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Chen T, Lau KSK, Singh A, Zhang YX, Taromsari SM, Salari M, Naguib HE, Morshead CM. Biodegradable stimulating electrodes for resident neural stem cell activation in vivo. Biomaterials 2025; 315:122957. [PMID: 39541841 DOI: 10.1016/j.biomaterials.2024.122957] [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: 06/28/2024] [Revised: 10/14/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
Brain stimulation has been recognized as a clinically effective strategy for treating neurological disorders. Endogenous brain neural precursor cells (NPCs) have been shown to be electrosensitive cells that respond to electrical stimulation by expanding in number, undergoing directed cathodal migration, and differentiating into neural phenotypes in vivo, supporting the application of electrical stimulation to promote neural repair. In this study, we present the design of a flexible and biodegradable brain stimulation electrode for temporally regulated neuromodulation of NPCs. Leveraging the cathodally skewed electrochemical window of molybdenum and the volumetric charge transfer properties of conductive polymer, we engineered the electrodes with high charge injection capacity for the delivery of biphasic monopolar stimulation. We demonstrate that the electrodes are biocompatible and can deliver an electric field sufficient for NPC activation for 7 days post implantation before undergoing resorption in physiological conditions, thereby eliminating the need for surgical extraction. The biodegradable electrode demonstrated its potential to be used for NPC-based neural repair strategies.
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Affiliation(s)
- Tianhao Chen
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Kylie Sin Ki Lau
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Aryan Singh
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Yi Xin Zhang
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Sara Mohseni Taromsari
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Meysam Salari
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Hani E Naguib
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada; Department of Materials Science and Engineering, University of Toronto, Toronto, Ontario, Canada.
| | - Cindi M Morshead
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada; CRANIA, University Health Network and University of Toronto, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
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Gharandouq MH, Ismail MA, Saleh T, Zihlif M, Ababneh NA. Metformin Protects Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons from Oxidative Damage Through Antioxidant Mechanisms. Neurotox Res 2025; 43:15. [PMID: 40100475 DOI: 10.1007/s12640-025-00734-6] [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: 07/28/2024] [Revised: 02/18/2025] [Accepted: 03/08/2025] [Indexed: 03/20/2025]
Abstract
The antidiabetic drug metformin possesses antioxidant and cell protective effects including in neuronal cells, suggesting its potential use for treating neurodegenerative diseases. This study aimed to assess metformin's effects on viability and antioxidant activity in human-induced pluripotent stem cell (hiPSC)-derived neurons under varying concentrations and stress conditions. Six lines of hiPSC-derived neuronal progenitors derived from healthy human iPSCs were treated with metformin (1-500 µM) on day 18 of differentiation. For mature neurons (day 30), three concentrations (10 µM, 50 µM, and 100 µM) were used to assess cytotoxicity. MG132 proteasomal inhibitor and sodium arsenite (NaArs) were used to investigate oxidative stress, and 50 µM of metformin was tested for its protective effects against oxidative stress in hiPSC-derived neurons. Metformin treatment did not affect cell viability, neuronal differentiation, or trigger reactive oxygen species (ROS) generation in healthy hiPSC-derived motor neurons. Additionally, mitochondrial membrane potential (MMP) loss was not observed at 50 µM metformin. Metformin effectively protected neurons from stress agents and elevated the expression of antioxidant genes when treated with MG132. However, an interplay between MG132 and metformin resulted in lower expression of Nrf2 and NQO1 compared to the MG132 group alone, indicating reduced JC-1 aggregate levels due to MG132 proteasomal inhibition. Metformin upregulated antioxidant genes in hiPSC-derived neurons under stress conditions and protected the cells from oxidative damage.
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Affiliation(s)
- Mohammad H Gharandouq
- Faculty of Biological Sciences, The University of Jordan, Amman, Jordan
- Cell Therapy Center, The University of Jordan, Queen Rania Street, Amman, 11942, Jordan
| | - Mohammad A Ismail
- Cell Therapy Center, The University of Jordan, Queen Rania Street, Amman, 11942, Jordan
- South Australian ImmunoGENomics Cancer Institute, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Tareq Saleh
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
- Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Malik Zihlif
- Department of Pharmaceutical Sciences, School of Medicine, University of Jordan, Amman, Jordan
| | - Nidaa A Ababneh
- Cell Therapy Center, The University of Jordan, Queen Rania Street, Amman, 11942, Jordan.
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Leddy E, Attachaipanich T, Chattipakorn N, Chattipakorn SC. Investigating the effect of metformin on chemobrain: Reports from cells to bedside. Exp Neurol 2025; 385:115129. [PMID: 39733854 DOI: 10.1016/j.expneurol.2024.115129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/10/2024] [Accepted: 12/21/2024] [Indexed: 12/31/2024]
Abstract
Chemobrain can be defined as the development of cognitive side effects following chemotherapy, which is increasingly reported in cancer survivor patients. Chemobrain leads to reduced patients' quality of life by causing different symptoms ranging from strokes and seizures to memory loss and mood disorders. Metformin, an antidiabetic drug, has been proposed as a potential treatment to improve the symptoms of chemotherapy-induced cognitive dysfunction. Several benefits of metformin on chemobrain have been suggested, including anti-inflammation, anti-oxidative stress, restoring impaired mitochondrial function, stabilizing apoptosis, ameliorating impairments to dendritic spine density, normalizing brain senescence protein levels, and attenuating reductions in cell viability, along with reversing learning and memory deficits. These benefits occur through various pathways of metformin, including adenosine monophosphate-activated protein kinase (AMPK), TAp73, and phosphatidylinositol 3-kinase/protein kinase B (Akt) pathways. In addition, metformin can exert neuroprotective effects and restore deficits in brain homeostasis caused by chemotherapy. Furthermore, activation of AMPK following metformin therapy promotes autophagy, stimulates energy production, and improves cell survival. Metformin's interaction with Tap73 and Akt pathways allows for regulated cell proliferation in adult neural precursor cells and cell growth, respectively. Although the negative effects on cerebral function induced by chemotherapeutics have been alleviated by metformin in several instances, further studies are required to confirm its beneficial effects. This research is essential as it addresses the pressing issue of chemobrain, which is on the rise alongside global increases in cancer. Exploring metformin's potential as a neuroprotective agent offers a promising avenue for mitigating these cognitive impairments and highlights the need for further studies to validate its therapeutic mechanisms. This review comprehensively summarises evidence from both in vitro and in vivo studies to demonstrate metformin's effects on cognitive function when co-administered with chemotherapy and identifies gaps in knowledge for further investigation.
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Affiliation(s)
- Evelyn Leddy
- School of Biological Sciences, The University of Manchester, Greater Manchester M13 9PL, United Kingdom; Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Tanawat Attachaipanich
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Research Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.
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Willis A, Jeong D, Liu Y, Lithopoulos MA, Yuzwa SA, Frankland PW, Kaplan DR, Miller FD. Single cell approaches define neural stem cell niches and identify microglial ligands that can enhance precursor-mediated oligodendrogenesis. Cell Rep 2025; 44:115194. [PMID: 39823226 DOI: 10.1016/j.celrep.2024.115194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/24/2024] [Accepted: 12/19/2024] [Indexed: 01/19/2025] Open
Abstract
Here, we used single cell RNA sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under homeostatic and injury conditions. We defined the dorsal and lateral ventricular-subventricular zones (V-SVZs) as two distinct neighborhoods and showed that, after white matter injury, NSCs are activated to make oligodendrocytes dorsally for remyelination. This activation is coincident with an increase in transcriptionally distinct microglia in the dorsal V-SVZ niche. We modeled ligand-receptor interactions within this changing niche and identified two remyelination-associated microglial ligands, insulin growth factor 1 and oncostatin M, that promote precursor proliferation and oligodendrogenesis in culture. Infusion of either ligand into the lateral ventricles also enhanced oligodendrogenesis, even in the lateral V-SVZ, where NSCs normally make neuroblasts. These data support a model where gliogenesis versus neurogenesis is determined by the local NSC neighborhood and where injury-induced niche alterations promote NSC activation, local oligodendrogenesis, and likely contribute to myelin repair.
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Affiliation(s)
- Ashleigh Willis
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Danielle Jeong
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Yunlong Liu
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Marissa A Lithopoulos
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Scott A Yuzwa
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Paul W Frankland
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Psychology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - David R Kaplan
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Freda D Miller
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
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Balbinot G, Milosevic M, Morshead CM, Iwasa SN, Zariffa J, Milosevic L, Valiante TA, Hoffer JA, Popovic MR. The mechanisms of electrical neuromodulation. J Physiol 2025; 603:247-284. [PMID: 39740777 DOI: 10.1113/jp286205] [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: 02/11/2024] [Accepted: 11/20/2024] [Indexed: 01/02/2025] Open
Abstract
The central and peripheral nervous systems are specialized to conduct electrical currents that underlie behaviour. When this multidimensional electrical system is disrupted by degeneration, damage, or disuse, externally applied electrical currents may act to modulate neural structures and provide therapeutic benefit. The administration of electrical stimulation can exert precise and multi-faceted effects at cellular, circuit and systems levels to restore or enhance the functionality of the central nervous system by providing an access route to target specific cells, fibres of passage, neurotransmitter systems, and/or afferent/efferent communication to enable positive changes in behaviour. Here we examine the neural mechanisms that are thought to underlie the therapeutic effects seen with current neuromodulation technologies. To gain further insights into the mechanisms associated with electrical stimulation, we summarize recent findings from genetic dissection studies conducted in animal models. KEY POINTS: Electricity is everywhere around us and is essential for how our nerves communicate within our bodies. When nerves are damaged or not working properly, using exogenous electricity can help improve their function at distinct levels - inside individual cells, within neural circuits, and across entire systems. This method can be tailored to target specific types of cells, nerve fibres, neurotransmitters and communication pathways, offering significant therapeutic potential. This overview explains how exogenous electricity affects nerve function and its potential benefits, based on research in animal studies. Understanding these effects is important because electrical neuromodulation plays a key role in medical treatments for neurological conditions.
