologies. These conditions demonstrated a range of MSC-EV preparation quality and lipidome, allowing us to discover a novel MSC-EV manufacturing condition, as well as gain insight into potential mechanisms of MSC-EV microglia modulation. Our novel screening approach and application of priming to MSC-EV bioreactor manufacturing informs refinement of larger-scale manufacturing and enhancement of MSC-EV function.
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Affiliation(s)
- Andrew M. Larey
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Thomas M. Spoerer
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Kanupriya R. Daga
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Maria G. Morfin
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Hannah M. Hynds
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Jana Carpenter
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Kelly M. Hines
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Ross A. Marklein
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
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11
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Zhang X, Sang X, Chen Y, Yu H, Sun Y, Liang X, Zheng X, Wang X, Yang H, Bi J, Zhang L, Wang P. VCAM-1 + hUC-MSCs Exert Considerable Neuroprotection Against Cerebral Infarction in Rats by Suppression of NLRP3-Induced Pyroptosis. Neurochem Res 2023; 48:3084-3098. [PMID: 37336824 DOI: 10.1007/s11064-023-03968-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/07/2023] [Accepted: 06/08/2023] [Indexed: 06/21/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) are spindle-like heterogeneous cell populations with advantageous bidirectional immunomodulatory and hematopoietic support effects. Vascular cellular adhesion molecule-1 (VCAM-1)+ MSCs have been reported to exhibit immunoregulatory and proangiogenic capacities. Here, we studied the effects of VCAM-1+ human umbilical cord (hUC)-MSCs on neuroprotection against cerebral infarction. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO), and VCAM-1- and VCAM-1+ hUC-MSCs were intravenously injected into the rat 4 h post-MCAO surgery. Thereafter, modified neurological severity scores (mNSS) were determined, and the Morris water maze test, 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin (H&E), Nissl, TUNEL staining, and qRT-PCR were conducted. Following induction of oxygen-glucose deprivation/reoxygenation (OGD/R), SH-SY5Y cells were co-cultured with VCAM-1- and VCAM-1+ hUC-MSCs. CCK-8, flow cytometry, ELISA, and western blot analyses were performed in vitro. Compared with VCAM-1- hUC-MSCs, administration of VCAM-1+ hUC-MSCs revealed improved therapeutic efficacy against cerebral infarction in rats, as confirmed by lower mNSS scores and infarct volumes, as well as improved learning and memory capacities. In addition, VCAM-1+ hUC-MSCs exhibited improved efficacy against neurological defects in rats with cerebral infarction, accompanied by inhibition of the NLRP3-mediated inflammatory response. VCAM-1+ hUC-MSC co-culture improved the viability and diminished NLRP3-mediated inflammatory response in OGD/R-treated SH-SY5Y cells. Moreover, NLRP3 overexpression in SH-SY5Y cells prevented the beneficial effects of VCAM-1+ hUC-MSC co-culture. Overall, our findings demonstrated the relevance of VCAM-1+ hUC-MSC-based cytotherapy for preclinical neuroprotection against cerebral infarction.
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Affiliation(s)
- Xiao Zhang
- Department of Neurology, The Second Hospital of Shandong University, Jinan, 250033, China
| | - Xiaoyu Sang
- Department of Neurology, The Second Hospital of Shandong University, Jinan, 250033, China
| | - Yanting Chen
- Department of Neurology, The Second Hospital of Shandong University, Jinan, 250033, China
| | - Hao Yu
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yuan Sun
- The Second Hospital of Shandong University, Jinan, 250033, China
| | - Xilong Liang
- Department of Biostatistics, School of Public Health, Yale University, 38 Crown Street, APT 203, New Haven, CT, 06510, USA
| | - Xiaolei Zheng
- Department of Neurology, The Second Hospital of Shandong University, Jinan, 250033, China
| | - Xiao Wang
- Department of Neurology, The Second Hospital of Shandong University, Jinan, 250033, China
| | - Hui Yang
- Department of Neurology, The Second Hospital of Shandong University, Jinan, 250033, China
| | - Jianzhong Bi
- Department of Neurology, The Second Hospital of Shandong University, Jinan, 250033, China
| | - Leisheng Zhang
- Department of Neurosurgery, Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, China.
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, 730000, China.
- Key Laboratory of Radiation Technology and Biophysics, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
| | - Ping Wang
- Department of Neurology, The Second Hospital of Shandong University, Jinan, 250033, China.
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12
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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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13
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Vargas-Rodríguez P, Cuenca-Martagón A, Castillo-González J, Serrano-Martínez I, Luque RM, Delgado M, González-Rey E. Novel Therapeutic Opportunities for Neurodegenerative Diseases with Mesenchymal Stem Cells: The Focus on Modulating the Blood-Brain Barrier. Int J Mol Sci 2023; 24:14117. [PMID: 37762420 PMCID: PMC10531435 DOI: 10.3390/ijms241814117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/08/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Neurodegenerative disorders encompass a broad spectrum of profoundly disabling situations that impact millions of individuals globally. While their underlying causes and pathophysiology display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, is a common feature among them. Consequently, targeting the BBB has emerged as an innovative therapeutic strategy for addressing neurological disorders. Within this review, we not only explore the neuroprotective, neurotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will investigate the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological conditions like Alzheimer's disease, Parkinson's disease, and stroke, as well as immune-mediated diseases such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological contexts.
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Affiliation(s)
- Pablo Vargas-Rodríguez
- Institute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSIC, PT Salud, 18016 Granada, Spain; (P.V.-R.); (J.C.-G.); (I.S.-M.); (M.D.)
| | - Alejandro Cuenca-Martagón
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (A.C.-M.); (R.M.L.)
| | - Julia Castillo-González
- Institute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSIC, PT Salud, 18016 Granada, Spain; (P.V.-R.); (J.C.-G.); (I.S.-M.); (M.D.)
| | - Ignacio Serrano-Martínez
- Institute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSIC, PT Salud, 18016 Granada, Spain; (P.V.-R.); (J.C.-G.); (I.S.-M.); (M.D.)
| | - Raúl M. Luque
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain; (A.C.-M.); (R.M.L.)
- Department of Cell Biology, Physiology, and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain
| | - Mario Delgado
- Institute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSIC, PT Salud, 18016 Granada, Spain; (P.V.-R.); (J.C.-G.); (I.S.-M.); (M.D.)
| | - Elena González-Rey
- Institute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSIC, PT Salud, 18016 Granada, Spain; (P.V.-R.); (J.C.-G.); (I.S.-M.); (M.D.)
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14
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Gao J, Li L. Enhancement of neural regeneration as a therapeutic strategy for Alzheimer's disease (Review). Exp Ther Med 2023; 26:444. [PMID: 37614437 PMCID: PMC10443056 DOI: 10.3892/etm.2023.12143] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 07/18/2023] [Indexed: 08/25/2023] Open
Abstract
Alzheimer's disease (AD), the most common cause of dementia worldwide, has gradually become a global health concern for society and individuals with the process of global ageing. Although extensive research has been carried out on AD, the etiology and pathological mechanism of the disease are still unclear, and there is no specific drug to cure or delay AD progression. The exploration of enhancing nerve regeneration in AD has gradually attracted increasing attention. In the current review, the existing therapeutic strategies were summarized to induce nerve regeneration which can increase the number of neurons, and improve the survival of neurons, the plasticity of synapses and synaptic activity. The strategies include increasing neurotrophic expression (such as brain-derived neurotrophic factor and nerve growth factor), inhibiting acetylcholinesterase (such as donepezil, tacrine, rivastigmine and galanthamine), elevating histone deacetylase levels (such as RGFP-966, Tasquinimod, CM-414 and 44B), stimulating the brain by physiotherapy (such as near-infrared light, repetitive transcranial magnetic stimulation, and transcranial direct current stimulation) and transplanting exogenous neural stem cells. However, further evaluations need to be performed to determine the optimal treatment. The present study reviews recent interventions for enhancing adult neurogenesis and attempts to elucidate their mechanisms of action, which may provide a theoretical basis for inducing nerve regeneration to fight against AD.
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Affiliation(s)
- Junyan Gao
- Department of Physiology and Pharmacology, Health Science Centre, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Liping Li
- Department of Physiology and Pharmacology, Health Science Centre, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
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15
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Salimi L, Seyedaghamiri F, Karimipour M, Mobarak H, Mardi N, Taghavi M, Rahbarghazi R. Physiological and pathological consequences of exosomes at the blood-brain-barrier interface. Cell Commun Signal 2023; 21:118. [PMID: 37208741 DOI: 10.1186/s12964-023-01142-z] [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: 01/16/2023] [Accepted: 04/22/2023] [Indexed: 05/21/2023] Open
Abstract
Blood-brain barrier (BBB) interface with multicellular structure controls strictly the entry of varied circulating macromolecules from the blood-facing surface into the brain parenchyma. Under several pathological conditions within the central nervous system, the integrity of the BBB interface is disrupted due to the abnormal crosstalk between the cellular constituents and the recruitment of inflammatory cells. Exosomes (Exos) are nano-sized extracellular vesicles with diverse therapeutic outcomes. These particles transfer a plethora of signaling molecules with the potential to modulate target cell behavior in a paracrine manner. Here, in the current review article, the therapeutic properties of Exos and their potential in the alleviation of compromised BBB structure were discussed. Video Abstract.
