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Calvo B, Schembri-Wismayer P, Durán-Alonso MB. Age-Related Neurodegenerative Diseases: A Stem Cell's Perspective. Cells 2025; 14:347. [PMID: 40072076 PMCID: PMC11898746 DOI: 10.3390/cells14050347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 02/22/2025] [Accepted: 02/24/2025] [Indexed: 03/15/2025] Open
Abstract
Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and a concomitant decline in neurological function. Examples of this type of clinical condition are Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis. Age has been identified as a major risk in the etiology of these disorders, which explains their increased incidence in developed countries. Unfortunately, despite continued and intensive efforts, no cure has yet been found for any of these diseases; reliable markers that allow for an early diagnosis of the disease and the identification of key molecular events leading to disease onset and progression are lacking. Altered adult neurogenesis appears to precede the appearance of severe symptoms. Given the scarcity of human samples and the considerable differences with model species, increasingly complex human stem-cell-based models are being developed. These are shedding light on the molecular alterations that contribute to disease development, facilitating the identification of new clinical targets and providing a screening platform for the testing of candidate drugs. Moreover, the secretome and other promising features of these cell types are being explored, to use them as replacement cells of high plasticity or as co-adjuvant therapy in combinatorial treatments.
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Affiliation(s)
- Belén Calvo
- Faculty of Health Sciences, Catholic University of Ávila, 05005 Ávila, Spain;
| | - Pierre Schembri-Wismayer
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
| | - María Beatriz Durán-Alonso
- Department of Biochemistry and Molecular Biology and Physiology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain
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2
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Lee SW, Lim YJ, Kim HY, Kim W, Park WT, Ma MJ, Lee J, Seo MS, Kim YI, Park S, Choi SK, Lee GW. Immortalization of epidural fat-derived mesenchymal stem cells: In vitro characterization and adipocyte differentiation potential. World J Stem Cells 2025; 17:98777. [PMID: 39866894 PMCID: PMC11752455 DOI: 10.4252/wjsc.v17.i1.98777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 10/12/2024] [Accepted: 12/03/2024] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are promising candidates for regenerative therapy due to their self-renewal capability, multilineage differentiation potential, and immunomodulatory effects. The molecular characteristics of MSCs are influenced by their location. Recently, epidural fat (EF) and EF-derived MSCs (EF-MSCs) have garnered attention due to their potential benefits to the spinal microenvironment and their high expression of neural SC markers. However, their clinical applications are limited due to cell senescence and limited accessibility of EF. Although many studies have attempted to establish an immortalized, stable SC line, the characteristics of immortalized EF-MSCs remain to be clarified. AIM To establish and analyze stable immortalized EF-MSCs. METHODS The phenotypes of EF-MSCs were analyzed using optical microscopy. Cell immortalization was performed using lentiviral vectors. The biomolecular characteristics of the cells were analyzed by immunoblotting, quantitative PCR, and proteomics. RESULTS The immortalized EF-MSCs demonstrated a significantly extended lifespan compared to the control group, with well-preserved adipogenic potential and SC surface marker expression. Introduction of human telomerase reverse transcriptase genes markedly increased the lifespan of EF-MSCs. Proteomics analysis revealed substantial increase in the expression of DNA replication pathway components in immortalized EF-MSCs. CONCLUSION Immortalized EF-MSCs exhibited significantly enhanced proliferative capacity, retained adipogenic potential, and upregulated the expression of DNA replication pathway components.
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Affiliation(s)
- Seoung-Woo Lee
- Core Protein Resources Center, Daegu-Gyeongbuk Institute of Science and Technology, Daegu 42988, South Korea
| | - Young-Ju Lim
- Department of Orthopedic Surgery, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu 42415, South Korea
| | - Hee-Yeon Kim
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, South Korea
| | - Wansoo Kim
- School of Life Science, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, South Korea
| | - Wook-Tae Park
- Department of Orthopedic Surgery, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu 42415, South Korea
| | - Min-Jung Ma
- Laboratory of Veterinary Tissue Engineering, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, South Korea
| | - Junho Lee
- College of Veterinary Medicine, Kyungpook National University, Daegu 41566, South Korea
| | - Min-Soo Seo
- Department of Veterinary Tissue Engineering, Kyungpook National University, Daegu 41566, South Korea
| | | | - Sangbum Park
- Michigan State University, Institute for Quantitative Health Science & Engineering, East Lansing, MI 48824, United States
| | - Seong-Kyoon Choi
- Core Protein Resources Center, Daegu-Gyeongbuk Institute of Science and Technology, Daegu 42988, South Korea
| | - Gun Woo Lee
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Daegu 42415, South Korea.
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3
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Tong H, Yang T, Xu S, Li X, Liu L, Zhou G, Yang S, Yin S, Li XJ, Li S. Huntington's Disease: Complex Pathogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:3845. [PMID: 38612657 PMCID: PMC11011923 DOI: 10.3390/ijms25073845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/21/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
Huntington's disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (HTT), resulting in the production of the mutant huntingtin protein (mHTT) with a polyglutamine stretch in its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates and accumulates abnormally in neuronal nuclei and processes, leading to disruptions in multiple cellular functions. Although there is currently no effective curative treatment for HD, significant progress has been made in developing various therapeutic strategies to treat HD. In addition to drugs targeting the neuronal toxicity of mHTT, gene therapy approaches that aim to reduce the expression of the mutant HTT gene hold great promise for effective HD therapy. This review provides an overview of current HD treatments, discusses different therapeutic strategies, and aims to facilitate future therapeutic advancements in the field.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Xiao-Jiang Li
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (H.T.); (T.Y.); (S.X.); (X.L.); (L.L.); (G.Z.); (S.Y.); (S.Y.)
| | - Shihua Li
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (H.T.); (T.Y.); (S.X.); (X.L.); (L.L.); (G.Z.); (S.Y.); (S.Y.)