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Affiliation(s)
- Gustavo Balbinot
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
- Institute for Neuroscience and Neurotechnology, Simon Fraser University, Burnaby, BC, Canada
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
| | - Matija Milosevic
- The Miami Project to Cure Paralysis, University of Miami, Miami, FL, USA
- Department of Neurological Surgery, University of Miami, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - Cindi M Morshead
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
- KITE Research Institute - University Health Network, Toronto, ON, Canada
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, ON, Canada
- The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada
| | - Stephanie N Iwasa
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
- KITE Research Institute - University Health Network, Toronto, ON, Canada
| | - Jose Zariffa
- KITE Research Institute - University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada
- Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada
| | - Luka Milosevic
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
- KITE Research Institute - University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Taufik A Valiante
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
- KITE Research Institute - University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada
| | - Joaquín Andrés Hoffer
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Milos R Popovic
- Center for Advancing Neurotechnological Innovation to Application - CRANIA, University Health Network, Toronto, ON, Canada
- KITE Research Institute - University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada
- Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada
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6
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Li H, Liu R, Liu J, Qu Y. The Role and Mechanism of Metformin in the Treatment of Nervous System Diseases. Biomolecules 2024; 14:1579. [PMID: 39766286 PMCID: PMC11673726 DOI: 10.3390/biom14121579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/29/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025] Open
Abstract
Nervous system diseases represent a significant global burden, affecting approximately 16% of the world's population and leading to disability and mortality. These conditions, encompassing both central nervous system (CNS) and peripheral nervous system (PNS) disorders, have substantial social and economic impacts. Metformin, a guanidine derivative derived from a plant source, exhibits therapeutic properties in various health conditions such as cancer, aging, immune-related disorders, polycystic ovary syndrome, cardiovascular ailments, and more. Recent studies highlight metformin's ability to cross the blood-brain barrier, stimulate neurogenesis, and provide beneficial effects in specific neurological disorders through diverse mechanisms. This review discusses the advancements in research on metformin's role and mechanisms in treating neurological disorders within both the central and peripheral nervous systems, aiming to facilitate further investigation, utilization, and clinical application of metformin in neurology.
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Affiliation(s)
- Hui Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; (H.L.); (J.L.)
- Department of General Internal Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China;
| | - Ruhui Liu
- Department of General Internal Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China;
| | - Junyan Liu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; (H.L.); (J.L.)
| | - Yi Qu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; (H.L.); (J.L.)
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7
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Roberts CT, Raabe N, Wiegand L, Kadar Shahib A, Rastegar M. Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease. Pharmaceuticals (Basel) 2024; 17:1601. [PMID: 39770443 PMCID: PMC11677501 DOI: 10.3390/ph17121601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
Metformin is a commonly used drug for treating type 2 diabetes. Metformin is an inexpensive drug with low/no side effects and is well tolerated in human patients of different ages. Recent therapeutic strategies for human disease have considered the benefits of drug repurposing. This includes the use of the anti-diabetic drug metformin. Accordingly, the anti-inflammatory, anti-cancer, anti-viral, neuroprotective, and cardioprotective potentials of metformin have deemed it a suitable candidate for treating a plethora of human diseases. As results from preclinical studies using cellular and animal model systems appear promising, clinical trials with metformin in the context of non-diabetes-related illnesses have been started. Here, we aim to provide a comprehensive overview of the therapeutic potential of metformin in different animal models of human disease and its suggested relationship to epigenetics and ailments with epigenetic components.
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Affiliation(s)
| | | | | | | | - Mojgan Rastegar
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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Iwasa SN, Liu X, Naguib HE, Kalia SK, Popovic MR, Morshead CM. Electrical Stimulation for Stem Cell-Based Neural Repair: Zapping the Field to Action. eNeuro 2024; 11:ENEURO.0183-24.2024. [PMID: 39256040 PMCID: PMC11391505 DOI: 10.1523/eneuro.0183-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/18/2024] [Accepted: 07/22/2024] [Indexed: 09/12/2024] Open
Affiliation(s)
- Stephanie N Iwasa
- The KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, Ontario M5G 2A2, Canada
- CRANIA, University Health Network and University of Toronto, Toronto, Ontario M5G 2A2, Canada
| | - Xilin Liu
- The KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, Ontario M5G 2A2, Canada
- CRANIA, University Health Network and University of Toronto, Toronto, Ontario M5G 2A2, Canada
- Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada
| | - Hani E Naguib
- The KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, Ontario M5G 2A2, Canada
- CRANIA, University Health Network and University of Toronto, Toronto, Ontario M5G 2A2, Canada
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario M5S 3G8, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9, Canada
- Department of Materials Science & Engineering, University of Toronto, Toronto, Ontario M5S 3E4, Canada
| | - Suneil K Kalia
- The KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, Ontario M5G 2A2, Canada
- CRANIA, University Health Network and University of Toronto, Toronto, Ontario M5G 2A2, Canada
- Department of Neurosurgery, University Health Network, University of Toronto, Toronto, Ontario M5T 2S8, Canada
- Krembil Research Institute, Toronto, Ontario M5T 2S8, Canada
| | - Milos R Popovic
- The KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, Ontario M5G 2A2, Canada
- CRANIA, University Health Network and University of Toronto, Toronto, Ontario M5G 2A2, Canada
- Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario M5S 3G8, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9, Canada
| | - Cindi M Morshead
- The KITE Research Institute, Toronto Rehabilitation Institute-University Health Network, Toronto, Ontario M5G 2A2, Canada
- CRANIA, University Health Network and University of Toronto, Toronto, Ontario M5G 2A2, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9, Canada
- Department of Surgery, University of Toronto, Toronto, Ontario M5T 1P5, Canada
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9
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Rumajogee P, Altamentova S, Li J, Puvanenthirarajah N, Wang J, Asgarihafshejani A, Van Der Kooy D, Fehlings MG. Constraint-Induced Movement Therapy (CIMT) and Neural Precursor Cell (NPC) Transplantation Synergistically Promote Anatomical and Functional Recovery in a Hypoxic-Ischemic Mouse Model. Int J Mol Sci 2024; 25:9403. [PMID: 39273353 PMCID: PMC11395467 DOI: 10.3390/ijms25179403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/20/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Cerebral palsy (CP) is a common neurodevelopmental disorder characterized by pronounced motor dysfunction and resulting in physical disability. Neural precursor cells (NPCs) have shown therapeutic promise in mouse models of hypoxic-ischemic (HI) perinatal brain injury, which mirror hemiplegic CP. Constraint-induced movement therapy (CIMT) enhances the functional use of the impaired limb and has emerged as a beneficial intervention for hemiplegic CP. However, the precise mechanisms and optimal application of CIMT remain poorly understood. The potential synergy between a regenerative approach using NPCs and a rehabilitation strategy using CIMT has not been explored. We employed the Rice-Vannucci HI model on C57Bl/6 mice at postnatal day (PND) 7, effectively replicating the clinical and neuroanatomical characteristics of hemiplegic CP. NPCs were transplanted in the corpus callosum (CC) at PND21, which is the age corresponding to a 2-year-old child from a developmental perspective and until which CP is often not formally diagnosed, followed or not by Botulinum toxin injections in the unaffected forelimb muscles at PND23, 26, 29 and 32 to apply CIMT. Both interventions led to enhanced CC myelination and significant functional recovery (as shown by rearing and gait analysis testing), through the recruitment of endogenous oligodendrocytes. The combinatorial treatment indicated a synergistic effect, as shown by newly recruited oligodendrocytes and functional recovery. This work demonstrates the mechanistic effects of CIMT and NPC transplantation and advocates for their combined therapeutic potential in addressing hemiplegic CP.
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Affiliation(s)
- Prakasham Rumajogee
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada
| | - Svetlana Altamentova
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada
| | - Junyi Li
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada
| | - Nirushan Puvanenthirarajah
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada
| | - Jian Wang
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada
| | - Azam Asgarihafshejani
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada
| | - Derek Van Der Kooy
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Michael G Fehlings
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 3E1, Canada
- Division of Neurosurgery and Spine Program, Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
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10
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Xing C, Liu S, Wang L, Ma H, Zhou M, Zhong H, Zhu S, Wu Q, Ning G. Metformin enhances endogenous neural stem cells proliferation, neuronal differentiation, and inhibits ferroptosis through activating AMPK pathway after spinal cord injury. J Transl Med 2024; 22:723. [PMID: 39103875 PMCID: PMC11302024 DOI: 10.1186/s12967-024-05436-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 06/25/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Inadequate nerve regeneration and an inhibitory local microenvironment are major obstacles to the repair of spinal cord injury (SCI). The activation and differentiation fate regulation of endogenous neural stem cells (NSCs) represent one of the most promising repair approaches. Metformin has been extensively studied for its antioxidative, anti-inflammatory, anti-aging, and autophagy-regulating properties in central nervous system diseases. However, the effects of metformin on endogenous NSCs remains to be elucidated. METHODS The proliferation and differentiation abilities of NSCs were evaluated using CCK-8 assay, EdU/Ki67 staining and immunofluorescence staining. Changes in the expression of key proteins related to ferroptosis in NSCs were detected using Western Blot and immunofluorescence staining. The levels of reactive oxygen species, glutathione and tissue iron were measured using corresponding assay kits. Changes in mitochondrial morphology and membrane potential were observed using transmission electron microscopy and JC-1 fluorescence probe. Locomotor function recovery after SCI in rats was assessed through BBB score, LSS score, CatWalk gait analysis, and electrophysiological testing. The expression of the AMPK pathway was examined using Western Blot. RESULTS Metformin promoted the proliferation and neuronal differentiation of NSCs both in vitro and in vivo. Furthermore, a ferroptosis model of NSCs using erastin treatment was established in vitro, and metformin treatment could reverse the changes in the expression of key ferroptosis-related proteins, increase glutathione synthesis, reduce reactive oxygen species production and improve mitochondrial membrane potential and morphology. Moreover, metformin administration improved locomotor function recovery and histological outcomes following SCI in rats. Notably, all the above beneficial effects of metformin were completely abolished upon addition of compound C, a specific inhibitor of AMP-activated protein kinase (AMPK). CONCLUSION Metformin, driven by canonical AMPK-dependent regulation, promotes proliferation and neuronal differentiation of endogenous NSCs while inhibiting ferroptosis, thereby facilitating recovery of locomotor function following SCI. Our study further elucidates the protective mechanism of metformin in SCI, providing new mechanistic insights for its candidacy as a therapeutic agent for SCI.
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Affiliation(s)
- Cong Xing
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
- International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China
- Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Song Liu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
- International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China
- Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Liyue Wang
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
- International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China
- Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Hongpeng Ma
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
- International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China
- Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Mi Zhou
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
- International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China
- Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Hao Zhong
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
- International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China
- Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Shibo Zhu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
- International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China
- Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Qiang Wu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
- International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China
- Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China
| | - Guangzhi Ning
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China.