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Affiliation(s)
- Leila Salimi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemehsadat Seyedaghamiri
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Karimipour
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Halimeh Mobarak
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Mardi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Taghavi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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16
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Alhodieb FS, Rahman MA, Barkat MA, Alanezi AA, Barkat HA, Hadi HA, Harwansh RK, Mittal V. Nanomedicine-driven therapeutic interventions of autophagy and stem cells in the management of Alzheimer's disease. Nanomedicine (Lond) 2023; 18:145-168. [PMID: 36938800 DOI: 10.2217/nnm-2022-0108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2023] Open
Abstract
Drug-loaded, brain-targeted nanocarriers could be a promising tool in overcoming the challenges associated with Alzheimer's disease therapy. These nanocargoes are enormously flexible to functionalize and facilitate the delivery of drugs to brain cells by bridging the blood-brain barrier and into brain cells. To date, modifications have included nanoparticles (NPs) coating with tunable surfactants/phospholipids, covalently attaching polyethylene glycol chains (PEGylation), and tethering different targeting ligands to cell-penetrating peptides in a manner that facilitates their entry across the BBB and downregulates various pathological hallmarks as well as intra- and extracellular signaling pathways. This review provides a brief update on drug-loaded, multifunctional nanocarriers and the therapeutic intervention of autophagy and stem cells in the management of Alzheimer's disease.
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Affiliation(s)
- Fahad Saad Alhodieb
- Department of Clinical Nutrition, College of Applied Health Sciences in Arras, Qassim University, Ar Rass, 51921, Saudi Arabia
| | | | - Muhammad Abul Barkat
- Department of Pharmaceutics, College of Pharmacy, University of Hafr Al-Batin, Al Jamiah, Hafr Al Batin, 39524, Saudi Arabia
| | - Abdulkareem A Alanezi
- Department of Pharmaceutics, College of Pharmacy, University of Hafr Al-Batin, Al Jamiah, Hafr Al Batin, 39524, Saudi Arabia
| | - Harshita Abul Barkat
- Department of Pharmaceutics, College of Pharmacy, University of Hafr Al-Batin, Al Jamiah, Hafr Al Batin, 39524, Saudi Arabia.,Dermatopharmaceutics Research Group, Faculty of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, 25200, Malaysia
| | - Hazrina Ab Hadi
- Dermatopharmaceutics Research Group, Faculty of Pharmacy, International Islamic University Malaysia, Kuantan, Pahang, 25200, Malaysia
| | - Ranjit K Harwansh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
| | - Vineet Mittal
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, 124001, India
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17
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Velasco MG, Satué K, Chicharro D, Martins E, Torres-Torrillas M, Peláez P, Miguel-Pastor L, Del Romero A, Damiá E, Cuervo B, Carrillo JM, Cugat R, Sopena JJ, Rubio M. Multilineage-Differentiating Stress-Enduring Cells (Muse Cells): The Future of Human and Veterinary Regenerative Medicine. Biomedicines 2023; 11:biomedicines11020636. [PMID: 36831171 PMCID: PMC9953712 DOI: 10.3390/biomedicines11020636] [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: 01/31/2023] [Revised: 02/13/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
In recent years, several studies have been conducted on Muse cells mainly due to their pluripotency, high tolerance to stress, self-renewal capacity, ability to repair DNA damage and not being tumoral. Additionally, since these stem cells can be isolated from different tissues in the adult organism, obtaining them is not considered an ethical problem, providing an advantage over embryonic stem cells. Regarding their therapeutic potential, few studies have reported clinical applications in the treatment of different diseases, such as aortic aneurysm and chondral injuries in the mouse or acute myocardial infarction in the swine, rabbit, sheep and in humans. This review aims to describe the characterization of Muse cells, show their biological characteristics, explain the differences between Muse cells and mesenchymal stem cells, and present their contribution to the treatment of some diseases.
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Affiliation(s)
- María Gemma Velasco
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Katy Satué
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Deborah Chicharro
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Emma Martins
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Marta Torres-Torrillas
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Pau Peláez
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Laura Miguel-Pastor
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Ayla Del Romero
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Elena Damiá
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Belén Cuervo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - José María Carrillo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Ramón Cugat
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Joaquín Jesús Sopena
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
- Correspondence:
| | - Mónica Rubio
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
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18
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Sun F, Zhang Y, Wu X, Xu X, Zhu C, Huang W. Breviscapine Combined with BMSCs Reduces Aβ Deposition in Rat with Alzheimer's Disease by Regulating Circular RNA ciRS-7. Curr Mol Med 2023; 23:76-86. [PMID: 35048805 DOI: 10.2174/1566524022666220113151044] [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: 05/01/2021] [Revised: 11/05/2021] [Accepted: 11/25/2021] [Indexed: 12/16/2022]
Abstract
AIMS This study aimed to clarify that breviscapine combined with bone marrow mesenchymal stem cells (BMSCs) treatment can reduce Aβ deposition in Alzheimer's disease (AD) patients. BACKGROUND AD is a common degenerative disease of the central nervous system. Aβ protein deposition in the cerebral cortex and hippocampus causes neuronal peroxidation damage, synaptic dysfunction, neuroinflammation, and nerve cell apoptosis, and ultimately leads to AD. OBJECTIVE To investigate whether breviscapine combined with BMSCs treatment can reduce Aβ deposition in AD. METHODS The AD rat model was successfully induced by Aβ1-42. The expression of protein and mRNA was detected by western blot and reverse transcription-quantitative PCR (RT-qPCR), respectively. RESULTS In AD rat brain tissue, the expression of circular RNA ciRS-7 (ciRS-7), ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), and NF-kappaB p65 was significantly downregulated, and the expression of β-amyloid precursor protein (APP), β-site APPcleaving enzyme 1 (BAEC1), and Aβ was upregulated. The expression of ciRS-7, UCHL1, and p65 was significantly upregulated after breviscapine or BMSCs treatment, and there was increased APP and BAEC1 degradation. Notably, breviscapine combined with BMSCs treatment was more effective than either treatment alone. In SH-SY5Y cells, overexpression of ciRS-7 reduced Aβ deposition by upregulating UCHL1 to degrade APP and BAEC1, but these effects were reversed with inhibition of NF-kB signaling. Finally, knockdown of ciRS-7 elevated Aβ, APP, and BAEC1 expression in each group of rats compared with the control. CONCLUSION Breviscapine combined with BMSCs treatment can reduce Aβ deposition in AD rats and promote the degradation of APP and BAEC1 by activating NF-kB to promote UCHL1 expression.
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Affiliation(s)
- Fengqin Sun
- Department of Neurology, The Third People's Hospital of Yunnan Province, 292 Beijing Road, Kunming, 650011, China
| | - Yulin Zhang
- Department of Neurology, The Third People's Hospital of Yunnan Province, 292 Beijing Road, Kunming, 650011, China
| | - Xinran Wu
- Teaching Research Department, The Third People's Hospital of Yunnan Province, 292 Beijing Road, Kunming, 650011, China
| | - Xu Xu
- Department of Neurology, The Third People's Hospital of Yunnan Province, 292 Beijing Road, Kunming, 650011, China
| | - Chaodie Zhu
- Department of Neurology, The Third People's Hospital of Yunnan Province, 292 Beijing Road, Kunming, 650011, China
| | - Wei Huang
- Department of Neurology, The Third People's Hospital of Yunnan Province, 292 Beijing Road, Kunming, 650011, China
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19
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Bone Tissue and the Nervous System: What Do They Have in Common? Cells 2022; 12:cells12010051. [PMID: 36611845 PMCID: PMC9818711 DOI: 10.3390/cells12010051] [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: 09/29/2022] [Revised: 12/12/2022] [Accepted: 12/16/2022] [Indexed: 12/25/2022] Open
Abstract
Degenerative diseases affecting bone tissues and the brain represent important problems with high socio-economic impact. Certain bone diseases, such as osteoporosis, are considered risk factors for the progression of neurological disorders. Often, patients with neurodegenerative diseases have bone fractures or reduced mobility linked to osteoarthritis. The bone is a dynamic tissue involved not only in movement but also in the maintenance of mineral metabolism. Bone is also associated with the generation of both hematopoietic stem cells (HSCs), and thus the generation of the immune system, and mesenchymal stem cells (MSCs). Bone marrow is a lymphoid organ and contains MSCs and HSCs, both of which are involved in brain health via the production of cytokines with endocrine functions. Hence, it seems clear that bone is involved in the regulation of the neuronal system and vice versa. This review summarizes the recent knowledge on the interactions between the nervous system and bone and highlights the importance of the interaction between nerve and bone cells. In addition, experimental models that study the interaction between nerve and skeletal cells are discussed, and innovative models are suggested to better evaluate the molecular interactions between these two cell types.