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4
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Yang L, Liu SC, Liu YY, Zhu FQ, Xiong MJ, Hu DX, Zhang WJ. Therapeutic role of neural stem cells in neurological diseases. Front Bioeng Biotechnol 2024; 12:1329712. [PMID: 38515621 PMCID: PMC10955145 DOI: 10.3389/fbioe.2024.1329712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 02/12/2024] [Indexed: 03/23/2024] Open
Abstract
The failure of endogenous repair is the main feature of neurological diseases that cannot recover the damaged tissue and the resulting dysfunction. Currently, the range of treatment options for neurological diseases is limited, and the approved drugs are used to treat neurological diseases, but the therapeutic effect is still not ideal. In recent years, different studies have revealed that neural stem cells (NSCs) have made exciting achievements in the treatment of neurological diseases. NSCs have the potential of self-renewal and differentiation, which shows great foreground as the replacement therapy of endogenous cells in neurological diseases, which broadens a new way of cell therapy. The biological functions of NSCs in the repair of nerve injury include neuroprotection, promoting axonal regeneration and remyelination, secretion of neurotrophic factors, immune regulation, and improve the inflammatory microenvironment of nerve injury. All these reveal that NSCs play an important role in improving the progression of neurological diseases. Therefore, it is of great significance to better understand the functional role of NSCs in the treatment of neurological diseases. In view of this, we comprehensively discussed the application and value of NSCs in neurological diseases as well as the existing problems and challenges.
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Affiliation(s)
- Ling Yang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
- Department of Physical Examination, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Si-Cheng Liu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Yi-Yi Liu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Fu-Qi Zhu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Mei-Juan Xiong
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Dong-Xia Hu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
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5
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Speidell A, Bin Abid N, Yano H. Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington's Disease: Mechanisms and Potential Therapeutics. Biomedicines 2023; 11:2275. [PMID: 37626771 PMCID: PMC10452871 DOI: 10.3390/biomedicines11082275] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is a major neurotrophin whose loss or interruption is well established to have numerous intersections with the pathogenesis of progressive neurological disorders. There is perhaps no greater example of disease pathogenesis resulting from the dysregulation of BDNF signaling than Huntington's disease (HD)-an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive impairments associated with basal ganglia dysfunction and the ultimate death of striatal projection neurons. Investigation of the collection of mechanisms leading to BDNF loss in HD highlights this neurotrophin's importance to neuronal viability and calls attention to opportunities for therapeutic interventions. Using electronic database searches of existing and forthcoming research, we constructed a literature review with the overarching goal of exploring the diverse set of molecular events that trigger BDNF dysregulation within HD. We highlighted research that investigated these major mechanisms in preclinical models of HD and connected these studies to those evaluating similar endpoints in human HD subjects. We also included a special focus on the growing body of literature detailing key transcriptomic and epigenetic alterations that affect BDNF abundance in HD. Finally, we offer critical evaluation of proposed neurotrophin-directed therapies and assessed clinical trials seeking to correct BDNF expression in HD individuals.
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Affiliation(s)
- Andrew Speidell
- Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; (A.S.); (N.B.A.)
| | - Noman Bin Abid
- Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; (A.S.); (N.B.A.)
| | - Hiroko Yano
- Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; (A.S.); (N.B.A.)
- Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
- Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
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Voloshin N, Tyurin-Kuzmin P, Karagyaur M, Akopyan Z, Kulebyakin K. Practical Use of Immortalized Cells in Medicine: Current Advances and Future Perspectives. Int J Mol Sci 2023; 24:12716. [PMID: 37628897 PMCID: PMC10454025 DOI: 10.3390/ijms241612716] [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: 06/21/2023] [Revised: 07/23/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
In modern science, immortalized cells are not only a convenient tool in fundamental research, but they are also increasingly used in practical medicine. This happens due to their advantages compared to the primary cells, such as the possibility to produce larger amounts of cells and to use them for longer periods of time, the convenience of genetic modification, the absence of donor-to-donor variability when comparing the results of different experiments, etc. On the other hand, immortalization comes with drawbacks: possibilities of malignant transformation and/or major phenotype change due to genetic modification itself or upon long-term cultivation appear. At first glance, such issues are huge hurdles in the way of immortalized cells translation into medicine. However, there are certain ways to overcome such barriers that we describe in this review. We determined four major areas of usage of immortalized cells for practical medicinal purposes, and each has its own means to negate the drawbacks associated with immortalization. Moreover, here we describe specific fields of application of immortalized cells in which these problems are of much lesser concern, for example, in some cases where the possibility of malignant growth is not there at all. In general, we can conclude that immortalized cells have their niches in certain areas of practical medicine where they can successfully compete with other therapeutic approaches, and more preclinical and clinical trials with them should be expected.
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Affiliation(s)
- Nikita Voloshin
- Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia; (N.V.); (P.T.-K.); (M.K.)
| | - Pyotr Tyurin-Kuzmin
- Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia; (N.V.); (P.T.-K.); (M.K.)
| | - Maxim Karagyaur
- Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia; (N.V.); (P.T.-K.); (M.K.)
| | - Zhanna Akopyan
- Medical Research and Education Center, Lomonosov Moscow State University, 119234 Moscow, Russia;
| | - Konstantin Kulebyakin
- Faculty of Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia; (N.V.); (P.T.-K.); (M.K.)