- International Science and Technology Cooperation Base of Spinal Cord lnjury, Tianjin, China.
- Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin, China.
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11
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Islam R, Noman H, Azimi A, Siu R, Chinchalongporn V, Schuurmans C, Morshead CM. Primitive and Definitive Neural Precursor Cells Are Present in Human Cerebral Organoids. Int J Mol Sci 2024; 25:6549. [PMID: 38928255 PMCID: PMC11203442 DOI: 10.3390/ijms25126549] [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: 05/01/2024] [Revised: 06/04/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Activation of neural stem cells (NSCs) correlates with improved functional outcomes in mouse models of injury. In the murine brain, NSCs have been extensively characterized and comprise (1) primitive NSCs (pNSCs) and (2) definitive NSCs (dNSCs). pNSCs are the earliest cells in the NSC lineage giving rise to dNSCs in the embryonic and adult mouse brain. pNSCs are quiescent under baseline conditions and can be activated upon injury. Herein, we asked whether human pNSCs and dNSCs can be isolated during the maturation of human cerebral organoids (COs) and activated by drugs known to regulate mouse NSC behavior. We demonstrate that self-renewing, multipotent pNSC and dNSC populations are present in human COs and express genes previously characterized in mouse NSCs. The drug NWL283, an inhibitor of apoptosis, reduced cell death in COs but did not improve NSC survival. Metformin, a drug used to treat type II diabetes that is known to promote NSC activation in mice, was found to expand human NSC pools. Together, these findings are the first to identify and characterize human pNSCs, advancing our understanding of the human NSC lineage and highlighting drugs that enhance their activity.
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Affiliation(s)
- Rehnuma Islam
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 3E1, Canada
| | - Humna Noman
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 3E1, Canada
| | - Ashkan Azimi
- Department of Surgery, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada
| | - Ricky Siu
- Department of Surgery, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada
| | | | - Carol Schuurmans
- Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada
- Department of Biochemistry, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 3E1, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 3E1, Canada
| | - Cindi M. Morshead
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 3E1, Canada
- Department of Surgery, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada
- Institute of Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada
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12
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Skocic J, Richard L, Ferkul A, Cox E, Tseng J, Laughlin S, Bouffet E, Mabbott DJ. Multimodal imaging with magnetization transfer and diffusion tensor imaging reveals evidence of myelin damage in children and youth treated for a brain tumor. Neurooncol Pract 2024; 11:307-318. [PMID: 38737604 PMCID: PMC11085850 DOI: 10.1093/nop/npae003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2024] Open
Abstract
Background The microstructural damage underlying compromise of white matter following treatment for pediatric brain tumors is unclear. We use multimodal imaging employing advanced diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) MRI methods to examine chronic microstructural damage to white matter in children and adolescents treated for pediatric brain tumor. Notably, MTI may be more sensitive to macromolecular content, including myelin, than DTI. Methods Fifty patients treated for brain tumors (18 treated with surgery ± chemotherapy and 32 treated with surgery followed by cranial-spinal radiation; time from diagnosis to scan ~6 years) and 45 matched healthy children completed both MTI and DTI scans. Voxelwise and region-of-interest approaches were employed to compare white matter microstructure metrics (magnetization transfer ratio (MTR); DTI- fractional anisotropy [FA], radial diffusivity [RD], axial diffusivity [AD], mean diffusivity [MD]) between patients and healthy controls. Results MTR was decreased across multiple white matter tracts in patients when compared to healthy children, P < .001. These differences were observed for both patients treated with radiation and those treated with only surgery, P < .001. We also found that children and adolescents treated for brain tumors exhibit decreased FA and increased RD/AD/MD compared to their healthy counterparts in several white matter regions, Ps < .02. Finally, we observed that MTR and DTI metrics were related to multiple white matter tracts in patients, Ps < .01, but not healthy control children. Conclusions Our findings provide evidence that the white matter damage observed in patients years after treatment of pediatric posterior fossa tumors, likely reflects myelin disruption.
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Affiliation(s)
- Jovanka Skocic
- Program in Neurosciences and Mental Health, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Logan Richard
- Program in Neurosciences and Mental Health, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Ashley Ferkul
- Program in Neurosciences and Mental Health, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Elizabeth Cox
- Program in Neurosciences and Mental Health, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Psychology, University of Toronto, Toronto, Ontario, Canada
| | - Julie Tseng
- Program in Neurosciences and Mental Health, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Suzanne Laughlin
- Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada
- Medical Imaging, University of Toronto, Toronto, Ontario, Canada
| | - Eric Bouffet
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Donald James Mabbott
- Program in Neurosciences and Mental Health, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Psychology, University of Toronto, Toronto, Ontario, Canada
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13
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Loan A, Syal C, Lui M, He L, Wang J. Promising use of metformin in treating neurological disorders: biomarker-guided therapies. Neural Regen Res 2024; 19:1045-1055. [PMID: 37862207 PMCID: PMC10749596 DOI: 10.4103/1673-5374.385286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/25/2023] [Accepted: 07/29/2023] [Indexed: 10/22/2023] Open
Abstract
Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases (Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), cerebrovascular conditions (stroke), and neurodevelopmental disorders (autism spectrum disorder). Although they affect millions of individuals around the world, only a limited number of effective treatment options are available today. Since most neurological disorders express mitochondria-related metabolic perturbations, metformin, a biguanide type II antidiabetic drug, has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism. However, controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders. Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging, lifestyle, genetics, and environment, it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders. These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment, ultimately developing targeted therapy. In this review, we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.
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Affiliation(s)
- Allison Loan
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON, Canada
| | - Charvi Syal
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Margarita Lui
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Ling He
- Department of Pediatrics and Medicine, Johns Hopkins Medical School, Baltimore, MD, USA
| | - Jing Wang
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
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14
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Chen G, Tong K, Li S, Huang Z, Liu S, Zhu H, Zhong Y, Zhou Z, Jiao G, Wei F, Chen N. Extracellular vesicles released by transforming growth factor-beta 1-preconditional mesenchymal stem cells promote recovery in mice with spinal cord injury. Bioact Mater 2024; 35:135-149. [PMID: 38312519 PMCID: PMC10837068 DOI: 10.1016/j.bioactmat.2024.01.013] [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: 12/12/2023] [Revised: 01/10/2024] [Accepted: 01/15/2024] [Indexed: 02/06/2024] Open
Abstract
Spinal cord injury (SCI) causes neuroinflammation, neuronal death, and severe axonal connections. Alleviating neuroinflammation, protecting residual cells and promoting neuronal regeneration via endogenous neural stem cells (eNSCs) represent potential strategies for SCI treatment. Extracellular vesicles (EVs) released by mesenchymal stem cells have emerged as pathological mediators and alternatives to cell-based therapies following SCI. In the present study, EVs isolated from untreated (control, C-EVs) and TGF-β1-treated (T-EVs) mesenchymal stem cells were injected into SCI mice to compare the therapeutic effects and explore the underlying mechanisms. Our study demonstrated for the first time that the application of T-EVs markedly enhanced the proliferation and antiapoptotic ability of NSCs in vitro. The infusion of T-EVs into SCI mice increased the shift from the M1 to M2 polarization of reactive microglia, alleviated neuroinflammation, and enhanced the neuroprotection of residual cells during the acute phase. Moreover, T-EVs increased the number of eNSCs around the epicenter. Consequently, T-EVs further promoted neurite outgrowth, increased axonal regrowth and remyelination, and facilitated locomotor recovery in the chronic stage. Furthermore, the use of T-EVs in Rictor-/- SCI mice (conditional knockout of Rictor in NSCs) showed that T-EVs failed to increase the activation of eNSCs and improve neurogenesis sufficiently, which suggested that T-EVs might induce the activation of eNSCs by targeting the mTORC2/Rictor pathway. Taken together, our findings indicate the prominent role of T-EVs in the treatment of SCI, and the therapeutic efficacy of T-EVs for SCI treatment might be optimized by enhancing the activation of eNSCs via the mTORC2/Rictor signaling pathway.
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Affiliation(s)
- Guoliang Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
- Dongguan Key Laboratory of Central Nervous System Injury and Repair / Department of Orthopedic Surgery, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Kuileung Tong
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Shiming Li
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Zerong Huang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
| | - Shuangjiang Liu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
- Dongguan Key Laboratory of Central Nervous System Injury and Repair / Department of Orthopedic Surgery, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China
| | - Haoran Zhu
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Jinan University (Heyuan Shenhe People's Hospital), Heyuan, 517400, China
| | - Yanheng Zhong
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
| | - Zhisen Zhou
- Dongguan Key Laboratory of Central Nervous System Injury and Repair / Department of Orthopedic Surgery, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China
| | - Genlong Jiao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
- Dongguan Key Laboratory of Central Nervous System Injury and Repair / Department of Orthopedic Surgery, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China
| | - Fuxin Wei
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Ningning Chen
- Department of Orthopedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
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15
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Froldi G. View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences. Pharmaceuticals (Basel) 2024; 17:478. [PMID: 38675438 PMCID: PMC11054066 DOI: 10.3390/ph17040478] [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: 03/12/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Metformin is a synthetic biguanide used as an antidiabetic drug in type 2 diabetes mellitus, achieved by studying the bioactive metabolites of Galega officinalis L. It is also used off-label for various other diseases, such as subclinical diabetes, obesity, polycystic ovary syndrome, etc. In addition, metformin is proposed as an add-on therapy for several conditions, including autoimmune diseases, neurodegenerative diseases, and cancer. Although metformin has been used for many decades, it is still the subject of many pharmacodynamic and pharmacokinetic studies in light of its extensive use. Metformin acts at the mitochondrial level by inhibiting the respiratory chain, thus increasing the AMP/ATP ratio and, subsequently, activating the AMP-activated protein kinase. However, several other mechanisms have been proposed, including binding to presenilin enhancer 2, increasing GLP1 release, and modification of microRNA expression. Regarding its pharmacokinetics, after oral administration, metformin is absorbed, distributed, and eliminated, mainly through the renal route, using transporters for cationic solutes, since it exists as an ionic molecule at physiological pH. In this review, particular consideration has been paid to literature data from the last 10 years, deepening the study of clinical trials inherent to new uses of metformin, the differences in effectiveness and safety observed between the sexes, and the unwanted side effects. For this last objective, metformin safety was also evaluated using both VigiBase and EudraVigilance, respectively, the WHO and European databases of the reported adverse drug reactions, to assess the extent of metformin side effects in real-life use.