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20
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Zhang L, Xiang J, Zhang F, Liu L, Hu C. MSCs can be a double-edged sword in tumorigenesis. Front Oncol 2022; 12:1047907. [PMID: 36439438 PMCID: PMC9685321 DOI: 10.3389/fonc.2022.1047907] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/14/2022] [Indexed: 08/10/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been used to treat various diseases including Alzheimer's disease and cancer. In particular, the immunomodulatory function of MSCs plays a major role in cancer therapy using stem cells. However, MSCs exert promotive and inhibitory effects on cancer. The immunomodulatory effects of MSCs in the tumor microenvironment (TME) are ambiguous, which is the primary reason for the different outcomes of MSCs therapies for tumors. This review discusses the use of MSCs in cancer immunotherapy and their immunomodulatory mechanisms in cancers.
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Affiliation(s)
- Lu Zhang
- Oncology Laboratory, Chongqing Key Laboratory of Translational Research for Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Junyu Xiang
- Department of Biomedical Materials Science, Third Military Medical University, Chongqing, China
| | - Fang Zhang
- Oncology Laboratory, Chongqing Key Laboratory of Translational Research for Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Limei Liu
- Oncology Laboratory, Chongqing Key Laboratory of Translational Research for Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Chongling Hu
- Hematological Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
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21
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Thanaskody K, Jusop AS, Tye GJ, Wan Kamarul Zaman WS, Dass SA, Nordin F. MSCs vs. iPSCs: Potential in therapeutic applications. Front Cell Dev Biol 2022; 10:1005926. [PMID: 36407112 PMCID: PMC9666898 DOI: 10.3389/fcell.2022.1005926] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/21/2022] [Indexed: 01/24/2023] Open
Abstract
Over the past 2 decades, mesenchymal stem cells (MSCs) have attracted a lot of interest as a unique therapeutic approach for a variety of diseases. MSCs are capable of self-renewal and multilineage differentiation capacity, immunomodulatory, and anti-inflammatory properties allowing it to play a role in regenerative medicine. Furthermore, MSCs are low in tumorigenicity and immune privileged, which permits the use of allogeneic MSCs for therapies that eliminate the need to collect MSCs directly from patients. Induced pluripotent stem cells (iPSCs) can be generated from adult cells through gene reprogramming with ectopic expression of specific pluripotency factors. Advancement in iPS technology avoids the destruction of embryos to make pluripotent cells, making it free of ethical concerns. iPSCs can self-renew and develop into a plethora of specialized cells making it a useful resource for regenerative medicine as they may be created from any human source. MSCs have also been used to treat individuals infected with the SARS-CoV-2 virus. MSCs have undergone more clinical trials than iPSCs due to high tumorigenicity, which can trigger oncogenic transformation. In this review, we discussed the overview of mesenchymal stem cells and induced pluripotent stem cells. We briefly present therapeutic approaches and COVID-19-related diseases using MSCs and iPSCs.
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Affiliation(s)
- Kalaiselvaan Thanaskody
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Amirah Syamimi Jusop
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Gee Jun Tye
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Wan Safwani Wan Kamarul Zaman
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia,Centre for Innovation in Medical Engineering (CIME), Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Sylvia Annabel Dass
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Fazlina Nordin
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia,*Correspondence: Fazlina Nordin,
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22
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Sun Y, Wang TE, Hu Q, Zhang W, Zeng Y, Lai X, Zhang L, Shi M. Systematic comparation of the biological and transcriptomic landscapes of human amniotic mesenchymal stem cells under serum-containing and serum-free conditions. Stem Cell Res Ther 2022; 13:490. [PMID: 36195964 PMCID: PMC9530421 DOI: 10.1186/s13287-022-03179-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 09/23/2022] [Indexed: 11/17/2022] Open
Abstract
Background Human amniotic mesenchymal stem cells (hAMSCs) are splendid cell sources for clinical application in the administration of numerous refractory and relapse diseases. Despite the preferable prospect of serum-free (SF) condition for cell product standardization and pathogenic contamination remission, yet the systematic and detailed impact upon hAMSCs at both cellular and transcriptomic levels is largely obscure. Methods For the purpose, we preconditioned hAMSCs under serum-containing (SC) and SF medium for 48 h and compared the biological signatures and biofunctions from the view of cell morphology, immunophenotypes, multi-lineage differentiation in vitro, cell vitality, cytokine expression, and immunosuppressive effect upon the subpopulations of T lymphocytes, together with the PI3K-AKT-mTOR signaling reactivation upon cell vitality. Meanwhile, we took advantage of RNA-SEQ and bioinformatic analyses to verify the gene expression profiling and genetic variation spectrum in the indicated hAMSCs. Results Compared with those maintained in SC medium, hAMSCs pretreated in SF conditions manifested conservation in cell morphology, immunophenotypes, adipogenic differentiation, and immunosuppressive effect upon the proliferation and activation of most of the T cell subpopulations, but with evaluated cytokine expression (e.g., TGF-β1, IDO1, NOS2) and declined osteogenic differentiation and cell proliferation as well as proapoptotic and apoptotic cells. The declined proliferation in the SF group was efficiently rescued by PI3K-AKT-mTOR signaling reactivation. Notably, hAMSCs cultured in SF and SC conditions revealed similarities in gene expression profiling and variations in genetic mutation at the transcriptome level. Instead, based on the differentially expressed genes and variable shear event analyses, we found those genes were mainly involved in DNA synthesis-, protein metabolism-, and cell vitality-associated biological processes and signaling pathways (e.g., P53, KRAS, PI3K-Akt-mTOR). Conclusions Collectively, our data revealed the multifaceted cellular and molecular properties of hAMSCs under SC and SF conditions, which suggested the feasibility of serum-free culture for the preferable preparation of standardized cell products for hAMSC drug development and clinical application. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03179-2.
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Affiliation(s)
- Yunyan Sun
- Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Hematology Research Center of Yunnan Province, Kunming, 650032, China.,Department of Hematology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, Kunming, 650118, China
| | - Ti-Er Wang
- Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Hematology Research Center of Yunnan Province, Kunming, 650032, China
| | - Qianwen Hu
- Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Hematology Research Center of Yunnan Province, Kunming, 650032, China
| | - Wenxia Zhang
- Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Yun Zeng
- Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Hematology Research Center of Yunnan Province, Kunming, 650032, China.
| | - Xun Lai
- Department of Hematology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, Kunming, 650118, China.
| | - Leisheng Zhang
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province & NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, 730000, China. .,Key Laboratory of Radiation Technology and Biophysics, Hefei Institute of Physical Science, Chinese Academy of Sciences, 350 Shushanhu Road, Shushan District, Hefei, 230031, Anhui, China. .,Center for Cellular Therapies, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, China.
| | - Mingxia Shi
- Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Hematology Research Center of Yunnan Province, Kunming, 650032, China.
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23
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Thamm K, Möbus K, Towers R, Baertschi S, Wetzel R, Wobus M, Segeletz S. A chemically defined biomimetic surface for enhanced isolation efficiency of high-quality human mesenchymal stromal cells under xenogeneic/serum-free conditions. Cytotherapy 2022; 24:1049-1059. [PMID: 35931601 DOI: 10.1016/j.jcyt.2022.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 05/23/2022] [Accepted: 06/10/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) are one of the most frequently used cell types in regenerative medicine and cell therapy. Generating sufficient cell numbers for MSC-based therapies is constrained by (i) their low abundance in tissues of origin, which imposes the need for significant ex vivo cell expansion; (ii) donor-specific characteristics, including MSC frequency/quality, that decline with disease state and increasing age; and (iii) cellular senescence, which is promoted by extensive cell expansion and results in decreased therapeutic functionality. The final yield of a manufacturing process is therefore primarily determined by the applied isolation procedure and its efficiency in isolating therapeutically active cells from donor tissue. To date, MSCs are predominantly isolated using media supplemented with either serum or its derivatives, which poses safety and consistency issues. METHODS To overcome these limitations while enabling robust MSC production with constant high yield and quality, the authors developed a chemically defined biomimetic surface coating called isoMATRIX (denovoMATRIX GmbH, Dresden, Germany) and tested its performance during isolation of MSCs. RESULTS The isoMATRIX facilitates the isolation of significantly higher numbers of MSCs in xenogeneic (xeno)/serum-free and chemically defined conditions. The isolated cells display a smaller cell size and higher proliferation rate than those derived from a serum-containing isolation procedure and a strong immunomodulatory capacity. The high proliferation rates can be maintained up to 5 passages after isolation and cells even benefit from a switch towards a proliferation-specific MSC matrix (myMATRIX MSC) (denovoMATRIX GmbH, Dresden, Germany). CONCLUSION In sum, isoMATRIX promotes enhanced xeno/serum-free and chemically defined isolation of human MSCs and supports consistent and reliable cell performance for improved stem cell-based therapies.