- Medical Research and Education Center, Lomonosov Moscow State University, 119234 Moscow, Russia;
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7
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Toh WS, Yarani R, El Andaloussi S, Cho BS, Choi C, Corteling R, De Fougerolles A, Gimona M, Herz J, Khoury M, Robbins PD, Williams D, Weiss DJ, Rohde E, Giebel B, Lim SK. A report on the International Society for Cell & Gene Therapy 2022 Scientific Signature Series, "Therapeutic advances with native and engineered human extracellular vesicles". Cytotherapy 2023; 25:810-814. [PMID: 36931996 DOI: 10.1016/j.jcyt.2023.02.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 02/15/2023] [Indexed: 03/17/2023]
Abstract
The International Society for Cell & Gene Therapy Scientific Signature Series event "Therapeutic Advances With Native and Engineered Human EVs" took place as part of the International Society for Cell & Gene Therapy 2022 Annual Meeting, held from May 4 to 7, 2022, in San Francisco, California, USA. This was the first signature series event on extracellular vesicles (EVs) and a timely reflection of the growing interest in EVs, including both native and engineered human EVs, for therapeutic applications. The event successfully gathered academic and industrial key opinion leaders to discuss the current state of the art in developing and understanding native and engineered EVs and applying our knowledge toward advancing EV therapeutics. Latest advancements in understanding the mechanisms by which native and engineered EVs exert their therapeutic effects against different diseases in animal models were presented, with some diseases such as psoriasis and osteoarthritis already reaching clinical testing of EVs. The discussion also covered various aspects relevant to advancing the clinical translation of EV therapies, including EV preparation, manufacturing, consistency, site(s) of action, route(s) of administration, and luminal cargo delivery of RNA and other compounds.
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Affiliation(s)
- Wei Seong Toh
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center, Copenhagen, Denmark
| | - Samir El Andaloussi
- Biomolecular Medicine, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Evox Therapeutics Limited, Oxford, UK
| | - Byong Seung Cho
- ExoCoBio Exosome Institute (EEI), ExoCoBio Inc., Seoul, South Korea
| | - Chulhee Choi
- ILIAS Innovation Center, ILIAS Biologics Inc., Daejeon, South Korea; Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
| | | | | | - Mario Gimona
- Good Manufacturing Practice Laboratory, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria; Department of Transfusion Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Josephine Herz
- Department of Pediatrics I, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Maroun Khoury
- IMPACT, Center for Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Paul D Robbins
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - Daniel J Weiss
- University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Eva Rohde
- Good Manufacturing Practice Laboratory, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria; Department of Transfusion Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
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8
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Jin Y, Li S, Yu Q, Chen T, Liu D. Application of stem cells in regeneration medicine. MedComm (Beijing) 2023; 4:e291. [PMID: 37337579 PMCID: PMC10276889 DOI: 10.1002/mco2.291] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 04/25/2023] [Accepted: 05/08/2023] [Indexed: 06/21/2023] Open
Abstract
Regeneration is a complex process affected by many elements independent or combined, including inflammation, proliferation, and tissue remodeling. Stem cells is a class of primitive cells with the potentiality of differentiation, regenerate with self-replication, multidirectional differentiation, and immunomodulatory functions. Stem cells and their cytokines not only inextricably linked to the regeneration of ectodermal and skin tissues, but also can be used for the treatment of a variety of chronic wounds. Stem cells can produce exosomes in a paracrine manner. Stem cell exosomes play an important role in tissue regeneration, repair, and accelerated wound healing, the biological properties of which are similar with stem cells, while stem cell exosomes are safer and more effective. Skin and bone tissues are critical organs in the body, which are essential for sustaining life activities. The weak repairing ability leads a pronounced impact on the quality of life of patients, which could be alleviated by stem cell exosomes treatment. However, there are obstacles that stem cells and stem cells exosomes trough skin for improved bioavailability. This paper summarizes the applications and mechanisms of stem cells and stem cells exosomes for skin and bone healing. We also propose new ways of utilizing stem cells and their exosomes through different nanoformulations, liposomes and nanoliposomes, polymer micelles, microspheres, hydrogels, and scaffold microneedles, to improve their use in tissue healing and regeneration.
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Affiliation(s)
- Ye Jin
- School of PharmacyChangchun University of Chinese MedicineChangchunJilinChina
| | - Shuangyang Li
- School of PharmacyChangchun University of Chinese MedicineChangchunJilinChina
| | - Qixuan Yu
- School of PharmacyChangchun University of Chinese MedicineChangchunJilinChina
| | - Tianli Chen
- School of PharmacyChangchun University of Chinese MedicineChangchunJilinChina
| | - Da Liu
- School of PharmacyChangchun University of Chinese MedicineChangchunJilinChina
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9
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Sutyagina OI, Beilin AK, Vorotelyak EA, Vasiliev AV. Immortalization Reversibility in the Context of Cell Therapy Biosafety. Int J Mol Sci 2023; 24:7738. [PMID: 37175444 PMCID: PMC10178325 DOI: 10.3390/ijms24097738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Immortalization (genetically induced prevention of replicative senescence) is a promising approach to obtain cellular material for cell therapy or for bio-artificial organs aimed at overcoming the problem of donor material shortage. Immortalization is reversed before cells are used in vivo to allow cell differentiation into the mature phenotype and avoid tumorigenic effects of unlimited cell proliferation. However, there is no certainty that the process of de-immortalization is 100% effective and that it does not cause unwanted changes in the cell. In this review, we discuss various approaches to reversible immortalization, emphasizing their advantages and disadvantages in terms of biosafety. We describe the most promising approaches in improving the biosafety of reversibly immortalized cells: CRISPR/Cas9-mediated immortogene insertion, tamoxifen-mediated self-recombination, tools for selection of successfully immortalized cells, using a decellularized extracellular matrix, and ensuring post-transplant safety with the use of suicide genes. The last process may be used as an add-on for previously existing reversible immortalized cell lines.