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Affiliation(s)
- Guglielmina Froldi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
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16
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Gilbert EAB, Livingston J, Flores EG, Khan M, Kandavel H, Morshead CM. Metformin treatment reduces inflammation, dysmyelination and disease severity in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis. Brain Res 2024; 1822:148648. [PMID: 37890574 DOI: 10.1016/j.brainres.2023.148648] [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: 07/30/2023] [Revised: 09/30/2023] [Accepted: 10/24/2023] [Indexed: 10/29/2023]
Abstract
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation, death or damage of oligodendrocytes, and axonal degeneration. Current MS treatments are non-curative, associated with undesired side-effects, and expensive, highlighting the need for expanded therapeutic options for patients. There is great interest in developing interventions using drugs or therapeutics to reduce symptom onset and protect pre-existing myelin. Metformin is a well-tolerated drug used to treat Type 2 diabetes that has pleiotropic effects in the central nervous system (CNS), including reducing inflammation, enhancing oligodendrogenesis, increasing the survival/proliferation of neural stem cells (NSCs), and increasing myelination. Here, we investigated whether metformin administration could improve functional outcomes, modulate oligodendrocyte precursor cells (OPCs), and reduce inflammation in a well-established mouse model of MS- experimental autoimmune encephalomyelitis (EAE). Male and female mice received metformin treatment at the time of EAE induction ("acute") or upon presentation of disease symptoms ("delayed"). We found that acute metformin treatment improved functional outcomes, concomitant with reduced microglia numbers and decreased dysmyelination. Conversely, delayed metformin treatment did not improve functional outcomes. Our findings reveal that metformin administration can improve EAE outcomes when administered before symptom onset in both sexes.
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Affiliation(s)
- Emily A B Gilbert
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, ON M5S1A8, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1, Canada
| | - Jessica Livingston
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, ON M5S1A8, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1, Canada
| | - Emilio Garcia Flores
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S3E1, Canada
| | - Monoleena Khan
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, ON M5S1A8, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1, Canada
| | - Harini Kandavel
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, ON M5S1A8, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1, Canada
| | - Cindi M Morshead
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, ON M5S1A8, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S3E1, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5S1A8, Canada.
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17
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Khodabakhsh P, Asgari Taei A, Shafaroodi H, Pournajaf S, Dargahi L. Effect of Metformin on Epidermal Neural Crest Stem Cells and Their Potential Application in Ameliorating Paclitaxel-induced Neurotoxicity Phenotype. Stem Cell Rev Rep 2024; 20:394-412. [PMID: 37924435 DOI: 10.1007/s12015-023-10642-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2023] [Indexed: 11/06/2023]
Abstract
AIMS Epidermal Neural Crest Stem Cells (EPI-NCSCs) have emerged as prospective ideal candidates to meet the fundamental requirements of cell-based therapies in neurodegenerative disorders. The present study aimed to identify the potential of metformin in driving EPI-NCSCs to neuronal/glial differentiation and express neurotrophic factors as well as assess their therapeutic potential for mitigating the main behavioral manifestations of chemotherapy-induced neurotoxicity (CIN). MAIN METHODS EPI-NCSCs were extracted from the bulge region of hair follicle. Following expansion, transcript and protein expression profiles of key markers for stemness (Nestin, EGR-1, SOX-2 and 10), neurotrophic activity (BDNF, GDNF, NGF, FGF-2, and IL-6), and neuronal (TUB3, DCX, NRF and NeuN) and glial (PDGFRα, NG2, GFAP, and MBP) differentiation were determined on days 1 and 7 post-treatment with 10 and 100 μM metformin using real time-PCR and immunocytochemistry methods. Then, the in vivo function of metformin-treated stem cells was evaluated in the context of paclitaxel CIN. To do so, thermal hyperalgesia, mechanical allodynia, and spatial learning and memory tests were evaluated by Hotplate, Von Frey, and Morris water maze tests. KEY FINDINGS Our result indicated that exposure of EPI-NCSCs to metformin was associated with progressive decline in stemness markers and enhanced expression levels of several neurotrophic, neuron and oligodendrocyte-specific markers. Further, it was observed that intranasal metformin-treated EPI-NCSCs improved the cognitive impairment, and mechanical and thermal hypersensitivity induced by paclitaxel in rats. SIGNIFICANCE Collectively, we reasoned that metformin pretreatment of EPI-NCSCs might further enhance their therapeutic benefits against CIN.
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Affiliation(s)
- Pariya Khodabakhsh
- Institute of Physiology, Department Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Afsaneh Asgari Taei
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shafaroodi
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Safura Pournajaf
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Leila Dargahi
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Greco A, Coperchini F, Croce L, Magri F, Teliti M, Rotondi M. Drug repositioning in thyroid cancer treatment: the intriguing case of anti-diabetic drugs. Front Pharmacol 2023; 14:1303844. [PMID: 38146457 PMCID: PMC10749369 DOI: 10.3389/fphar.2023.1303844] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 11/30/2023] [Indexed: 12/27/2023] Open
Abstract
Cancer represents the main cause of death worldwide. Thyroid cancer (TC) shows an overall good rate of survival, however there is a percentage of patients that do not respond or are refractory to common therapies. Thus new therapeutics strategies are required. In the past decade, drug repositioning become very important in the field of cancer therapy. This approach shows several advantages including the saving of: i) time, ii) costs, iii) de novo studies regarding the safety (just characterized) of a drug. Regarding TC, few studies considered the potential repositioning of drugs. On the other hand, certain anti-diabetic drugs, were the focus of interesting studies on TC therapy, in view of the fact that they exhibited potential anti-tumor effects. Among these anti-diabetic compounds, not all were judjed as appropriate for repositioning, in view of well documented side effects. However, just to give few examples biguanides, DPP-4-inhibitors and Thiazolidinediones were found to exert strong anti-cancer effects in TC. Indeed, their effects spaced from induction of citotoxicity and inhibition of metastatic spread, to induction of de-differentiation of TC cells and modulation of TC microenvironment. Thus, the multifacial anti-cancer effect of these compounds would make the basis also for combinatory strategies. The present review is aimed at discuss data from studies regarding the anti-cancer effects of several anti-diabetic drugs recently showed in TC in view of their potential repositioning. Specific examples of anti-diabetic repositionable drugs for TC treatment will also be provided.
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Affiliation(s)
- Alessia Greco
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Laboratory for Endocrine Disruptors, Unit of Endocrinology and Metabolism, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Francesca Coperchini
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Laboratory for Endocrine Disruptors, Unit of Endocrinology and Metabolism, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Laura Croce
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Laboratory for Endocrine Disruptors, Unit of Endocrinology and Metabolism, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Flavia Magri
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Laboratory for Endocrine Disruptors, Unit of Endocrinology and Metabolism, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Marsida Teliti
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Laboratory for Endocrine Disruptors, Unit of Endocrinology and Metabolism, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Mario Rotondi
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Laboratory for Endocrine Disruptors, Unit of Endocrinology and Metabolism, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
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Dagsuyu E, Koroglu P, Gul IB, Bulan OK, Yanardag R. Oxidative brain and cerebellum injury in diabetes and prostate cancer model: Protective effect of metformin. J Biochem Mol Toxicol 2023; 37:e23440. [PMID: 37354076 DOI: 10.1002/jbt.23440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 05/24/2023] [Accepted: 06/14/2023] [Indexed: 06/26/2023]
Abstract
The body can host the spread of prostate cancer cells. Metastases from prostate cancer are more frequently seen in the brain, liver, lungs, and lymph nodes. A well-known antidiabetic drug, metformin, is also known to have antitumor effects. Our study focuses on the evaluation of potential metformin protective effects on brain and cerebellum damage in streptozotocin (STZ)-induced diabetic and Dunning prostate cancer models. In this investigation, six groups of male Copenhagen rats were created: control, diabetic (D), cancer (C), diabetic + cancer (DC), cancer + metformin, and diabetic + cancer + metformin. The brain and cerebellum tissues of the rats were taken after sacrifice. Oxidative stress markers including reduced glutathione level, lipid peroxidation, glutathione reductase, glutathione peroxidase, glutathione-S-transferase, catalase, superoxide dismutase activities, reactive oxygen species, total oxidant and total antioxidant status, lactate dehydrogenase, xanthine oxidase, acetylcholinesterase activities, protein carbonyl contents, nitric oxide and OH-proline levels, sodium potassium ATPase, carbonic anhydrase, and glucose-6-phosphate dehydrogenase activities; glycoprotein levels including hexose, hexosamine, fucose, and sialic acid levels; and histone deacetylase activity as a cancer marker were determined. Oxidative stress markers were impaired and glycoprotein levels and histone deacetylase activity were increased in the D, C, and DC groups. Metformin therapy reversed these effects. Metformin was found to protect the brain and cerebellum of STZ-induced diabetic rats with Dunning prostate cancer from harm caused by MAT-Lylu metastatic cells.
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Affiliation(s)
- Eda Dagsuyu
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpaşa, Istanbul, Turkey
| | - Pınar Koroglu
- Department of Histology and Embryology, Faculty of Medicine, Halic University, Istanbul, Turkey
| | - Ilknur B Gul
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Turkey
| | - Omur K Bulan
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Turkey
| | - Refiye Yanardag
- Department of Chemistry, Faculty of Engineering, Istanbul University-Cerrahpaşa, Istanbul, Turkey
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20
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Yuan T, Wang T, Zhang J, Liu P, Xu J, Gu Z, Xu J, Li Y. Robust and Multifunctional Nanoparticles Assembled from Natural Polyphenols and Metformin for Efficient Spinal Cord Regeneration. ACS NANO 2023; 17:18562-18575. [PMID: 37708443 DOI: 10.1021/acsnano.3c06991] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/16/2023]
Abstract
The treatment of spinal cord injury (SCI) remains unsatisfactory owing to the complex pathophysiological microenvironments at the injury site and the limited regenerative potential of the central nervous system. Metformin has been proven in clinical and animal experiments to repair damaged structures and functions by promoting endogenous neurogenesis. However, in the early stage of acute SCI, the adverse pathophysiological microenvironment of the injury sites, such as reactive oxygen species and inflammatory factor storm, can prevent the activation of endogenous neural stem cells (NSCs) and the differentiation of NSCs into neurons, decreasing the whole repair effect. To address those issues, a series of robust and multifunctional natural polyphenol-metformin nanoparticles (polyphenol-Met NPs) were fabricated with pH-responsiveness and excellent antioxidative capacities. The resulting NPs possessed several favorable advantages: First, the NPs were composed of active ingredients with different biological properties, without the need for carriers; second, the pH-responsiveness feature could allow targeted drug delivery at the injured site; more importantly, NPs enabled drugs with different performances to exhibit strong synergistic effects. The results demonstrated that the improved microenvironment by natural polyphenols boosted the differentiation of activated NSCs into neurons and oligodendrocytes, which could efficiently repair the injured nerve structures and enhance the functional recovery of the SCI rats. This work highlighted the design and fabrication of robust and multifunctional NPs for SCI treatment via efficient microenvironmental regulation and targeted NSCs activation.