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Affiliation(s)
| | - Kristin Möbus
- Universitätskrankenhaus Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
| | - Russell Towers
- Universitätskrankenhaus Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
| | | | | | - Manja Wobus
- Universitätskrankenhaus Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
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24
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Hu J, Wang X. Alzheimer’s Disease: From Pathogenesis to Mesenchymal Stem Cell Therapy – Bridging the Missing Link. Front Cell Neurosci 2022; 15:811852. [PMID: 35197824 PMCID: PMC8859419 DOI: 10.3389/fncel.2021.811852] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide. With the increasing trend of population aging, the estimated number of AD continues to climb, causing enormous medical, social and economic burden to the society. Currently, no drug is available to cure the disease or slow down its progression. There is an urgent need to improve our understanding on the pathogenesis of AD and develop novel therapy to combat it. Despite the two well-known pathological hallmarks (extracellular amyloid plaques and intracellular Neurofibrillary Tangles), the exact mechanisms for selective degeneration and loss of neurons and synapses in AD remain to be elucidated. Cumulative studies have shown neuroinflammation plays a central role in pathogenesis of AD. Neuroinflammation is actively involved both in the onset and the subsequent progression of AD. Microglia are the central player in AD neuroinflammation. In this review, we first introduced the different theories proposed for the pathogenesis of AD, focusing on neuroinflammation, especially on microglia, systemic inflammation, and peripheral and central immune system crosstalk. We explored the possible mechanisms of action of stem cell therapy, which is the only treatment modality so far that has pleiotropic effects and can target multiple mechanisms in AD. Mesenchymal stem cells are currently the most widely used stem cell type in AD clinical trials. We summarized the ongoing major mesenchymal stem cell clinical trials in AD and showed how translational stem cell therapy is bridging the gap between basic science and clinical intervention in this devastating disorder.
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Affiliation(s)
- Jingqiong Hu
- Stem Cell Center, Department of Cell Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jingqiong Hu,
| | - Xiaochuan Wang
- Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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25
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Campos HC, Ribeiro DE, Hashiguchi D, Hukuda DY, Gimenes C, Romariz SAA, Ye Q, Tang Y, Ulrich H, Longo BM. Distinct Effects of the Hippocampal Transplantation of Neural and Mesenchymal Stem Cells in a Transgenic Model of Alzheimer's Disease. Stem Cell Rev Rep 2022; 18:781-791. [PMID: 34997526 DOI: 10.1007/s12015-021-10321-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2021] [Indexed: 12/19/2022]
Abstract
Alzheimer's disease (AD) is a severe disabling condition with no cure currently available, which accounts for 60-70% of all dementia cases worldwide. Therefore, the investigation of possible therapeutic strategies for AD is necessary. To this end, animal models corresponding to the main aspects of AD in humans have been widely used. Similar to AD patients, the double transgenic APPswe/PS1dE9 (APP/PS1) mice show cognitive deficits, hyperlocomotion, amyloid-β (Αβ) plaques in the cortex and hippocampus, and exacerbated inflammatory responses. Recent studies have shown that these neuropathological features could be reversed by stem cell transplantation. However, the effects induced by neural (NSC) and mesenchymal (MSC) stem cells has never been compared in an AD animal model. Therefore, the present study aimed to investigate whether transplantation of NSC or MSC into the hippocampus of APP/PS1 mice reverses AD-induced pathological alterations, evaluated by the locomotor activity (open field test), short- and long-term memory (object recognition) tests, Αβ plaques (6-E10), microglia distribution (Iba-1), M1 (iNOS) and M2 (ARG-1) microglial phenotype frequencies. NSC and MSC engraftment reduced the number of Αβ plaques and produced an increase in M2 microglia polarization in the hippocampus of APP/PS1 mice, suggesting an anti-inflammatory effect of stem cell transplantation. NSC also reversed the hyperlocomotor activity and increased the number of microglia in the hippocampus of APP/PS1 mice. No impairment of short or long-term memory was observed in APP/PS1 mice. Overall, this study highlights the potential beneficial effects of transplanting NSC or MSC for AD treatment.
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Affiliation(s)
- Henrique C Campos
- Laboratório de Neurofisiologia, Depto. Fisiologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Deidiane Elisa Ribeiro
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil
| | - Debora Hashiguchi
- Laboratório de Neurofisiologia, Depto. Fisiologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil.,Laboratório de Plasticidade Sináptica, Brain Institute, Federal University of Rio Grande do Norte, Natal, RN, 59078-900, Caixa Postal: 1524, Brazil
| | - Deborah Y Hukuda
- Laboratório de Neurofisiologia, Depto. Fisiologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Christiane Gimenes
- Laboratório de Neurofisiologia, Depto. Fisiologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Simone A A Romariz
- Laboratório de Neurofisiologia, Depto. Fisiologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Qing Ye
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil.,International Collaborative Centre On Big Science Plan for Purinergic Signalling, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.,Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, 610075, China
| | - Yong Tang
- International Collaborative Centre On Big Science Plan for Purinergic Signalling, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.,Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, 610075, China
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil.,International Collaborative Centre On Big Science Plan for Purinergic Signalling, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Beatriz Monteiro Longo
- Laboratório de Neurofisiologia, Depto. Fisiologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
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26
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Hastings N, Kuan WL, Osborne A, Kotter MRN. Therapeutic Potential of Astrocyte Transplantation. Cell Transplant 2022; 31:9636897221105499. [PMID: 35770772 PMCID: PMC9251977 DOI: 10.1177/09636897221105499] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cell transplantation is an attractive treatment strategy for a variety of brain disorders, as it promises to replenish lost functions and rejuvenate the brain. In particular, transplantation of astrocytes has come into light recently as a therapy for amyotrophic lateral sclerosis (ALS); moreover, grafting of astrocytes also showed positive results in models of other conditions ranging from neurodegenerative diseases of older age to traumatic injury and stroke. Despite clear differences in etiology, disorders such as ALS, Parkinson's, Alzheimer's, and Huntington's diseases, as well as traumatic injury and stroke, converge on a number of underlying astrocytic abnormalities, which include inflammatory changes, mitochondrial damage, calcium signaling disturbance, hemichannel opening, and loss of glutamate transporters. In this review, we examine these convergent pathways leading to astrocyte dysfunction, and explore the existing evidence for a therapeutic potential of transplantation of healthy astrocytes in various models. Existing literature presents a wide variety of methods to generate astrocytes, or relevant precursor cells, for subsequent transplantation, while described outcomes of this type of treatment also differ between studies. We take technical differences between methodologies into account to understand the variability of therapeutic benefits, or lack thereof, at a deeper level. We conclude by discussing some key requirements of an astrocyte graft that would be most suitable for clinical applications.
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Affiliation(s)
- Nataly Hastings
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.,Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Wei-Li Kuan
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Andrew Osborne
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Mark R N Kotter
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.,Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
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27
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Complement System in Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms222413647. [PMID: 34948444 PMCID: PMC8705098 DOI: 10.3390/ijms222413647] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/10/2021] [Accepted: 12/15/2021] [Indexed: 01/02/2023] Open
Abstract
Alzheimer’s disease is a type of dementia characterized by problems with short-term memory, cognition, and difficulties with activities of daily living. It is a progressive, neurodegenerative disorder. The complement system is an ancient part of the innate immune system and comprises of more than thirty serum and membrane-bound proteins. This system has three different activating pathways and culminates into the formation of a membrane attack complex that ultimately causes target cell lysis (usually pathogens) The complement system is involved in several important functions in the central nervous system (CNS) that include neurogenesis, synaptic pruning, apoptosis, and neuronal plasticity. Here, we discuss how the complement system is involved in the effective functioning of CNS, while also contributing to chronic neuroinflammation leading to neurodegenerative disorders such as Alzheimer’s disease. We also discuss potential targets in the complement system for stopping its harmful effects via neuroinflammation and provide perspective for the direction of future research in this field.
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28
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Chen C, Hu N, Wang J, Xu L, Jia XL, Fan X, Shi JX, Chen F, Tu Y, Wang YW, Li XH. Umbilical cord mesenchymal stem cells promote neurological repair after traumatic brain injury through regulating Treg/Th17 balance. Brain Res 2021; 1775:147711. [PMID: 34793756 DOI: 10.1016/j.brainres.2021.147711] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 10/18/2021] [Accepted: 11/03/2021] [Indexed: 12/11/2022]
Abstract
Traumatic brain injury (TBI) is a brain injury resulting from blunt mechanical external forces, which is a crucial public health and socioeconomic problem worldwide. TBI is one of the leading causes of death or disability. The primary injury of TBI is generally irreversible. Secondary injury caused by neuroinflammation could result in exacerbation of patients, which indicated that anti-inflammation and immunomodulatory were necessary for the treatment of TBI. Accumulated evidence reveals that the transplantation of umbilical cord mesenchymal stem cells (UCMSCs) could regulate the microenvironment in vivo and keep a balance of helper T 17(Th17)/ regulatory T cell (Treg). Therefore, it is reasonable to hypothesize that the UCMSCs could repair neurological impairment by maintaining the balance of Th17/Treg after TBI. In the study, we observed the phenomenon of trans-differentiation of T lymphocytes into Th17 cells after TBI. Rats were divided into Sham, TBI, and TBI + UCMSCs groups to explore the effects of the UCMSCs. The results manifested that trans-differentiation of Th17 into Treg was facilitated by UCMSCs, which was followed by promotion of neurological recovery and improvement of learning and memory in TBI rats. Furthermore, UCMSCs decreased the phosphorylation of nuclear factor-kappa B (NF-κB) and increased the expression of mothers against decapentaplegic homolog 3 (Smad3) in vivo and vitro experiments. In conclusion, UCMSCs maintained Th17/Treg balance via the transforming growth factor-β (TGF-β)/ Smad3/ NF-κB signaling pathway.