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Affiliation(s)
- Oksana I. Sutyagina
- N.K. Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Laboratory of Cell Biology, Vavilov Str. 26, 119334 Moscow, Russia
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10
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de Almeida MMA, Goodkey K, Voronova A. Regulation of microglia function by neural stem cells. Front Cell Neurosci 2023; 17:1130205. [PMID: 36937181 PMCID: PMC10014810 DOI: 10.3389/fncel.2023.1130205] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/13/2023] [Indexed: 03/05/2023] Open
Abstract
Neural stem and precursor cells (NPCs) build and regenerate the central nervous system (CNS) by maintaining their pool (self-renewal) and differentiating into neurons, astrocytes, and oligodendrocytes (multipotency) throughout life. This has inspired research into pro-regenerative therapies that utilize transplantation of exogenous NPCs or recruitment of endogenous adult NPCs for CNS regeneration and repair. Recent advances in single-cell RNA sequencing and other "omics" have revealed that NPCs express not just traditional progenitor-related genes, but also genes involved in immune function. Here, we review how NPCs exert immunomodulatory function by regulating the biology of microglia, immune cells that are present in NPC niches and throughout the CNS. We discuss the role of transplanted and endogenous NPCs in regulating microglia fates, such as survival, proliferation, migration, phagocytosis and activation, in the developing, injured and degenerating CNS. We also provide a literature review on NPC-specific mediators that are responsible for modulating microglia biology. Our review highlights the immunomodulatory properties of NPCs and the significance of these findings in the context of designing pro-regenerative therapies for degenerating and diseased CNS.
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Affiliation(s)
- Monique M. A. de Almeida
- Department of Medical Genetics, Faculty of Medicine & Dentistry, Edmonton, AB, Canada
- Faculty of Medicine & Dentistry, Neuroscience and Mental Health Institute, Edmonton, AB, Canada
| | - Kara Goodkey
- Department of Medical Genetics, Faculty of Medicine & Dentistry, Edmonton, AB, Canada
- Women and Children’s Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, Edmonton, AB, Canada
| | - Anastassia Voronova
- Department of Medical Genetics, Faculty of Medicine & Dentistry, Edmonton, AB, Canada
- Faculty of Medicine & Dentistry, Neuroscience and Mental Health Institute, Edmonton, AB, Canada
- Women and Children’s Health Research Institute, 5-083 Edmonton Clinic Health Academy, University of Alberta, Edmonton, AB, Canada
- Department of Cell Biology, Faculty of Medicine & Dentistry, Edmonton, AB, Canada
- Multiple Sclerosis Centre and Department of Cell Biology, Faculty of Medicine & Dentistry, Edmonton, AB, Canada
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11
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Mortimer KRH, Vernon-Browne H, Zille M, Didwischus N, Boltze J. Potential effects of commonly applied drugs on neural stem cell proliferation and viability: A hypothesis-generating systematic review and meta-analysis. Front Mol Neurosci 2022; 15:975697. [PMID: 36277493 PMCID: PMC9581168 DOI: 10.3389/fnmol.2022.975697] [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: 06/22/2022] [Accepted: 09/09/2022] [Indexed: 11/13/2022] Open
Abstract
Neural stem cell (NSC) transplantation is an emerging and promising approach to combat neurodegenerative diseases. While NSCs can differentiate into neural cell types, many therapeutic effects are mediated by paracrine, "drug-like" mechanisms. Neurodegenerative diseases are predominantly a burden of the elderly who commonly suffer from comorbidities and thus are subject to pharmacotherapies. There is substantial knowledge about drug-drug interactions but almost nothing is known about a potential impact of pharmacotherapy on NSCs. Such knowledge is decisive for designing tailored treatment programs for individual patients. Previous studies revealed preliminary evidence that the anti-depressants fluoxetine and imipramine may affect NSC viability and proliferation. Here, we derive a hypothesis on how commonly applied drugs, statins and antihypertensives, may affect NSC viability, proliferation, and differentiation. We conducted a systematic review and meta-analysis looking at potential effects of commonly prescribed antihypertensive and antihyperlipidemic medication on NSC function. PubMed and Web of Science databases were searched on according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Publications were assessed against a priori established selection criteria for relevancy. A meta-analysis was then performed on data extracted from publications eligible for full text review to estimate drug effects on NSC functions. Our systematic review identified 1,017 potential studies, 55 of which were eligible for full text review. Out of those, 21 were included in the qualitative synthesis. The meta-analysis was performed on 13 publications; the remainder were excluded as they met exclusion criteria or lacked sufficient data to perform a meta-analysis. The meta-analysis revealed that alpha-2 adrenoceptor agonists, an anti-hypertensive drug class [p < 0.05, 95% confidence intervals (CI) = -1.54; -0.35], and various statins [p < 0.05, 95% CI = -3.17; -0.0694] had an inhibiting effect on NSC proliferation. Moreover, we present preliminary evidence that L-type calcium channel blockers and statins, particularly lovastatin, may reduce NSC viability. Although the data available in the literature is limited, there are clear indications for an impact of commonly applied drugs, in particular statins, on NSC function. Considering the modes of action of the respective drugs, we reveal plausible mechanisms by which this impact may be mediated, creating a testable hypothesis, and providing insights into how future confirmative research on this topic may be conducted.