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Affiliation(s)
- Taoyang Yuan
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tianyou Wang
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
| | - Jianhua Zhang
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
| | - Pengyu Liu
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
| | - Jiayi Xu
- Core Facilities, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhipeng Gu
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
| | - Jianguo Xu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yiwen Li
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
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21
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Gilbert EAB, Livingston J, Garcia-Flores E, Kehtari T, Morshead CM. Metformin Improves Functional Outcomes, Activates Neural Precursor Cells, and Modulates Microglia in a Sex-Dependent Manner After Spinal Cord Injury. Stem Cells Transl Med 2023:7174953. [PMID: 37209417 DOI: 10.1093/stcltm/szad030] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 04/20/2023] [Indexed: 05/22/2023] Open
Abstract
Spinal cord injury (SCI) results in devastating patient outcomes with few treatment options. A promising approach to improve outcomes following SCI involves the activation of endogenous precursor populations including neural stem and progenitor cells (NSPCs) which are located in the periventricular zone (PVZ), and oligodendrocyte precursor cells (OPCs) found throughout the parenchyma. In the adult spinal cord, resident NSPCs are primarily mitotically quiescent and aneurogenic, while OPCs contribute to ongoing oligodendrogenesis into adulthood. Each of these populations is responsive to SCI, increasing their proliferation and migration to the site of injury; however, their activation is not sufficient to support functional recovery. Previous work has shown that administration of the FDA-approved drug metformin is effective at promoting endogenous brain repair following injury, and this is correlated with enhanced NSPC activation. Here, we ask whether metformin can promote functional recovery and neural repair following SCI in both males and females. Our results reveal that acute, but not delayed metformin administration improves functional outcomes following SCI in both sexes. The functional improvement is concomitant with OPC activation and oligodendrogenesis. Our data also reveal sex-dependent effects of metformin following SCI with increased activation of NSPCs in females and reduced microglia activation in males. Taken together, these findings support metformin as a viable therapeutic strategy following SCI and highlight its pleiotropic effects in the spinal cord.
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Affiliation(s)
- Emily A B Gilbert
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Canada
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Jessica Livingston
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Canada
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Emilio Garcia-Flores
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Canada
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Canada
| | - Tarlan Kehtari
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Canada
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Cindi M Morshead
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Canada
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Canada
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22
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Nashif SK, Mahr RM, Jena S, Jo S, Nelson AB, Sadowski D, Crawford PA, Puchalska P, Alejandro EU, Gearhart MD, Wernimont SA. Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner. Front Cell Dev Biol 2023; 11:1167097. [PMID: 37250894 PMCID: PMC10213689 DOI: 10.3389/fcell.2023.1167097] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 05/05/2023] [Indexed: 05/31/2023] Open
Abstract
Metformin is a widely prescribed medication whose mechanism of action is not completely defined and whose role in gestational diabetes management remains controversial. In addition to increasing the risk of fetal growth abnormalities and preeclampsia, gestational diabetes is associated with abnormalities in placental development including impairments in trophoblast differentiation. Given that metformin impacts cellular differentiation events in other systems, we assessed metformin's impact on trophoblast metabolism and differentiation. Using established cell culture models of trophoblast differentiation, oxygen consumption rates and relative metabolite abundance were determined following 200 µM (therapeutic range) and 2000 µM (supra-therapeutic range) metformin treatment using Seahorse and mass-spectrometry approaches. While no differences in oxygen consumption rates or relative metabolite abundance were detected between vehicle and 200 µM metformin-treated cells, 2000 µM metformin impaired oxidative metabolism and increased the abundance of lactate and TCA cycle intermediates, α-ketoglutarate, succinate, and malate. Examining differentiation, treatment with 2000 μM, but not 200 µM metformin, impaired HCG production and expression of multiple trophoblast differentiation markers. Overall, this work suggests that supra-therapeutic concentrations of metformin impair trophoblast metabolism and differentiation whereas metformin concentrations in the therapeutic range do not strongly impact these processes.
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Affiliation(s)
- Sereen K. Nashif
- Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota, Minneapolis, MN, United States
| | - Renee M. Mahr
- Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota, Minneapolis, MN, United States
| | - Snehalata Jena
- Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota, Minneapolis, MN, United States
| | - Seokwon Jo
- Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Alisa B. Nelson
- Division of Molecular Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Danielle Sadowski
- Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota, Minneapolis, MN, United States
| | - Peter A. Crawford
- Division of Molecular Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, United States
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, United States
| | - Patrycja Puchalska
- Division of Molecular Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Emilyn U. Alejandro
- Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Micah D. Gearhart
- Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota, Minneapolis, MN, United States
| | - Sarah A. Wernimont
- Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota, Minneapolis, MN, United States
- Division of Molecular Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, United States
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23
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A novel ex vivo assay to define charge-balanced electrical stimulation parameters for neural precursor cell activation in vivo. Brain Res 2023; 1804:148263. [PMID: 36702184 DOI: 10.1016/j.brainres.2023.148263] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 01/17/2023] [Accepted: 01/21/2023] [Indexed: 01/25/2023]
Abstract
Endogenous neural stem cells and their progeny (together termed neural precursor cells (NPCs)) are promising candidates to facilitate neuroregeneration. Charge-balanced biphasic monopolar stimulation (BPMP) is a clinically relevant approach that can activate NPCs both in vitro and in vivo. Herein, we established a novel ex vivo stimulation system to optimize the efficacy of BPMP electric field (EF) application in activating endogenous NPCs. Using the ex vivo system, we discerned that cathodal amplitude of 200 μA resulted in the greatest NPC pool expansion and enhanced cathodal migration. Application of the same stimulation parameters in vivo resulted in the same NPC activation in the mouse brain. The design and implementation of the novel ex vivo model bridges the gap between in vitro and in vivo systems, enabling a moderate throughput stimulation system to explore and optimize EF parameters that can be applied to clinically relevant brain injury/disease models.
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24
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Nashif SK, Mahr RM, Jena S, Jo S, Nelson AB, Sadowski D, Crawford PA, Puchalska P, Alejandro EU, Gearhart MD, Wernimont SA. Metformin impairs trophoblast metabolism and differentiation in dose dependent manner. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.14.528531. [PMID: 36824783 PMCID: PMC9949099 DOI: 10.1101/2023.02.14.528531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Metformin is a widely prescribed medication whose mechanism of action is not completely defined and whose role in gestational diabetes management remains controversial. In addition to increasing risks of fetal growth abnormalities and preeclampsia, gestational diabetes is associated with abnormalities in placental development including impairments in trophoblast differentiation. Given that metformin impacts cellular differentiation events in other systems, we assessed metformin's impact on trophoblast metabolism and differentiation. Using established cell culture models of trophoblast differentiation, oxygen consumption rates and relative metabolite abundance were determined following 200 μM (therapeutic range) and 2000 μM (supra-therapeutic range) metformin treatment using Seahorse and mass-spectrometry approaches. While no differences in oxygen consumption rates or relative metabolite abundance were detected between vehicle and 200 μM metformin treated cells, 2000 μM metformin impaired oxidative metabolism and increased abundance of lactate and TCA cycle intermediates, α-ketoglutarate, succinate, and malate. Examining differentiation, treatment with 2000 μM, but not 200 μM metformin, impaired HCG production and expression of multiple trophoblast differentiation markers. Overall, this work suggests that supra-therapeutic concentrations of metformin impairs trophoblast metabolism and differentiation whereas metformin concentrations in the therapeutic range do not strongly impact these processes.
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25
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Metformin enhances neural precursor cells migration and functional recovery after ischemic stroke in mice. Exp Brain Res 2023; 241:505-515. [PMID: 36611122 DOI: 10.1007/s00221-023-06547-3] [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: 08/26/2022] [Accepted: 01/03/2023] [Indexed: 01/09/2023]
Abstract
Resident neural precursor cells (NPCs) activation is a promising therapeutic strategy for brain repair. This strategy involves stimulating multiple stages of NPCs development, including proliferation, self-renewal, migration, and differentiation. Metformin, an FDA-approved diabetes drug, has been shown to promote the proliferation and differentiation of NPCs. However, it is still unclear whether metformin promotes the migration of NPCs. EVOS living cell imaging system was used for observing the migration for primary NPCs dynamically in vitro after metformin treatment. For in vivo study, a mouse model of ischemic stroke was established through middle cerebral artery occlusion (MCAO). To label the proliferating cell in subventricular zone, BrdU was injected intraperitoneally into the mice. After co-staining with BrdU and doublecortin (DCX), a marker for NPCs, the migration of Brdu and DCX double positive NPCs was detected along the rostral migratory stream (RMS) and around the infarct area using frozen brain sections. Finally, the rotarod test, corner test and beam walking were performed to evaluate the motor functions of the mice after stroke in different groups. The results showed that metformin enhanced NPCs migration in vivo and in vitro by promoting F-actin assembly and lamellipodia formation. What's more, metformin treatment also significantly reduced the infarct volume and alleviated functional dysfunction after stroke. Mechanistically, metformin promoted NPCs migration via up-regulating the CDC42 expression. Taken together, metformin represents an optimal candidate agent for neural repair that is capable of not only expanding the adult NPC population but also subsequently driving them toward the destination for neuronal differentiation.