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Affiliation(s)
- Chong Chen
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Brain Science and Neural Engineering, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Neurotrauma Repair, Pingjin Hospital Brain Center, Characteristic Medical Center of PAPF, Tianjin 300162, China
| | - Nan Hu
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Brain Science and Neural Engineering, Tianjin University, Tianjin 300072, China
| | - Jing Wang
- Tianjin Key Laboratory of Neurotrauma Repair, Pingjin Hospital Brain Center, Characteristic Medical Center of PAPF, Tianjin 300162, China; Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
| | - Lin Xu
- Medical Psychology Section, Hubei General Hospital of Armed Police Force, Wuhan 430071, China
| | - Xiao-Li Jia
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Brain Science and Neural Engineering, Tianjin University, Tianjin 300072, China
| | - Xiu Fan
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Brain Science and Neural Engineering, Tianjin University, Tianjin 300072, China
| | - Jian-Xin Shi
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Brain Science and Neural Engineering, Tianjin University, Tianjin 300072, China
| | - Feng Chen
- Tianjin Key Laboratory of Neurotrauma Repair, Pingjin Hospital Brain Center, Characteristic Medical Center of PAPF, Tianjin 300162, China
| | - Yue Tu
- Tianjin Key Laboratory of Neurotrauma Repair, Pingjin Hospital Brain Center, Characteristic Medical Center of PAPF, Tianjin 300162, China
| | - You-Wei Wang
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Brain Science and Neural Engineering, Tianjin University, Tianjin 300072, China.
| | - Xiao-Hong Li
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Brain Science and Neural Engineering, Tianjin University, Tianjin 300072, China.
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29
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Lee C, Kim M, Han J, Yoon M, Jung Y. Mesenchymal Stem Cells Influence Activation of Hepatic Stellate Cells, and Constitute a Promising Therapy for Liver Fibrosis. Biomedicines 2021; 9:1598. [PMID: 34829827 PMCID: PMC8615475 DOI: 10.3390/biomedicines9111598] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/29/2021] [Accepted: 10/30/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a common feature of chronic liver disease. Activated hepatic stellate cells (HSCs) are the main drivers of extracellular matrix accumulation in liver fibrosis. Hence, a strategy for regulating HSC activation is crucial in treating liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent stem cells derived from various post-natal organs. Therapeutic approaches involving MSCs have been studied extensively in various diseases, including liver disease. MSCs modulate hepatic inflammation and fibrosis and/or differentiate into hepatocytes by interacting directly with immune cells, HSCs, and hepatocytes and secreting modulators, thereby contributing to reduced liver fibrosis. Cell-free therapy including MSC-released secretomes and extracellular vesicles has elicited extensive attention because they could overcome MSC transplantation limitations. Herein, we provide basic information on hepatic fibrogenesis and the therapeutic potential of MSCs. We also review findings presenting the effects of MSC itself and MSC-based cell-free treatments in liver fibrosis, focusing on HSC activation. Growing evidence supports the anti-fibrotic function of either MSC itself or MSC modulators, although the mechanism underpinning their effects on liver fibrosis has not been established. Further studies are required to investigate the detailed mechanism explaining their functions to expand MSC therapies using the cell itself and cell-free treatments for liver fibrosis.
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Affiliation(s)
- Chanbin Lee
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Minju Kim
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Jinsol Han
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Myunghee Yoon
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Biomedical Research Institute, Pusan National University, Pusan 46241, Korea;
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
- Departments of Biological Sciences, Pusan National University, Pusan 46241, Korea
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30
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Vatsa P, Negi R, Ansari UA, Khanna VK, Pant AB. Insights of Extracellular Vesicles of Mesenchymal Stem Cells: a Prospective Cell-Free Regenerative Medicine for Neurodegenerative Disorders. Mol Neurobiol 2021; 59:459-474. [PMID: 34714469 DOI: 10.1007/s12035-021-02603-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/15/2021] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent, adult stem cells which are found in numerous tissues like the umbilical cord, Wharton's jelly, bone marrow, and adipose tissue. They possess the capacity of self-renewal by dividing and differentiating into various cellular lineages. Their characteristic therapeutic potential exploited so far has made them a desirable candidate in regenerative medicine. Neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and ischemic stroke have been treated with MSCs and MSC-derived products. Over the past few decades, we have witnessed significant contributions in discovering the etiology of various NDs and their possible therapeutic solutions. One of the MSC-based therapeutics is extracellular vesicles (EVs), which contain multiple biologically active molecules like nucleic acids and proteins. The contents of EVs are ferried between cells for intercellular communication which then leads to regulation of the homeostasis of recipient cells. EVs serve as a considerable means of cell-free therapies like for tissue repair or regeneration as EVs can maintain therapeutically effective cargo of parent cells and are free of various ethical issues in cell-based therapies. Due to paucity of standard protocols in extraction procedures of EVs and their pharmacological properties and mechanisms, the development of new EV dependent therapies is challenging. With this review, an attempt has been made to annotate these mechanisms, which can help advance the novel therapeutic approaches towards the treat and define a more narrowed down approach for each ND to devise effective MSC-based therapies to cure and avert these diseases.
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Affiliation(s)
- P Vatsa
- System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, P.O. Box No. 80, Lucknow, Uttar Pradesh, 226001, India
- CSIR-Human Resource Development Centre (CSIR-HRDC) Campus, Academy of Scientific and Innovative Research (AcSIR), Postal Staff College Area, Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India
| | - R Negi
- System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, P.O. Box No. 80, Lucknow, Uttar Pradesh, 226001, India
- CSIR-Human Resource Development Centre (CSIR-HRDC) Campus, Academy of Scientific and Innovative Research (AcSIR), Postal Staff College Area, Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India
| | - U A Ansari
- System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, P.O. Box No. 80, Lucknow, Uttar Pradesh, 226001, India
- CSIR-Human Resource Development Centre (CSIR-HRDC) Campus, Academy of Scientific and Innovative Research (AcSIR), Postal Staff College Area, Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India
| | - V K Khanna
- System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, P.O. Box No. 80, Lucknow, Uttar Pradesh, 226001, India
- CSIR-Human Resource Development Centre (CSIR-HRDC) Campus, Academy of Scientific and Innovative Research (AcSIR), Postal Staff College Area, Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India
| | - A B Pant
- System Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, P.O. Box No. 80, Lucknow, Uttar Pradesh, 226001, India.
- CSIR-Human Resource Development Centre (CSIR-HRDC) Campus, Academy of Scientific and Innovative Research (AcSIR), Postal Staff College Area, Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India.
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do Prado-Lima PAS, Costa-Ferro ZSM, Souza BSDF, da Cruz IBM, Lab B. Is there a place for cellular therapy in depression? World J Psychiatry 2021; 11:553-567. [PMID: 34631460 PMCID: PMC8474995 DOI: 10.5498/wjp.v11.i9.553] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/05/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Although efforts have been made to improve the pharmacological treatment of depression, approximately one-third of patients with depression do not respond to conventional therapy using antidepressants. Other potential non-pharmacological therapies have been studied in the last years, including the use of mesenchymal stem cell therapies to treat depression. These therapies are reviewed here since it is clinically relevant to develop innovative therapeutics to treat psychiatric patients. Experimental data corroborate that mesenchymal stem cell therapy could be considered a potential treatment for depression based on its anti-inflammatory and neurotrophic properties. However, some clinical trials involving treatment of depression with stem cells are in progress, but with no published results. These studies and other future clinical investigations will be crucial to define how much mesenchymal stem cells can effectively be used in psychiatric clinics as a strategy for supporting depression treatment.
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Affiliation(s)
- Pedro Antônio Schmidt do Prado-Lima
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Rio Grande do Sul, Brazil
| | - Zaquer Suzana Munhoz Costa-Ferro
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Rio Grande do Sul, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador 41253-190, Bahia, Brazil
- D’Or Institute for Research and Education (IDOR), Salvador 41253-190, Bahia, Brazil
| | - Bruno Solano de Freitas Souza
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador 41253-190, Bahia, Brazil
- D’Or Institute for Research and Education (IDOR), Salvador 41253-190, Bahia, Brazil
- Laboratory of Tissue Engineering and Immunopharmacology, Gonçalo Moniz Institute, Fiocruz, Salvador 40296-710, Bahia, Brazil
| | | | - Biogenomics Lab
- Health Sciences Center, Federal University of Santa Maria, Santa Maria 97105900, RS, Brazil
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Lee DY, Lee SE, Kwon DH, Nithiyanandam S, Lee MH, Hwang JS, Basith S, Ahn JH, Shin TH, Lee G. Strategies to Improve the Quality and Freshness of Human Bone Marrow-Derived Mesenchymal Stem Cells for Neurological Diseases. Stem Cells Int 2021; 2021:8444599. [PMID: 34539792 PMCID: PMC8445711 DOI: 10.1155/2021/8444599] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/26/2021] [Indexed: 12/14/2022] Open
Abstract
Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) have been studied for their application to manage various neurological diseases, owing to their anti-inflammatory, immunomodulatory, paracrine, and antiapoptotic ability, as well as their homing capacity to specific regions of brain injury. Among mesenchymal stem cells, such as BM-MSCs, adipose-derived MSCs, and umbilical cord MSCs, BM-MSCs have many merits as cell therapeutic agents based on their widespread availability and relatively easy attainability and in vitro handling. For stem cell-based therapy with BM-MSCs, it is essential to perform ex vivo expansion as low numbers of MSCs are obtained in bone marrow aspirates. Depending on timing, before hBM-MSC transplantation into patients, after detaching them from the culture dish, cell viability, deformability, cell size, and membrane fluidity are decreased, whereas reactive oxygen species generation, lipid peroxidation, and cytosolic vacuoles are increased. Thus, the quality and freshness of hBM-MSCs decrease over time after detachment from the culture dish. Especially, for neurological disease cell therapy, the deformability of BM-MSCs is particularly important in the brain for the development of microvessels. As studies on the traditional characteristics of hBM-MSCs before transplantation into the brain are very limited, omics and machine learning approaches are needed to evaluate cell conditions with indepth and comprehensive analyses. Here, we provide an overview of hBM-MSCs, the application of these cells to various neurological diseases, and improvements in their quality and freshness based on integrated omics after detachment from the culture dish for successful cell therapy.