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Affiliation(s)
- Katherine R. H. Mortimer
- School of Life Sciences, University of Warwick, Coventry, United Kingdom
- Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | | | - Marietta Zille
- Division of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria
| | - Nadine Didwischus
- School of Life Sciences, University of Warwick, Coventry, United Kingdom
- Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
- Center for the Neural Basis of Cognition and Center for Neuroscience, McGowan Institute for Regenerative Medicine, Pittsburgh, PA, United States
| | - Johannes Boltze
- School of Life Sciences, University of Warwick, Coventry, United Kingdom
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Zhang SY, Zhao J, Ni JJ, Li H, Quan ZZ, Qing H. Application and prospects of high-throughput screening for in vitro neurogenesis. World J Stem Cells 2022; 14:393-419. [PMID: 35949394 PMCID: PMC9244953 DOI: 10.4252/wjsc.v14.i6.393] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/07/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Over the past few decades, high-throughput screening (HTS) has made great contributions to new drug discovery. HTS technology is equipped with higher throughput, minimized platforms, more automated and computerized operating systems, more efficient and sensitive detection devices, and rapid data processing systems. At the same time, in vitro neurogenesis is gradually becoming important in establishing models to investigate the mechanisms of neural disease or developmental processes. However, challenges remain in generating more mature and functional neurons with specific subtypes and in establishing robust and standardized three-dimensional (3D) in vitro models with neural cells cultured in 3D matrices or organoids representing specific brain regions. Here, we review the applications of HTS technologies on in vitro neurogenesis, especially aiming at identifying the essential genes, chemical small molecules and adaptive microenvironments that hold great prospects for generating functional neurons or more reproductive and homogeneous 3D organoids. We also discuss the developmental tendency of HTS technology, e.g., so-called next-generation screening, which utilizes 3D organoid-based screening combined with microfluidic devices to narrow the gap between in vitro models and in vivo situations both physiologically and pathologically.
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Affiliation(s)
- Shu-Yuan Zhang
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Juan Zhao
- Aerospace Medical Center, Aerospace Center Hospital, Beijing 100049, China
| | - Jun-Jun Ni
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Hui Li
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Zhen-Zhen Quan
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Hong Qing
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
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13
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Khodayari S, Khodayari H, Ebrahimi-Barough S, Khanmohammadi M, Islam MS, Vesovic M, Goodarzi A, Mahmoodzadeh H, Nayernia K, Aghdami N, Ai J. Stem Cell Therapy in Limb Ischemia: State-of-Art, Perspective, and Possible Impacts of Endometrial-Derived Stem Cells. Front Cell Dev Biol 2022; 10:834754. [PMID: 35676930 PMCID: PMC9168222 DOI: 10.3389/fcell.2022.834754] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
As an evidence-based performance, the rising incidence of various ischemic disorders has been observed across many nations. As a result, there is a growing need for the development of more effective regenerative approaches that could serve as main therapeutic strategies for the treatment of these diseases. From a cellular perspective, promoted complex inflammatory mechanisms, after inhibition of organ blood flow, can lead to cell death in all tissue types. In this case, using the stem cell technology provides a safe and regenerative approach for ischemic tissue revascularization and functional cell formation. Limb ischemia (LI) is one of the most frequent ischemic disease types and has been shown to have a promising regenerative response through stem cell therapy based on several clinical trials. Bone marrow-derived mononuclear cells (BM-MNCs), peripheral blood CD34-positive mononuclear cells (CD34+ PB-MNCs), mesenchymal stem cells (MSCs), and endothelial stem/progenitor cells (ESPCs) are the main, well-examined stem cell types in these studies. Additionally, our investigations reveal that endometrial tissue can be considered a suitable candidate for isolating new safe, effective, and feasible multipotent stem cells for limb regeneration. In addition to other teams’ results, our in-depth studies on endometrial-derived stem cells (EnSCs) have shown that these cells have translational potential for limb ischemia treatment. The EnSCs are able to generate diverse types of cells which are essential for limb reconstruction, including endothelial cells, smooth muscle cells, muscle cells, and even peripheral nervous system populations. Hence, the main object of this review is to present stem cell technology and evaluate its method of regeneration in ischemic limb tissue.
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Affiliation(s)
- Saeed Khodayari
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
- Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
- International Center for Personalized Medicine (P7MEDICINE), Düsseldorf, Germany
| | - Hamid Khodayari
- Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
- International Center for Personalized Medicine (P7MEDICINE), Düsseldorf, Germany
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Somayeh Ebrahimi-Barough
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Mehdi Khanmohammadi
- Skull Base Research Center, The Five Senses Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Md Shahidul Islam
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Miko Vesovic
- Department of Mathematics, Statistics, and Computer Science, University of Illinois at Chicago, Chicago, IL, United States
| | - Arash Goodarzi
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
| | | | - Karim Nayernia
- International Center for Personalized Medicine (P7MEDICINE), Düsseldorf, Germany
| | - Nasser Aghdami
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Infectious Diseases and Tropical Medicines, Tehran University of Medical Sciences, Tehran, Iran
- *Correspondence: Jafar Ai, ; Nasser Aghdami,
| | - Jafar Ai
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
- *Correspondence: Jafar Ai, ; Nasser Aghdami,
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14
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Du J, Liu X, Yarema KJ, Jia X. Glycoengineering human neural stem cells (hNSCs) for adhesion improvement using a novel thiol-modified N-acetylmannosamine (ManNAc) analog. BIOMATERIALS ADVANCES 2022; 134:112675. [PMID: 35599100 PMCID: PMC9300770 DOI: 10.1016/j.msec.2022.112675] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/16/2022] [Accepted: 01/18/2022] [Indexed: 12/20/2022]
Abstract
This study sets the stage for the therapeutic use of Ac5ManNTProp, an N-acetylmannosamine (ManNAc) analog that installs thiol-modified sialoglycans onto the surfaces of human neural stem cells (hNSC). First, we compared hNSC adhesion to the extracellular matrix (ECM) proteins laminin, fibronectin, and collagen and found preferential adhesion and concomitant changes to cell morphology and cell spreading for Ac5ManNTProp-treated cells to laminin, compared to fibronectin where there was a modest response, and collagen where there was no observable increase. PCR array transcript analysis identified several classes of cell adhesion molecules that responded to combined Ac5ManNTProp treatment and hNSC adhesion to laminin. Of these, we focused on integrin α6β1 expression, which was most strongly upregulated in analog-treated cells incubated on laminin. We also characterized downstream responses including vinculin display as well as the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-related kinase (ERK). In these experiments, Ac5ManNTProp more strongly induced all tested biological endpoints compared to Ac5ManNTGc, showing that the single methylene unit that structurally separates the two analogs finely tunes biological responses. Together, the concerted modulation of multiple pro-regenerative activities through Ac5ManNTProp treatment, in concert with crosstalk with ECM components, lays a foundation for using our metabolic glycoengineering approach to treat neurological disorders by favorably modulating endpoints that contribute to the viability of transplanted NSCs.