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26
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A blast from the past: To tame time with metformin. Mech Ageing Dev 2022; 208:111743. [PMID: 36279989 DOI: 10.1016/j.mad.2022.111743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/18/2022] [Accepted: 10/20/2022] [Indexed: 11/05/2022]
Abstract
The strong evidence of metformin use in subjects affected by type 2 diabetes (T2DM) on health outcomes, together with data from pre-clinical studies, has led the gerontological research to study the therapeutic potential of such a drug as a slow-aging strategy. However, despite clinical use for over fifty years as an anti-diabetic drug, the mechanisms of action beyond glycemic control remain unclear. In this review, we have deeply examined the literature, doing a narrative review from the metformin story, through mechanisms of action to slow down aging potential, from lower organisms to humans. Based on the available evidence, we conclude that metformin, as shown in lower organisms and mice, may be effective in humans' longevity. A complete analysis and follow-up of ongoing clinical trials may provide more definitive answers as to whether metformin should be promoted beyond its use to treat T2DM as a drug that enhances both healthspan and lifespan.
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27
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Badner A, Cummings BJ. The endogenous progenitor response following traumatic brain injury: a target for cell therapy paradigms. Neural Regen Res 2022; 17:2351-2354. [PMID: 35535870 PMCID: PMC9120693 DOI: 10.4103/1673-5374.335833] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/14/2021] [Accepted: 11/15/2021] [Indexed: 11/21/2022] Open
Abstract
Although there is ample evidence that central nervous system progenitor pools respond to traumatic brain injury, the reported effects are variable and likely contribute to both recovery as well as pathophysiology. Through a better understanding of the diverse progenitor populations in the adult brain and their niche-specific reactions to traumatic insult, treatments can be tailored to enhance the benefits and dampen the deleterious effects of this response. This review provides an overview of endogenous precursors, the associated effects on cognitive recovery, and the potential of exogenous cell therapeutics to modulate these endogenous repair mechanisms. Beyond the hippocampal dentate gyrus and subventricular zone of the lateral ventricles, more recently identified sites of adult neurogenesis, the meninges, as well as circumventricular organs, are also discussed as targets for endogenous repair. Importantly, this review highlights that progenitor proliferation alone is no longer a meaningful outcome and studies must strive to better characterize precursor spatial localization, transcriptional profile, morphology, and functional synaptic integration. With improved insight and a more targeted approach, the stimulation of endogenous neurogenesis remains a promising strategy for recovery following traumatic brain injury.
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Affiliation(s)
- Anna Badner
- Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA
| | - Brian J. Cummings
- Sue and Bill Gross Stem Cell Center, University of California-Irvine, Irvine, CA, USA
- Institute for Memory Impairments and Neurological Disorders, University of California-Irvine, Irvine, CA, USA
- Physical Medicine and Rehabilitation, University of California-Irvine, Irvine, CA, USA
- Department of Anatomy and Neurobiology, University of California-Irvine, Irvine, CA, USA
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28
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Mohammadi A, Higazy R, Gauda EB. PGC-1α activity and mitochondrial dysfunction in preterm infants. Front Physiol 2022; 13:997619. [PMID: 36225305 PMCID: PMC9548560 DOI: 10.3389/fphys.2022.997619] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/09/2022] [Indexed: 11/26/2022] Open
Abstract
Extremely low gestational age neonates (ELGANs) are born in a relatively hyperoxic environment with weak antioxidant defenses, placing them at high risk for mitochondrial dysfunction affecting multiple organ systems including the nervous, respiratory, ocular, and gastrointestinal systems. The brain and lungs are highly affected by mitochondrial dysfunction and dysregulation in the neonate, causing white matter injury (WMI) and bronchopulmonary dysplasia (BPD), respectively. Adequate mitochondrial function is important in providing sufficient energy for organ development as it relates to alveolarization and axonal myelination and decreasing oxidative stress via reactive oxygen species (ROS) and reactive nitrogen species (RNS) detoxification. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a master regulator of mitochondrial biogenesis and function. Since mitochondrial dysfunction is at the root of WMI and BPD pathobiology, exploring therapies that can regulate PGC-1α activity may be beneficial. This review article describes several promising therapeutic agents that can mitigate mitochondrial dysfunction through direct and indirect activation and upregulation of the PGC-1α pathway. Metformin, resveratrol, omega 3 fatty acids, montelukast, L-citrulline, and adiponectin are promising candidates that require further pre-clinical and clinical studies to understand their efficacy in decreasing the burden of disease from WMI and BPD in preterm infants.
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Affiliation(s)
- Atefeh Mohammadi
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Randa Higazy
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
| | - Estelle B. Gauda
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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29
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Savchuk S, Monje M. Mini-Review: Aplastic Myelin Following Chemotherapy. Neurosci Lett 2022; 790:136861. [PMID: 36055447 DOI: 10.1016/j.neulet.2022.136861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 05/12/2022] [Accepted: 08/26/2022] [Indexed: 11/16/2022]
Abstract
The contribution of chemotherapy to improved outcomes for cancer patients is unquestionable. Yet as its applications broaden, so do the concerns for the long-term implications of chemotherapy on the health of cancer survivors, with chemotherapy-related cognitive impairment as a cause for particular urgency. In this mini review, we explore myelin aplasticity following chemotherapy, discussing the role of myelin plasticity in healthy cognition and failure of myelin plasticity chiefly due microenvironmental aberrations in chemotherapy-related cognitive impairment. Possible therapeutic strategies to mitigate chemotherapy-induced myelin dysfunction are also discussed.
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Affiliation(s)
- Solomiia Savchuk
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA; Department of Pathology, Stanford University, Stanford, CA, 94305, USA; Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA, 94305, USA.
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30
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Liu T, Zhu W, Zhang X, He C, Liu X, Xin Q, Chen K, Wang H. Recent Advances in Cell and Functional Biomaterial Treatment for Spinal Cord Injury. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5079153. [PMID: 35978649 PMCID: PMC9377911 DOI: 10.1155/2022/5079153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/17/2022] [Accepted: 07/25/2022] [Indexed: 12/17/2022]
Abstract
Spinal cord injury (SCI) is a devastating central nervous system disease caused by accidental events, resulting in loss of sensory and motor function. Considering the multiple effects of primary and secondary injuries after spinal cord injury, including oxidative stress, tissue apoptosis, inflammatory response, and neuronal autophagy, it is crucial to understand the underlying pathophysiological mechanisms, local microenvironment changes, and neural tissue functional recovery for preparing novel treatment strategies. Treatment based on cell transplantation has become the forefront of spinal cord injury therapy. The transplanted cells provide physical and nutritional support for the damaged tissue. At the same time, the implantation of biomaterials with specific biological functions at the site of the SCI has also been proved to improve the local inhibitory microenvironment and promote axonal regeneration, etc. The combined transplantation of cells and functional biomaterials for SCI treatment can result in greater neuroprotective and regenerative effects by regulating cell differentiation, enhancing cell survival, and providing physical and directional support for axon regeneration and neural circuit remodeling. This article reviews the pathophysiology of the spinal cord, changes in the microenvironment after injury, and the mechanisms and strategies for spinal cord regeneration and repair. The article will focus on summarizing and discussing the latest intervention models based on cell and functional biomaterial transplantation and the latest progress in combinational therapies in SCI repair. Finally, we propose the future prospects and challenges of current treatment regimens for SCI repair, to provide references for scientists and clinicians to seek better SCI repair strategies in the future.
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Affiliation(s)
- Tianyi Liu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Wenhao Zhu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Xiaoyu Zhang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Chuan He
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Xiaolong Liu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Qiang Xin
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Kexin Chen
- Institute of Translational Medicine, First Hospital of Jilin University, Changchun 130021, China
| | - Haifeng Wang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
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31
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Bourget C, Adams KV, Morshead CM. Reduced microglia activation following metformin administration or microglia ablation is sufficient to prevent functional deficits in a mouse model of neonatal stroke. J Neuroinflammation 2022; 19:146. [PMID: 35705953 PMCID: PMC9199194 DOI: 10.1186/s12974-022-02487-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 04/29/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Neonatal stroke is a devastating insult that can lead to life-long impairments. In response to hypoxic-ischaemic injury, there is loss of neurons and glia as well as a neuroinflammatory response mediated by resident immune cells, including microglia and astrocytes, which can exacerbate damage. Administration of the antidiabetic drug metformin has been shown to improve functional outcomes in preclinical models of brain injury and the cellular basis for metformin-mediated recovery is unknown. Given metformin's demonstrated anti-inflammatory properties, we investigated its role in regulating the microglia activation and used a microglia ablation strategy to investigate the microglia-mediated outcomes in a mouse model of neonatal stroke. METHODS Hypoxia-ischaemia (H-I) was performed on post-natal day 8. Metformin was administered for one week, starting one day after injury. Immunohistochemistry was used to examine the spatiotemporal response of microglia and astrocytes after hypoxia-ischaemia, with or without metformin treatment. To evaluate the effects of microglia depletion after hypoxia-ischaemia, we delivered Plexxikon 5622 for 1 or 2 weeks post-injury. The regional pattern of microglia and astrocyte depletion was assessed through immunohistochemistry. Motor behaviour was assessed with the righting reflex, hindlimb suspension, grip strength and cylinder tests. RESULTS Herein, we revealed a spatiotemporally regulated response of microglia and astrocytes after hypoxia-ischaemia. Metformin treatment after hypoxia-ischaemia had no effect on microglia number and proliferation, but significantly reduced microglia activation in all regions examined, concomitant with improved behavioural outcomes in injured mice. Plexxikon 5622 treatment successfully ablated microglia, resulting in a > 90% depletion in microglia in the neonatal brain. Microglia rapidly repopulated upon treatment cessation of Plexxikon. Most interesting, microglia ablation was sufficient to reduce functional deficits after hypoxia-ischaemia, mimicking the effects of 1 week of metformin treatment post-injury. CONCLUSION These results highlight the importance of regulating the neuroinflammatory response after neonatal stroke to promote recovery.
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Affiliation(s)
- Clara Bourget
- Institute of Medical Sciences, University of Toronto, Toronto, M5S1A8, Canada
| | - Kelsey V Adams
- Institute of Medical Sciences, University of Toronto, Toronto, M5S1A8, Canada
| | - Cindi M Morshead
- Institute of Medical Sciences, University of Toronto, Toronto, M5S1A8, Canada.
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Room 1006, Toronto, ON, M5S3E1, Canada.
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, M5S1A8, Canada.
- Institute of Biomedical Engineering, University of Toronto, Toronto, M5S3E1, Canada.