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Affiliation(s)
- Da Yeon Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Sung Eun Lee
- Department of Emergency Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Do Hyeon Kwon
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | | | - Mi Ha Lee
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | - Ji Su Hwang
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | - Shaherin Basith
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jung Hwan Ahn
- Department of Emergency Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Tae Hwan Shin
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Gwang Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
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Skok M. Mesenchymal stem cells as a potential therapeutic tool to cure cognitive impairment caused by neuroinflammation. World J Stem Cells 2021; 13:1072-1083. [PMID: 34567426 PMCID: PMC8422935 DOI: 10.4252/wjsc.v13.i8.1072] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/28/2021] [Accepted: 07/29/2021] [Indexed: 02/06/2023] Open
Abstract
An established contribution of neuroinflammation to multiple brain pathologies has raised the requirement for therapeutic strategies to overcome it in order to prevent age- and disease-dependent cognitive decline. Mesenchymal stem cells (MSCs) produce multiple growth and neurotrophic factors and seem to evade immune rejection due to low expression of major histocompatibility complex class I molecules. Therefore, MSCs are widely used in experiments and clinical trials of regenerative medicine. This review summarizes recent data concerning the optimization of MSC use for therapeutic purposes with the emphasis on the achievements of the last 2 years. Specific attention is paid to extracellular vesicles secreted by MSCs and to the role of α7 nicotinic acetylcholine receptors. The reviewed data demonstrate that MSCs have a significant therapeutic potential in treating neuroinflammation-related cognitive disfunctions including age-related neurodegenerative diseases. The novel data demonstrate that maximal therapeutic effect is being achieved when MSCs penetrate the brain and produce their stimulating factors in situ. Consequently, therapeutic application using MSCs should include measures to facilitate their homing to the brain, support the survival in the brain microenvironment, and stimulate the production of neurotrophic and anti-inflammatory factors. These measures include but are not limited to genetic modification of MSCs and pre-conditioning before transplantation.
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Affiliation(s)
- Maryna Skok
- Department of Molecular Immunology, Palladin Institute of Biochemistry NAS of Ukraine, Kyiv 01054, Ukraine
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34
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Sharma HS, Muresanu DF, Castellani RJ, Nozari A, Lafuente JV, Buzoianu AD, Sahib S, Tian ZR, Bryukhovetskiy I, Manzhulo I, Menon PK, Patnaik R, Wiklund L, Sharma A. Alzheimer's disease neuropathology is exacerbated following traumatic brain injury. Neuroprotection by co-administration of nanowired mesenchymal stem cells and cerebrolysin with monoclonal antibodies to amyloid beta peptide. PROGRESS IN BRAIN RESEARCH 2021; 265:1-97. [PMID: 34560919 DOI: 10.1016/bs.pbr.2021.04.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Military personnel are prone to traumatic brain injury (TBI) that is one of the risk factors in developing Alzheimer's disease (AD) at a later stage. TBI induces breakdown of the blood-brain barrier (BBB) to serum proteins into the brain and leads to extravasation of plasma amyloid beta peptide (ΑβP) into the brain fluid compartments causing AD brain pathology. Thus, there is a need to expand our knowledge on the role of TBI in AD. In addition, exploration of the novel roles of nanomedicine in AD and TBI for neuroprotection is the need of the hour. Since stem cells and neurotrophic factors play important roles in TBI and in AD, it is likely that nanodelivery of these agents exert superior neuroprotection in TBI induced exacerbation of AD brain pathology. In this review, these aspects are examined in details based on our own investigations in the light of current scientific literature in the field. Our observations show that TBI exacerbates AD brain pathology and TiO2 nanowired delivery of mesenchymal stem cells together with cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments, and monoclonal antibodies to amyloid beta protein thwarted the development of neuropathology following TBI in AD, not reported earlier.
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Affiliation(s)
- 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.
| | - Dafin F Muresanu
- Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania; "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - Rudy J Castellani
- Department of Pathology, University of Maryland, Baltimore, MD, United States
| | - Ala Nozari
- Anesthesiology & Intensive Care, Massachusetts General Hospital, Boston, MA, United States
| | - 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
| | - Seaab Sahib
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Igor Bryukhovetskiy
- Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia; Laboratory of Pharmacology, National Scientific Center of Marine Biology, Far East Branch of the Russian Academy of Sciences, Vladivostok, Russia
| | - Igor Manzhulo
- Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia; Laboratory of Pharmacology, National Scientific Center of Marine Biology, Far East Branch of the Russian Academy of Sciences, Vladivostok, Russia
| | - Preeti K Menon
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Ranjana Patnaik
- Department of Biomaterials, School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
| | - 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
| | - 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.
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Wedzinska A, Figiel-Dabrowska A, Kozlowska H, Sarnowska A. The Effect of Proinflammatory Cytokines on the Proliferation, Migration and Secretory Activity of Mesenchymal Stem/Stromal Cells (WJ-MSCs) under 5% O 2 and 21% O 2 Culture Conditions. J Clin Med 2021; 10:1813. [PMID: 33919308 PMCID: PMC8122617 DOI: 10.3390/jcm10091813] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/24/2021] [Accepted: 04/17/2021] [Indexed: 11/16/2022] Open
Abstract
Treatment with Mesenchymal Stem/Stromal Cells (MSCs) in clinical trials is becoming one of the most-popular and fast-developing branches of modern regenerative medicine, as it is still in an experimental phase. The cross-section of diseases to which these cells are applied is very wide, ranging from degenerative diseases, through autoimmune processes and to acute inflammatory diseases, e.g., viral infections. Indeed, now that first clinical trials applying MSCs against COVID-19 have started, important questions concern not only the therapeutic properties of MSCs, but also the changes that might occur in the cell features as a response to the "cytokine storm" present in the acute phase of an infection and capable of posing a risk to a patient. The aim of our study was thus to assess changes potentially occurring in the biology of MSCs in the active inflammatory environment, e.g., in regards to the cell cycle, cell migration and secretory capacity. The study using MSCs derived from Wharton's jelly (WJ-MSCs) was conducted under two aerobic conditions: 21% O2 vs. 5% O2, since oxygen concentration is one of the key factors in inflammation. Under both oxygen conditions cells were exposed to proinflammatory cytokines involved significantly in acute inflammation, i.e., IFNγ, TNFα and IL-1β at different concentrations. Regardless of the aerobic conditions, WJ-MSCs in the inflammatory environment do not lose features typical for mesenchymal cells, and their proliferation dynamic remains unchanged. Sudden fluctuations in proliferation, the early indicator of potential genetic disturbance, were not observed, while the cells' migration activity increased. The presence of pro-inflammatory factors was also found to increase the secretion of such anti-inflammatory cytokines as IL-4 and IL-10. It is concluded that the inflammatory milieu in vitro does not cause phenotype changes or give rise to proliferation disruption of WJ-MSCs, and nor does it inhibit the secretory properties providing for their use against acute inflammation.
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Affiliation(s)
- Aleksandra Wedzinska
- Mossakowski Medical Research Centre, Translational Platform for Regenerative Medicine, Polish Academy of Sciences, 02-106 Warsaw, Poland; (A.W.); (A.F.-D.)
| | - Anna Figiel-Dabrowska
- Mossakowski Medical Research Centre, Translational Platform for Regenerative Medicine, Polish Academy of Sciences, 02-106 Warsaw, Poland; (A.W.); (A.F.-D.)
| | - Hanna Kozlowska
- Mossakowski Medical Research Centre, Laboratory of Advanced Microscopy Techniques, Polish Academy of Sciences, 02-106 Warsaw, Poland;
| | - Anna Sarnowska
- Mossakowski Medical Research Centre, Translational Platform for Regenerative Medicine, Polish Academy of Sciences, 02-106 Warsaw, Poland; (A.W.); (A.F.-D.)