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Affiliation(s)
- Jian Du
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Xiao Liu
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Kevin J. Yarema
- Department of Biomedical Engineering, The Johns Hopkins School of Medicine, Baltimore, MD, 21205,Translational Cell and Tissue Engineering Center, The Johns Hopkins School of Medicine, Baltimore, MD, 21231
| | - Xiaofeng Jia
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Biomedical Engineering, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
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15
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Yu H, Commander CW, Stavas JM. Stem Cell-Based Therapies: What Interventional Radiologists Need to Know. Semin Intervent Radiol 2021; 38:523-534. [PMID: 34853498 DOI: 10.1055/s-0041-1736657] [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: 10/19/2022]
Abstract
As the basic units of biological organization, stem cells and their progenitors are essential for developing and regenerating organs and tissue systems using their unique self-renewal capability and differentiation potential into multiple cell lineages. Stem cells are consistently present throughout the entire human development, from the zygote to adulthood. Over the past decades, significant efforts have been made in biology, genetics, and biotechnology to develop stem cell-based therapies using embryonic and adult autologous or allogeneic stem cells for diseases without therapies or difficult to treat. Stem cell-based therapies require optimum administration of stem cells into damaged organs to promote structural regeneration and improve function. Maximum clinical efficacy is highly dependent on the successful delivery of stem cells to the target tissue. Direct image-guided locoregional injections into target tissues offer an option to increase therapeutic outcomes. Interventional radiologists have the opportunity to perform a key role in delivering stem cells more efficiently using minimally invasive techniques. This review discusses the types and sources of stem cells and the current clinical applications of stem cell-based therapies. In addition, the regulatory considerations, logistics, and potential roles of interventional Radiology are also discussed with the review of the literature.
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Affiliation(s)
- Hyeon Yu
- Division of Vascular and Interventional Radiology, Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.,ProKidney LLC, Winston Salem, North Carolina
| | - Clayton W Commander
- Division of Vascular and Interventional Radiology, Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Joseph M Stavas
- Department of Radiology, Creighton University School of Medicine, Omaha, Nebraska
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16
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Kim IK, Park JH, Kim B, Hwang KC, Song BW. Recent advances in stem cell therapy for neurodegenerative disease: Three dimensional tracing and its emerging use. World J Stem Cells 2021; 13:1215-1230. [PMID: 34630859 PMCID: PMC8474717 DOI: 10.4252/wjsc.v13.i9.1215] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/20/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative disease is a brain disorder caused by the loss of structure and function of neurons that lowers the quality of human life. Apart from the limited potential for endogenous regeneration, stem cell-based therapies hold considerable promise for maintaining homeostatic tissue regeneration and enhancing plasticity. Despite many studies, there remains insufficient evidence for stem cell tracing and its correlation with endogenous neural cells in brain tissue with three-dimensional structures. Recent advancements in tissue optical clearing techniques have been developed to overcome the existing shortcomings of cross-sectional tissue analysis in thick and complex tissues. This review focuses on recent progress of stem cell treatments to improve neurodegenerative disease, and introduces tissue optical clearing techniques that can implement a three-dimensional image as a proof of concept. This review provides a more comprehensive understanding of stem cell tracing that will play an important role in evaluating therapeutic efficacy and cellular interrelationship for regeneration in neurodegenerative diseases.
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Affiliation(s)
- Il-Kwon Kim
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea
| | - Jun-Hee Park
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
| | - Bomi Kim
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea.
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17
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Dahlenburg H, Cameron D, Yang S, Bachman A, Pollock K, Cary W, Pham M, Hendrix K, White J, Nelson H, Deng P, Anderson JS, Fink K, Nolta J. A novel Huntington's disease mouse model to assess the role of neuroinflammation on disease progression and to develop human cell therapies. Stem Cells Transl Med 2021; 10:1033-1043. [PMID: 33710799 PMCID: PMC8235129 DOI: 10.1002/sctm.20-0431] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 01/08/2021] [Accepted: 02/13/2021] [Indexed: 02/06/2023] Open
Abstract
Huntington's disease (HD) is a fatal autosomal-dominant neurodegenerative disease caused by a trinucleotide CAG repeat expansion of the huntingtin gene (HTT) that affects 1 in every 10 000 individuals in the United States. Our lab developed a novel immune deficient HD mouse strain, the YACNSG, from a commonly used line, the YAC128 mouse, to enable transplantation studies using engineered human cells in addition to studying the impact of the immune system on disease progression. The primary goal of this project was to characterize this novel immune deQficient HD mouse model, using behavioral assays and histology to compare this new model to the immune competent YAC128 and immune deficient mice that had engraftment of a human immune system. Flow cytometry was used to confirm that the YACNSG strain lacked immune cells, and in vivo imaging was used to assess human mesenchymal stem/stromal cell (MSC) retention compared with a commonly used immune deficient line, the NSG mouse. We found that YACNSG were able to retain human MSCs longer than the immune competent YAC128 mice. We performed behavioral assessments starting at 4 months of age and continued testing monthly until 12 months on the accelerod and in the open field. At 12 months, brains were isolated and evaluated using immunohistochemistry for striatal volume. Results from these studies suggest that the novel immune deficient YACNSG strain of mice could provide a good model for human stem-cell based therapies and that the immune system appears to play an important role in the pathology of HD.