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Baklaushev VP, Yusubalieva GM, Samoilova EM, Belopasov VV. Resident Neural Stem Cell Niches and Regeneration: The Splendors and Miseries of Adult Neurogenesis. Russ J Dev Biol 2022. [DOI: 10.1134/s1062360422030080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Al Dahhan NZ, Cox E, Nieman BJ, Mabbott DJ. Cross-translational models of late-onset cognitive sequelae and their treatment in pediatric brain tumor survivors. Neuron 2022; 110:2215-2241. [PMID: 35523175 DOI: 10.1016/j.neuron.2022.04.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/21/2022] [Accepted: 04/08/2022] [Indexed: 10/18/2022]
Abstract
Pediatric brain tumor treatments have a high success rate, but survivors are at risk of cognitive sequelae that impact long-term quality of life. We summarize recent clinical and animal model research addressing pathogenesis or evaluating candidate interventions for treatment-induced cognitive sequelae. Assayed interventions encompass a broad range of approaches, including modifications to radiotherapy, modulation of immune response, prevention of treatment-induced cell loss or promotion of cell renewal, manipulation of neuronal signaling, and lifestyle/environmental adjustments. We further emphasize the potential of neuroimaging as a key component of cross-translation to contextualize laboratory research within broader clinical findings. This cross-translational approach has the potential to accelerate discovery to improve pediatric cancer survivors' long-term quality of life.
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Affiliation(s)
- Noor Z Al Dahhan
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada
| | - Elizabeth Cox
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada
| | - Brian J Nieman
- Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada; Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Donald J Mabbott
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada; Department of Psychology, Hospital for Sick Children, Toronto, ON, Canada.
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Jin L, Jin F, Guo S, Liu W, Wei B, Fan H, Li G, Zhang X, Su S, Li R, Fang D, Duan C, Li X. Metformin Inhibits NLR Family Pyrin Domain Containing 3 (NLRP)-Relevant Neuroinflammation via an Adenosine-5′-Monophosphate-Activated Protein Kinase (AMPK)-Dependent Pathway to Alleviate Early Brain Injury After Subarachnoid Hemorrhage in Mice. Front Pharmacol 2022; 13:796616. [PMID: 35370693 PMCID: PMC8969021 DOI: 10.3389/fphar.2022.796616] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 02/09/2022] [Indexed: 12/23/2022] Open
Abstract
Neuroinflammation plays a key role in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have shown that metformin exerts anti-inflammatory effects and promotes functional recovery in various central nervous system diseases. We designed this study to investigate the effects of metformin on EBI after SAH. Our results indicate that the use of metformin alleviates the brain edema, behavioral disorders, cell apoptosis, and neuronal injury caused by SAH. The SAH-induced NLRP3-associated inflammatory response and the activation of microglia are also suppressed by metformin. However, we found that the blockade of AMPK with compound C weakened the neuroprotective effects of metformin on EBI. Collectively, our findings indicate that metformin exerts its neuroprotective effects by inhibiting neuroinflammation in an AMPK-dependent manner, by modulating the production of NLRP3-associated proinflammatory factors and the activation of microglia.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Xifeng Li
- *Correspondence: Chuanzhi Duan, ; Xifeng Li,
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Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair. Cells 2022; 11:cells11050846. [PMID: 35269466 PMCID: PMC8909806 DOI: 10.3390/cells11050846] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 12/12/2022] Open
Abstract
Spinal cord injury (SCI) affects millions of individuals worldwide. Currently, there is no cure, and treatment options to promote neural recovery are limited. An innovative approach to improve outcomes following SCI involves the recruitment of endogenous populations of neural stem cells (NSCs). NSCs can be isolated from the neuroaxis of the central nervous system (CNS), with brain and spinal cord populations sharing common characteristics (as well as regionally distinct phenotypes). Within the spinal cord, a number of NSC sub-populations have been identified which display unique protein expression profiles and proliferation kinetics. Collectively, the potential for NSCs to impact regenerative medicine strategies hinges on their cardinal properties, including self-renewal and multipotency (the ability to generate de novo neurons, astrocytes, and oligodendrocytes). Accordingly, endogenous NSCs could be harnessed to replace lost cells and promote structural repair following SCI. While studies exploring the efficacy of this approach continue to suggest its potential, many questions remain including those related to heterogeneity within the NSC pool, the interaction of NSCs with their environment, and the identification of factors that can enhance their response. We discuss the current state of knowledge regarding populations of endogenous spinal cord NSCs, their niche, and the factors that regulate their behavior. In an attempt to move towards the goal of enhancing neural repair, we highlight approaches that promote NSC activation following injury including the modulation of the microenvironment and parenchymal cells, pharmaceuticals, and applied electrical stimulation.
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36
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Zhang L, Li Q, Wang H, Wu Y, Ye X, Gong Z, Li Q, Xuan A. Gadd45g, a novel antidepressant target, mediates metformin-induced neuronal differentiation of neural stem cells via DNA demethylation. Stem Cells 2022; 40:59-73. [DOI: 10.1093/stmcls/sxab001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 07/28/2021] [Indexed: 11/14/2022]
Abstract
Abstract
Increased neurogenesis elicits antidepressive-like effects. The antidiabetic drug metformin (Met) reportedly promotes hippocampal neurogenesis, which ameliorates spatial memory deficits and depression-like behaviors. However, the precise molecular mechanisms underpinning Met-induced neuronal differentiation of neural stem cells (NSCs) remain unclear. We showed that Met enhanced neuronal differentiation of NSCs via Gadd45g but not Gadd45a and Gadd45b. We further found that Gadd45g increased demethylation of neurogenic differentiation 1 (NeuroD1) promoter by regulating the activity of passive and active DNA demethylation enzymes through an AMPK-independent mechanism in Met-treated NSCs. Importantly, genetic deficiency of Gadd45g decreased hippocampal neurogenesis, which could contribute to spatial memory decline, and depression-like behaviors in the adult mice, whereas forced expression of Gadd45g alleviated the depressive-like behaviors. Our findings provide a model that Gadd45g-mediated DNA demethylation contributes to Met-induced neuronal genesis and its antidepressant-like effects, and propose the concept that targeting Gadd45g regulation of neurogenesis might serve as a novel antidepressant strategy.
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Affiliation(s)
- Le Zhang
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Qingfeng Li
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Huan Wang
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yuanfei Wu
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Xiujuan Ye
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Zhuo Gong
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Qingqing Li
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Aiguo Xuan
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
- Key Laboratory of Neurological Function and Health, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, China
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Cheng FF, Liu YL, Du J, Lin JT. Metformin's Mechanisms in Attenuating Hallmarks of Aging and Age-Related Disease. Aging Dis 2022; 13:970-986. [PMID: 35855344 PMCID: PMC9286921 DOI: 10.14336/ad.2021.1213] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 12/13/2021] [Indexed: 11/01/2022] Open
Affiliation(s)
- Fang-Fang Cheng
- College of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China.
- Stem Cell and Biotherapy Engineering Research Center of Henan, Xinxiang Medical University, Xinxiang 453003, China.
| | - Yan-Li Liu
- College of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China.
- Stem Cell and Biotherapy Engineering Research Center of Henan, Xinxiang Medical University, Xinxiang 453003, China.
| | - Jang Du
- Stem Cell and Biotherapy Engineering Research Center of Henan, Xinxiang Medical University, Xinxiang 453003, China.
| | - Jun-Tang Lin
- Stem Cell and Biotherapy Engineering Research Center of Henan, Xinxiang Medical University, Xinxiang 453003, China.
- Correspondence should be addressed to: Dr. Jun-Tang Lin, Stem Cell and Biotherapy Engineering Research Center of Henan, Xinxiang Medical University, Xinxiang, China.
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Imron A, Hernowo B, Hilmanto D, Wiriadisastra K, Hermanto Y. The Effects of Glucagon and Insulin Combination toward on Neurodegeneration Following Traumatic Brain Injury in Rat Model. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.7490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability in the productive age. Glutamate excitotoxicity and hyperglycemia those occur following TBI are among the factors those influence secondary brain injury.
AIM: This study aimed to determine the effect of glucagon and insulin combination on neuronal necrosis following TBI.
METHODS: A total of 28 male wistar rats were randomized into four experimental groups: placebo, insulin, glucagon, and combination of glucagon and insulin. Each animal underwent controlled cortical impact model of TBI. The blood glucose and glutamate levels were measured before and 4 h following TBI. The brain tissues were collected to evaluate neuronal necrosis.
RESULTS: Glucagon or glucagon and insulin combination were able to prevent the increased of blood glutamate levels following TBI (p < 0.05). Glucagon administration was associated high blood glucose level (198.10 ± 32.58 mg/dL); a combination with insulin was able to minimize the increased of blood glucose level (166.53 ± 18.48 mg/dL). Combination of glucagon and insulin had a lower number of neuronal necrosis compare to the other groups (p < 0.005).
CONCLUSION: The combination of glucagon and insulin potentially exhibit neuroprotection effect on rats following TBI as being demonstrated by lower number of neuronal necrosis. This finding further indicates the role of glucose homeostasis in neuroprotection.
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Yuen N, Szulc-Lerch KU, Li YQ, Morshead CM, Mabbott DJ, Wong CS, Nieman BJ. Metformin effects on brain development following cranial irradiation in a mouse model. Neuro Oncol 2021; 23:1523-1536. [PMID: 34042964 PMCID: PMC8408860 DOI: 10.1093/neuonc/noab131] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Cranial radiation therapy (CRT) is a mainstay of treatment for malignant pediatric brain tumors and high-risk leukemia. Although CRT improves survival, it has been shown to disrupt normal brain development and result in cognitive impairments in cancer survivors. Animal studies suggest that there is potential to promote brain recovery after injury using metformin. Our aim was to evaluate whether metformin can restore brain volume outcomes in a mouse model of CRT. METHODS C57BL/6J mice were irradiated with a whole-brain radiation dose of 7 Gy during infancy. Two weeks of metformin treatment started either on the day of or 3 days after irradiation. In vivo magnetic resonance imaging was performed prior to irradiation and at 3 subsequent time points to evaluate the effects of radiation and metformin on brain development. RESULTS Widespread volume loss in the irradiated brain appeared within 1 week of irradiation with limited subsequent recovery in volume outcomes. In many structures, metformin administration starting on the day of irradiation exacerbated radiation-induced injury, particularly in male mice. Metformin treatment starting 3 days after irradiation improved brain volume outcomes in subcortical regions, the olfactory bulbs, and structures of the brainstem and cerebellum. CONCLUSIONS Our results show that metformin treatment has the potential to improve neuroanatomical outcomes after CRT. However, both timing of metformin administration and subject sex affect structure outcomes, and metformin may also be deleterious. Our results highlight important considerations in determining the potential benefits of metformin treatment after CRT and emphasize the need for caution in repurposing metformin in clinical studies.