- Mossakowski Medical Research Centre, Stem Cell Bioengineering Unit, Polish Academy of Sciences, 02-106 Warsaw, Poland
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36
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Eradication of specific donor-dependent variations of mesenchymal stem cells in immunomodulation to enhance therapeutic values. Cell Death Dis 2021; 12:357. [PMID: 33824286 PMCID: PMC8024246 DOI: 10.1038/s41419-021-03644-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 12/16/2022]
Abstract
Mesenchymal stem cells (MSCs) are one of the most widely clinically trialed stem cells, due to their abilities to differentiate into multiple cell lineages, to secrete regenerative/rejuvenative factors, and to modulate immune functions, among others. In this study, we analyzed human umbilical-cord-derived MSCs from 32 donors and revealed donor-dependent variations in two non-correlated properties, (1) cell proliferation, and (2) immune modulatory functions in vitro and in vivo, which might explain inconsistent clinical efficacies of MSCs. Through unbiased transcriptomic analyses, we discovered that IFN-γ and NF-κB signaling were positively associated with immune modulatory function of MSCs. Activation of these two pathways via IFN-γ and TNF-α treatment eradicated donor-dependent variations. Additional transcriptomic analyses revealed that treatment with these two factors, while having abolished donor-dependent variations in immune modulatory function, did not overall make different donor-derived MSCs the same at whole transcriptomic levels, demonstrating that the cells were still different in many other biological perspectives, and may not perform equally for therapeutic purposes other than immune modulation. Pre-selection or pre-treatment to eradicate MSC variations in a disease-treatment-specific manner would therefore be necessary to ensure clinical efficacies. Together this study provided novel insights into the quality control perspective of using different-donor-derived MSCs to treat inflammation-related clinical conditions and/or autoimmune diseases.
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Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal Stem Cells for Neurological Disorders. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2002944. [PMID: 33854883 PMCID: PMC8024997 DOI: 10.1002/advs.202002944] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 11/23/2020] [Indexed: 05/13/2023]
Abstract
Neurological disorders are becoming a growing burden as society ages, and there is a compelling need to address this spiraling problem. Stem cell-based regenerative medicine is becoming an increasingly attractive approach to designing therapies for such disorders. The unique characteristics of mesenchymal stem cells (MSCs) make them among the most sought after cell sources. Researchers have extensively studied the modulatory properties of MSCs and their engineering, labeling, and delivery methods to the brain. The first part of this review provides an overview of studies on the application of MSCs to various neurological diseases, including stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and other less frequently studied clinical entities. In the second part, stem cell delivery to the brain is focused. This fundamental but still understudied problem needs to be overcome to apply stem cells to brain diseases successfully. Here the value of cell engineering is also emphasized to facilitate MSC diapedesis, migration, and homing to brain areas affected by the disease to implement precision medicine paradigms into stem cell-based therapies.
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Affiliation(s)
- Anna Andrzejewska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Sylwia Dabrowska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Barbara Lukomska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Miroslaw Janowski
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
- Center for Advanced Imaging ResearchDepartment of Diagnostic Radiology and Nuclear MedicineUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
- Tumor Immunology and Immunotherapy ProgramUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
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38
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Khan I, Prabhakar A, Delepine C, Tsang H, Pham V, Sur M. A low-cost 3D printed microfluidic bioreactor and imaging chamber for live-organoid imaging. BIOMICROFLUIDICS 2021; 15:024105. [PMID: 33868534 PMCID: PMC8043249 DOI: 10.1063/5.0041027] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/01/2021] [Indexed: 05/03/2023]
Abstract
Organoids are biological systems grown in vitro and are observed to self-organize into 3D cellular tissues of specific organs. Brain organoids have emerged as valuable models for the study of human brain development in health and disease. Researchers are now in need of improved culturing and imaging tools to capture the in vitro dynamics of development processes in the brain. Here, we describe the design of a microfluidic chip and bioreactor, to enable in situ tracking and imaging of brain organoids on-chip. The low-cost 3D printed microfluidic bioreactor supports organoid growth and provides an optimal imaging chamber for live-organoid imaging, with drug delivery support. This fully isolated design of a live-cell imaging and culturing platform enables long-term live-imaging of the intact live brain organoids as it grows. We can thus analyze their self-organization in a controlled environment with high temporal and spatial resolution.
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Affiliation(s)
- Ikram Khan
- Department of Electrical Engineering, Indian
Institute of Technology, Madras 600036, India
| | - Anil Prabhakar
- Department of Electrical Engineering, Indian
Institute of Technology, Madras 600036, India
| | - Chloe Delepine
- Picower Institute for Learning and Memory,
Department of Brain and Cognitive Sciences, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139, USA
| | - Hayley Tsang
- Picower Institute for Learning and Memory,
Department of Brain and Cognitive Sciences, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139, USA
| | - Vincent Pham
- Picower Institute for Learning and Memory,
Department of Brain and Cognitive Sciences, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139, USA
| | - Mriganka Sur
- Picower Institute for Learning and Memory,
Department of Brain and Cognitive Sciences, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139, USA
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Bagheri-Mohammadi S. Microglia in Alzheimer's Disease: The Role of Stem Cell-Microglia Interaction in Brain Homeostasis. Neurochem Res 2021; 46:141-148. [PMID: 33174075 DOI: 10.1007/s11064-020-03162-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 09/28/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022]
Abstract
Microglia as resident cells of the brain can regulate neural development and maintenance of neuronal networks. Any types of pathologic events or changes in brain homeostasis are involved in the activation of microglia. This activation depends on the context, type of the stressor, or pathology. Due to the release of a plethora of substances such as chemokines, cytokines, and growth factors, microglia able to influence the pathologic outcome. In Alzheimer's disease (AD) condition, the deposition of amyloid-β (Aβ) result in provokes the phenotypic activation of microglia and their elaboration of pro-inflammatory molecules. New investigations reveal that cellular therapy with stem cells might have therapeutic effects in preventing the pathogenesis of AD. Although many strategies have focused on the use of stem cells to regenerate damaged neurons, new researches have demonstrated the immune-regulatory feature of stem cells which can modulate the activity state of microglia as well as mediates neuroinflammation. Hence, understanding the molecular mechanisms involved in the brain homeostasis by the protective features of mesenchymal stem cells (MSCs) could lead to remedial treatment for AD.
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Affiliation(s)
- Saeid Bagheri-Mohammadi
- Department of Physiology and Neurophysiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Physiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
- Departments of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
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40
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Noueihed B, Rivera JC, Dabouz R, Abram P, Omri S, Lahaie I, Chemtob S. Mesenchymal Stromal Cells Promote Retinal Vascular Repair by Modulating Sema3E and IL-17A in a Model of Ischemic Retinopathy. Front Cell Dev Biol 2021; 9:630645. [PMID: 33553187 PMCID: PMC7859341 DOI: 10.3389/fcell.2021.630645] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022] Open
Abstract
Ischemic retinopathies (IRs), such as retinopathy of prematurity and diabetic retinopathy, are characterized by an initial phase of microvascular degeneration that results in retinal ischemia, followed by exaggerated pathologic neovascularization (NV). Mesenchymal stromal cells (MSCs) have potent pro-angiogenic and anti-inflammatory properties associated with tissue repair and regeneration, and in this regard exert protection to neurons in ischemic and degenerative conditions; however, the exact mechanisms underlying these functions remain largely unknown. Class III Semaphorins (A–G) are particularly implicated in regulating neural blood supply (as well as neurogenesis) by suppressing angiogenesis and affecting myeloid cell function; this is the case for distinct neuropillin-activating Sema3A as well as PlexinD1-activating Sema3E; but during IR the former Sema3A increases while Sema3E decreases. We investigated whether retinal vascular repair actions of MSCs are exerted by normalizing Semaphorin and downstream cytokines in IR. Intravitreal administration of MSCs or their secretome (MSCs-conditioned media [MSCs-CM]) significantly curtailed vasoobliteration as well as aberrant preretinal NV in a model of oxygen-induced retinopathy (OIR). The vascular repair effects of MSCs-CM in the ischemic retina were associated with restored levels of Sema3E. Vascular benefits of MSCs-CM were reversed by anti-Sema3E; while intravitreal injection of anti-angiogenic recombinant Sema3E (rSema3E) in OIR-subjected mice reproduced effects of MSCs-CM by inhibiting as expected preretinal NV but also by decreasing vasoobliteration. To explain these opposing vascular effects of Sema3E we found in OIR high retinal levels, respectively, of the pro- and anti-angiogenic IL-17A and Sema3A-regulating IL-1β; IL-17A positively affected expression of IL-1β. rSema3E decreased concentrations of these myeloid cell-derived pro-inflammatory cytokines in vitro and in vivo. Importantly, IL-17A suppression by MSCs-CM was abrogated by anti-Sema3E neutralizing antibody. Collectively, our findings provide novel evidence by which MSCs inhibit aberrant NV and diminish vasoobliteration (promoting revascularization) in retinopathy by restoring (at least in part) neuronal Sema3E levels that reduce pathological levels of IL-17A (and in turn other proinflammatory factors) in myeloid cells. The ability of MSCs to generate a microenvironment permissive for vascular regeneration by controlling the production of neuronal factors involved in immunomodulatory activities is a promising opportunity for stem cell therapy in ocular degenerative diseases.