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Affiliation(s)
- Heather Dahlenburg
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - David Cameron
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
- Department of NeurologyUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Sheng Yang
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Angelica Bachman
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Kari Pollock
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Whitney Cary
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Missy Pham
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Kyle Hendrix
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Jeannine White
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Haley Nelson
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Peter Deng
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
- Department of NeurologyUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Joseph S. Anderson
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Kyle Fink
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
- Department of NeurologyUniversity of California Davis HealthSacramentoCaliforniaUSA
| | - Jan Nolta
- Stem Cell Program and Institute for Regenerative CuresUniversity of California Davis HealthSacramentoCaliforniaUSA
- Department of Internal MedicineUniversity of California Davis HealthSacramentoCaliforniaUSA
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18
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Atkinson SP. A preview of selected articles-July 2021. Stem Cells Transl Med 2021; 10:939-942. [PMID: 34174022 PMCID: PMC8235125 DOI: 10.1002/sctm.21-0168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 05/05/2021] [Indexed: 11/27/2022] Open
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19
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Ye W, Yan Y, Tang Y, Dong X, Chen G, Kang J, Huang L, Xiong Q, Feng Z. Orexin-A Attenuates Inflammatory Responses in Lipopolysaccharide-Induced Neural Stem Cells by Regulating NF-KB and Phosphorylation of MAPK/P38/Erk Pathways. J Inflamm Res 2021; 14:2007-2017. [PMID: 34040413 PMCID: PMC8140926 DOI: 10.2147/jir.s308078] [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: 02/25/2021] [Accepted: 04/14/2021] [Indexed: 11/23/2022] Open
Abstract
Background Neuronal damage is the main cause of neurological diseases. Neural stem cells (NSCs) have the functions of cell repair and replacement of neurons, secretion of neurotrophic factors, and immune regulation of the neural microenvironment. Objective Previous study found that Orexin-A had a protective effect on neurons in the central nervous system, but it is lacking in making great efforts on the function of Orexin-A on NSCs. This study aimed to investigate the anti-inflammatory responses and signaling mechanisms of Orexin-A on lipopolysaccharide (LPS)-induced NSCs. Methods Quantitative real-time polymerase chain reaction was used to detect the mRNA level. Signaling pathway-related protein expression was detected by Western blot. The proliferation and migration of NSCs were investigated by Cell Counting Kit-8 (CCK-8) detection kit and transwell assay. Besides, the staining of hematoxylin and eosin (HE) was performed to study the morphology of cell. Results Orexin-A decreased the pro-inflammatory cytokines of IL-1β, TNF-α, and IL-6 induced by LPS by regulating nuclear factor-k-gene binding (NF-kB) and phosphorylation of P38/Erk-mitogen-activated protein kinases (MAPKs) pathways, but not p-JNK signaling. Conclusion Our findings indicate that Orexin-A can alleviate the inflammatory response of NSC. It can provide beneficial help in neural stem cell therapy applications.
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Affiliation(s)
- Wen Ye
- Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Yan Yan
- Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Yunliang Tang
- Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Xiaoyang Dong
- Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Gengfa Chen
- Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Junwei Kang
- Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Lianghua Huang
- Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Qi Xiong
- Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Zhen Feng
- Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
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20
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Ahani-Nahayati M, Shariati A, Mahmoodi M, Olegovna Zekiy A, Javidi K, Shamlou S, Mousakhani A, Zamani M, Hassanzadeh A. Stem cell in neurodegenerative disorders; an emerging strategy. Int J Dev Neurosci 2021; 81:291-311. [PMID: 33650716 DOI: 10.1002/jdn.10101] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/13/2021] [Accepted: 02/24/2021] [Indexed: 01/28/2023] Open
Abstract
Neurodegenerative disorders are a diversity of disorders, surrounding Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS) accompanied by some other less common diseases generally characterized by either developed deterioration of central or peripheral nervous system structurally or functionally. Today, with the viewpoint of an increasingly aging society, the number of patients with neurodegenerative diseases and sociomedical burdens will spread intensely. During the last decade, stem cell technology has attracted great attention for treating neurodegenerative diseases worldwide because of its unique attributes. As acknowledged, there are several categories of stem cells being able to proliferate and differentiate into various cellular lineages, highlighting their significance in the context of regenerative medicine. In preclinical models, stem cell therapy using mesenchymal stem/stromal cells (MSCs), hematopoietic stem cells (HSCs), and neural progenitor or stem cells (NPCs or NSCs) along with pluripotent stem cells (PSCs)-derived neuronal cells could elicit desired therapeutic effects, enabling functional deficit rescue partially. Regardless of the noteworthy progress in our scientific awareness and understanding of stem cell biology, there still exist various challenges to defeat. In the present review, we provide a summary of the therapeutic potential of stem cells and discuss the current status and prospect of stem cell strategy in neurodegenerative diseases, in particular, AD, PD, ALS, and HD.