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Affiliation(s)
- Baraa Noueihed
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada
| | - José Carlos Rivera
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada.,Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada
| | - Rabah Dabouz
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada
| | - Pénélope Abram
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada
| | - Samy Omri
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada
| | - Isabelle Lahaie
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada
| | - Sylvain Chemtob
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.,Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, Canada
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Yu Z, Ling Z, Lu L, Zhao J, Chen X, Xu P, Zou X. Regulatory Roles of Bone in Neurodegenerative Diseases. Front Aging Neurosci 2020; 12:610581. [PMID: 33408628 PMCID: PMC7779400 DOI: 10.3389/fnagi.2020.610581] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 11/24/2020] [Indexed: 12/18/2022] Open
Abstract
Osteoporosis and neurodegenerative diseases are two kinds of common disorders of the elderly, which often co-occur. Previous studies have shown the skeletal and central nervous systems are closely related to pathophysiology. As the main structural scaffold of the body, the bone is also a reservoir for stem cells, a primary lymphoid organ, and an important endocrine organ. It can interact with the brain through various bone-derived cells, mostly the mesenchymal and hematopoietic stem cells (HSCs). The bone marrow is also a place for generating immune cells, which could greatly influence brain functions. Finally, the proteins secreted by bones (osteokines) also play important roles in the growth and function of the brain. This article reviews the latest research studying the impact of bone-derived cells, bone-controlled immune system, and bone-secreted proteins on the brain, and evaluates how these factors are implicated in the progress of neurodegenerative diseases and their potential use in the diagnosis and treatment of these diseases.
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Affiliation(s)
- Zhengran Yu
- Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zemin Ling
- Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lin Lu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jin Zhao
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiang Chen
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Pingyi Xu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xuenong Zou
- Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Xu Z, Liu C, Wang R, Gao X, Hao C, Liu C. A combination of lycopene and human amniotic epithelial cells can ameliorate cognitive deficits and suppress neuroinflammatory signaling by choroid plexus in Alzheimer's disease rat. J Nutr Biochem 2020; 88:108558. [PMID: 33249184 DOI: 10.1016/j.jnutbio.2020.108558] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 10/09/2020] [Accepted: 11/21/2020] [Indexed: 12/31/2022]
Abstract
Neuroinflammation characterized by glial activation and release of proinflammatory mediators is considered to be correlated with cognitive deficits in Alzheimer's disease (AD). Previously, some studies have demonstrated that lycopene (LYCO) or human amniotic epithelial cells (HAECs) could attenuate inflammation in AD. Specifically, the choroid plexus (CP), an epithelial layer that forms the blood-cerebrospinal fluid barrier, is able to modulate the cognitive function, through changes in the neuroinflammatory response and in brain immune surveillance. However, it is unclear if LYCO can interact with HAECs to improve neuroinflammation at the CP. Thus, this study chose the region of interest, considered the feasibility of using a combination of LYCO and HAECs, as a therapeutic agent for immunomodulatory effects at the CP in an acutely induced AD rat model. Results showed that oral administration of LYCO, HAECs transplantation, and their combination significantly improved cognitive deficits in water maze test, decreased the level of proinflammatory mediators (TNF-α and IL-1β), increased the level of anti-inflammatory mediators (IL-10 and TGF-β1) in the cerebro-spinal fluid, and hippocampal tissue. Interestingly, LYCO administration, HAECs transplantation and their combination reversed the Aβ1-42 induced up-regulation of Toll like receptor 4 and nuclear factor-κB p65 mRNA and protein expressions at the CP. This study provided the novel experimental evidence for the influence of co-treatment with LYCO and HAECs on immunomodulatory capabilities of CP. It could also warrant therapeutic window for the pathophysiology of AD and the associated underlying mechanisms at the CP.
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Affiliation(s)
- Zhiguo Xu
- Xiehe Union East China Stem Cell & Gene Engineering Corp., Ltd; Zhejiang Umbilical Cord Blood Hematopoietic Stem Cell Bank; Huzhou, Zhejiang Province, P. R. China.
| | - Chao Liu
- Xiehe Union East China Stem Cell & Gene Engineering Corp., Ltd; Zhejiang Umbilical Cord Blood Hematopoietic Stem Cell Bank; Huzhou, Zhejiang Province, P. R. China.
| | - Rui Wang
- Department of Physiology, Huzhou University, Huzhou, Zhejiang Province, P. R. China.
| | - Xiren Gao
- Department of Physiology, Huzhou University, Huzhou, Zhejiang Province, P. R. China
| | - Chao Hao
- Xiehe Union East China Stem Cell & Gene Engineering Corp., Ltd; Zhejiang Umbilical Cord Blood Hematopoietic Stem Cell Bank; Huzhou, Zhejiang Province, P. R. China
| | - Chongbin Liu
- Department of Physiology, Huzhou University, Huzhou, Zhejiang Province, P. R. China; Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou University, Huzhou, Zhejiang Province, P. R. China.
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Wang LJ, Li XX, Hou J, Song XH, Xie WH, Shen L. Integrated Analyses of Mouse Stem Cell Transcriptomes Provide Clues for Stem Cell Maintenance and Transdifferentiation. Front Genet 2020; 11:563798. [PMID: 33101382 PMCID: PMC7500244 DOI: 10.3389/fgene.2020.563798] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 08/17/2020] [Indexed: 01/05/2023] Open
Abstract
In vivo cell fate reprogramming has emerged as a new method for understanding cell plasticity and as potential treatment for tissue regeneration. Highly efficient and precise reprogramming requires fully understanding of the transcriptomes which function within different cell types. Here, we adopt weighted gene co-expression network analysis (WGCNA) to explore the molecular mechanisms of self-renewal in several well-known stem cell types, including embryonic stem cells (ESC), primordial germ cells (PGC), spermatogonia stem cells (SSC), neural stem cells (NSC), mesenchymal stem cells (MSC), and hematopoietic stem cells (HSC). We identified 37 core genes that were up-regulated in all of the stem cell types examined, as well as stem cell correlated gene co-expression networks. The validation of the co-expression genes revealed a continued protein-protein interaction network that included 823 nodes and 3113 edges. Based on the topology, we identified six densely connected regions within the continued protein-protein interaction network. The SSC specific genes Itgam, Cxcr6, and Agtr2 bridged four densely connected regions that consisted primarily of HSC-, NSC-, and MSC-correlated genes. The expression levels of identified stem cell related transcription factors were confirmed consistent with bioinformatics prediction in ESCs and NSCs by qPCR. Exploring the mechanisms underlying adult stem cell self-renewal will aid in the understanding of stem cell pool maintenance and will promote more accurate and efficient strategies for tissue regeneration and repair.
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Affiliation(s)
- Li-Juan Wang
- Zibo Key Laboratory of New Drug Development of Neurodegenerative Diseases, Shandong Provincial Research Center for Bioinformatics Engineering and Technique, Institute of Biomedical Research, Shandong University of Technology, Zibo, China.,School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Xiao-Xiao Li
- Zibo Key Laboratory of New Drug Development of Neurodegenerative Diseases, Shandong Provincial Research Center for Bioinformatics Engineering and Technique, Institute of Biomedical Research, Shandong University of Technology, Zibo, China.,School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Jie Hou
- School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Xin-Hua Song
- School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Wen-Hai Xie
- Zibo Key Laboratory of New Drug Development of Neurodegenerative Diseases, Shandong Provincial Research Center for Bioinformatics Engineering and Technique, Institute of Biomedical Research, Shandong University of Technology, Zibo, China.,School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Liang Shen
- Zibo Key Laboratory of New Drug Development of Neurodegenerative Diseases, Shandong Provincial Research Center for Bioinformatics Engineering and Technique, Institute of Biomedical Research, Shandong University of Technology, Zibo, China.,School of Life Sciences, Shandong University of Technology, Zibo, China
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Binda A, Murano C, Rivolta I. Innovative Therapies and Nanomedicine Applications for the Treatment of Alzheimer's Disease: A State-of-the-Art (2017-2020). Int J Nanomedicine 2020; 15:6113-6135. [PMID: 32884267 PMCID: PMC7434571 DOI: 10.2147/ijn.s231480] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
The field of nanomedicine is constantly expanding. Since the first work dated in 1999, almost 28 thousand articles have been published, and more and more are published every year: just think that only in the last five years 20,855 have come out (source PUBMED) including original research and reviews. The goal of this review is to present the current knowledge about nanomedicine in Alzheimer’s disease, a widespread neurodegenerative disorder in the over 60 population that deeply affects memory and cognition. Thus, after a brief introduction on the pathology and on the state-of-the-art research for NPs passing the BBB, special attention is placed to new targets that can enter the interest of nanoparticle designers and to new promising therapies. The authors performed a literature review limited to the last three years (2017–2020) of available studies with the intention to present only novel formulations or approaches where at least in vitro studies have been performed. This choice was made because, while limiting the sector to nanotechnology applied to Alzheimer, an organic census of all the relevant news is difficult to obtain.
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Affiliation(s)
- Anna Binda
- School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB) 20900, Italy
| | - Carmen Murano
- School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB) 20900, Italy
| | - Ilaria Rivolta
- School of Medicine and Surgery, Nanomedicine Center NANOMIB, NeuroMI Milan Center for Neuroscience, University of Milano-Bicocca, Monza (MB) 20900, Italy
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