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Affiliation(s)
- Milad Ahani-Nahayati
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Ali Shariati
- Stem Cell Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Mahnaz Mahmoodi
- Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Angelina Olegovna Zekiy
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Kamran Javidi
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.,Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Shamlou
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Akbar Mousakhani
- Department of Plant Sciences, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Neurosciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
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21
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Bachoud-Lévi AC, Massart R, Rosser A. Cell therapy in Huntington's disease: Taking stock of past studies to move the field forward. Stem Cells 2021; 39:144-155. [PMID: 33176057 PMCID: PMC10234449 DOI: 10.1002/stem.3300] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/01/2020] [Accepted: 10/20/2020] [Indexed: 06/02/2023]
Abstract
Huntington's disease (HD) is a rare inherited neurodegenerative disease that manifests mostly in adulthood with progressive cognitive, behavioral, and motor dysfunction. Neuronal loss occurs predominantly in the striatum but also extends to other brain regions, notably the cortex. Most patients die around 20 years after motor onset, although there is variability in the rate of progression and some phenotypic heterogeneity. The most advanced experimental therapies currently are huntingtin-lowering strategies, some of which are in stage 3 clinical trials. However, even if these approaches are successful, it is unlikely that they will be applicable to all patients or will completely halt continued loss of neural cells in all cases. On the other hand, cellular therapies have the potential to restore atrophied tissues and may therefore provide an important complementary therapeutic avenue. Pilot studies of fetal cell grafts in the 2000s reported the most dramatic clinical improvements yet achieved for this disease, but subsequent studies have so far failed to identify methodology to reliably reproduce these results. Moving forward, a major challenge will be to generate suitable donor cells from (nonfetal) cell sources, but in parallel there are a host of procedural and trial design issues that will be important for improving reliability of transplants and so urgently need attention. Here, we consider findings that have emerged from clinical transplant studies in HD to date, in particular new findings emerging from the recent multicenter intracerebral transplant HD study, and consider how these data may be used to inform future cell therapy trials.
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Affiliation(s)
- Anne-Catherine Bachoud-Lévi
- Assistance Publique-Hôpitaux de Paris, National Reference Center for Huntington's Disease, Neurology Department, Henri Mondor-Albert Chenevier Hospital, Créteil, France
- Département d'Etudes Cognitives, École Normale Supérieure, PSL University, Paris, France
- Inserm U955, Institut Mondor de Recherche Biomédicale, Equipe E01 NeuroPsychologie Interventionnelle, Créteil, France
- NeurATRIS, Créteil, France
- Université Paris-Est Créteil, Faculté de Médecine, Créteil, France
| | - Renaud Massart
- Assistance Publique-Hôpitaux de Paris, National Reference Center for Huntington's Disease, Neurology Department, Henri Mondor-Albert Chenevier Hospital, Créteil, France
- Département d'Etudes Cognitives, École Normale Supérieure, PSL University, Paris, France
- Inserm U955, Institut Mondor de Recherche Biomédicale, Equipe E01 NeuroPsychologie Interventionnelle, Créteil, France
- NeurATRIS, Créteil, France
| | - Anne Rosser
- Centre for Trials Research, Cardiff University, Cardiff, UK
- Cardiff University Brain Repair Group, Life Sciences Building, School of Biosciences, Cardiff, UK
- Neuroscience and Mental Health Research Institute and Division of Psychological Medicine and Clinical Neurosciences, Hadyn Ellis Building, Cardiff, UK
- Brain Repair And Intracranial Neurotherapeutics (BRAIN) Unit, Cardiff University, Cardiff, UK
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22
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Yoon Y, Kim HS, Jeon I, Noh JE, Park HJ, Lee S, Park IH, Stevanato L, Hicks C, Corteling R, Barker RA, Sinden JD, Song J. Implantation of the clinical-grade human neural stem cell line, CTX0E03, rescues the behavioral and pathological deficits in the quinolinic acid-lesioned rodent model of Huntington's disease. Stem Cells 2020; 38:936-947. [PMID: 32374064 PMCID: PMC7496241 DOI: 10.1002/stem.3191] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 03/23/2020] [Accepted: 04/01/2020] [Indexed: 12/27/2022]
Abstract
Huntington's disease (HD) is a devastating, autosomal-dominant neurodegenerative disease, for which there are currently no disease-modifying therapies. Clinical trials to replace the damaged striatal medium spiny neurons (MSNs) have been attempted in the past two decades but have met with only limited success. In this study, we investigated whether a clonal, conditionally immortalized neural stem cell line (CTX0E03), which has already shown safety and signals of efficacy in chronic ischemic stroke patients, could rescue deficits seen in an animal model of HD. After CTX0E03 transplantation into the quinolinic acid-lesioned rat model of HD, behavioral changes were measured using the rotarod, stepping, and staircase tests. In vivo differentiation and neuronal connections of the transplanted CTX0E03 cells were evaluated with immunohistochemical staining and retrograde tracing with Fluoro-Gold. We found that transplantation of CTX0E03 gave rise to a significant behavioral improvement compared with the sham- or fibroblast-transplanted group. Transplanted CTX0E03 formed MSNs (DARPP-32) and GABAergic neurons (GABA, GAD65/67) with BDNF expression in the striatum, while cortically transplanted cells formed Tbr1-positive neurons. Using a retrograde label, we also found stable engraftment and connection of the transplanted cells with host brain tissues. CTX0E03 transplantation also reduced glial scar formation and inflammation, as well as increasing endogenous neurogenesis and angiogenesis. Overall, our results demonstrate that CTX0E03, a clinical-grade neural stem cell line, is effective for preclinical test in HD, and, therefore, will be useful for clinical development in the treatment of HD patients.
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Affiliation(s)
- Yongwoo Yoon
- Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Hyun Sook Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Iksoo Jeon
- Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jeong-Eun Noh
- Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Hyun Jung Park
- Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Suji Lee
- Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - In-Hyun Park
- Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut, USA
| | | | | | | | - Roger A Barker
- John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK
| | | | - Jihwan Song
- Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea.,iPS Bio, Inc., Seongnam-si, Gyeonggi-do, Republic of Korea
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