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Affiliation(s)
- Nili Yuen
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Kamila U Szulc-Lerch
- Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Yu-Qing Li
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Cindi M Morshead
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
- Terrence Donelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Donald J Mabbott
- Department of Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - C Shun Wong
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Brian J Nieman
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
- Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
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40
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Ru X, Gao L, Zhou J, Li Q, Zuo S, Chen Y, Liu Z, Feng H. Secondary White Matter Injury and Therapeutic Targets After Subarachnoid Hemorrhage. Front Neurol 2021; 12:659740. [PMID: 34335439 PMCID: PMC8319471 DOI: 10.3389/fneur.2021.659740] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 06/11/2021] [Indexed: 01/19/2023] Open
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) is one of the special stroke subtypes with high mortality and mobility. Although the mortality of SAH has decreased by 50% over the past two decades due to advances in neurosurgery and management of neurocritical care, more than 70% of survivors suffer from varying degrees of neurological deficits and cognitive impairments, leaving a heavy burden on individuals, families, and the society. Recent studies have shown that white matter is vulnerable to SAH, and white matter injuries may be one of the causes of long-term neurological deficits caused by SAH. Attention has recently focused on the pivotal role of white matter injury in the pathophysiological processes after SAH, mainly related to mechanical damage caused by increased intracerebral pressure and the metabolic damage induced by blood degradation and hypoxia. In the present review, we sought to summarize the pathophysiology processes and mechanisms of white matter injury after SAH, with a view to providing new strategies for the prevention and treatment of long-term cognitive dysfunction after SAH.
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Affiliation(s)
- Xufang Ru
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Ling Gao
- Department of General Practice, Audio-Visual Education Center, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jiru Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiang Li
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Shilun Zuo
- Department of Neurology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yujie Chen
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zhi Liu
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Hua Feng
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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41
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Derkach D, Kehtari T, Renaud M, Heidari M, Lakshman N, Morshead CM. Metformin pretreatment rescues olfactory memory associated with subependymal zone neurogenesis in a juvenile model of cranial irradiation. Cell Rep Med 2021; 2:100231. [PMID: 33948569 PMCID: PMC8080112 DOI: 10.1016/j.xcrm.2021.100231] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 09/12/2020] [Accepted: 03/09/2021] [Indexed: 01/23/2023]
Abstract
Cranial irradiation (IR) is an effective adjuvant therapy in the treatment of childhood brain tumors but results in long-lasting cognitive deficits associated with impaired neurogenesis, as evidenced in rodent models. Metformin has been shown to expand the endogenous neural stem cell (NSC) pool and promote neurogenesis under physiological conditions and in response to neonatal brain injury, suggesting a potential role in neurorepair. Here, we assess whether metformin pretreatment, a clinically feasible treatment for children receiving cranial IR, promotes neurorepair in a mouse cranial IR model. Using immunofluorescence and the in vitro neurosphere assay, we show that NSCs are depleted by cranial IR but spontaneously recover, although deficits to proliferative neuroblasts persist. Metformin pretreatment enhances the recovery of neurogenesis, attenuates the microglial response, and promotes recovery of long-term olfactory memory. These findings indicate that metformin is a promising candidate for further preclinical and clinical investigations of neurorepair in childhood brain injuries.
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Affiliation(s)
- Daniel Derkach
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Tarlan Kehtari
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Matthew Renaud
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Mohsen Heidari
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Nishanth Lakshman
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Cindi M. Morshead
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
- Division of Anatomy, Department of Surgery, University of Toronto, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
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42
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Li YQ, Wong CS. Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation. J Neuropathol Exp Neurol 2021; 80:467-475. [PMID: 33706379 DOI: 10.1093/jnen/nlab014] [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] [Indexed: 11/14/2022] Open
Abstract
5'-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.
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Affiliation(s)
- Yu-Qing Li
- From the Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - C Shun Wong
- From the Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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Esmaeilnejad S, Semnanian S, Javan M. Metformin Protects Myelin from Degeneration in A Mouse Model of Iysophosphatidylcholine-Induced Demyelination in The Optic Chiasm. CELL JOURNAL 2021; 23:119-128. [PMID: 33650828 PMCID: PMC7944130 DOI: 10.22074/cellj.2021.7174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 01/08/2020] [Indexed: 12/16/2022]
Abstract
Objective Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. The autoimmune
pathology and long-term inflammation lead to substantial demyelination. These events lead to a substantial loss
of oligodendrocytes (OLs), which in a longer period, results in axonal loss and long-term disabilities. Neural cells
protection approaches decelerate or inhibit the disease progress to avoid further disability. Previous studies showed
that metformin has beneficial effects against neurodegenerative conditions. In this experimental study, we examined
possible protective effects of metformin on toxin-induced myelin destruction in adult mice brains.
Materials and Methods Lysophosphatidylcholine (LPC) was used to induce demyelination in mice optic chiasm. We
examined the extent of demyelination at different time points post LPC injection using myelin staining and evaluated the
severity of inflammation. Functional state of optic pathway was evaluated by visual evoked potential (VEP) recording.
Results Metformin attenuated LPC-induced demyelination (P<0.05) and inflammation (P<0.05) and protected against
significant decrease (P<0.05) in functional conductivity of optic tract. These data indicated that metformin administration
attenuates the myelin degeneration following LPC injection which led to functional enhancement.
Conclusion Our findings suggest metformin for combination therapy for patients suffering from the myelin degenerative
diseases, especially multiple sclerosis; however, additional mechanistic studies are required.
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Affiliation(s)
- Saman Esmaeilnejad
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeed Semnanian
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Javan
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. .,Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Grisé KN, Bautista NX, Jacques K, Coles BLK, van der Kooy D. Glucocorticoid agonists enhance retinal stem cell self-renewal and proliferation. Stem Cell Res Ther 2021; 12:83. [PMID: 33494791 PMCID: PMC7831262 DOI: 10.1186/s13287-021-02136-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/01/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Adult mammalian retinal stem cells (RSCs) readily proliferate, self-renew, and generate progeny that differentiate into all retinal cell types in vitro. RSC-derived progeny can be induced to differentiate into photoreceptors, making them a potential source for retinal cell transplant therapies. Despite their proliferative propensity in vitro, RSCs in the adult mammalian eye do not proliferate and do not have a regenerative response to injury. Thus, identifying and modulating the mechanisms that regulate RSC proliferation may enhance the capacity to produce RSC-derived progeny in vitro and enable RSC activation in vivo. METHODS Here, we used medium-throughput screening to identify small molecules that can expand the number of RSCs and their progeny in culture. In vitro differentiation assays were used to assess the effects of synthetic glucocorticoid agonist dexamethasone on RSC-derived progenitor cell fate. Intravitreal injections of dexamethasone into adult mouse eyes were used to investigate the effects on endogenous RSCs. RESULTS We discovered that high-affinity synthetic glucocorticoid agonists increase RSC self-renewal and increase retinal progenitor proliferation up to 6-fold without influencing their differentiation in vitro. Intravitreal injection of synthetic glucocorticoid agonist dexamethasone induced in vivo proliferation in the ciliary epithelium-the niche in which adult RSCs reside. CONCLUSIONS Together, our results identify glucocorticoids as novel regulators of retinal stem and progenitor cell proliferation in culture and provide evidence that GCs may activate endogenous RSCs.
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Affiliation(s)
- Kenneth N Grisé
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
| | - Nelson X Bautista
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Krystal Jacques
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Brenda L K Coles
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada
| | - Derek van der Kooy
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, M5S 1A8, Canada
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45
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Bressan C, Saghatelyan A. Intrinsic Mechanisms Regulating Neuronal Migration in the Postnatal Brain. Front Cell Neurosci 2021; 14:620379. [PMID: 33519385 PMCID: PMC7838331 DOI: 10.3389/fncel.2020.620379] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 12/08/2020] [Indexed: 01/19/2023] Open
Abstract
Neuronal migration is a fundamental brain development process that allows cells to move from their birthplaces to their sites of integration. Although neuronal migration largely ceases during embryonic and early postnatal development, neuroblasts continue to be produced and to migrate to a few regions of the adult brain such as the dentate gyrus and the subventricular zone (SVZ). In the SVZ, a large number of neuroblasts migrate into the olfactory bulb (OB) along the rostral migratory stream (RMS). Neuroblasts migrate in chains in a tightly organized micro-environment composed of astrocytes that ensheath the chains of neuroblasts and regulate their migration; the blood vessels that are used by neuroblasts as a physical scaffold and a source of molecular factors; and axons that modulate neuronal migration. In addition to diverse sets of extrinsic micro-environmental cues, long-distance neuronal migration involves a number of intrinsic mechanisms, including membrane and cytoskeleton remodeling, Ca2+ signaling, mitochondria dynamics, energy consumption, and autophagy. All these mechanisms are required to cope with the different micro-environment signals and maintain cellular homeostasis in order to sustain the proper dynamics of migrating neuroblasts and their faithful arrival in the target regions. Neuroblasts in the postnatal brain not only migrate into the OB but may also deviate from their normal path to migrate to a site of injury induced by a stroke or by certain neurodegenerative disorders. In this review, we will focus on the intrinsic mechanisms that regulate long-distance neuroblast migration in the adult brain and on how these pathways may be modulated to control the recruitment of neuroblasts to damaged/diseased brain areas.
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Affiliation(s)
- Cedric Bressan
- CERVO Brain Research Center, Quebec City, QC, Canada.,Department of Psychiatry and Neuroscience, Université Laval, Quebec City, QC, Canada
| | - Armen Saghatelyan
- CERVO Brain Research Center, Quebec City, QC, Canada.,Department of Psychiatry and Neuroscience, Université Laval, Quebec City, QC, Canada
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Jiang LL, Liu L. Effect of metformin on stem cells: Molecular mechanism and clinical prospect. World J Stem Cells 2020; 12:1455-1473. [PMID: 33505595 PMCID: PMC7789120 DOI: 10.4252/wjsc.v12.i12.1455] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/28/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
Metformin is a first-line medication for type II diabetes. Numerous studies have shown that metformin not only has hypoglycemic effects, but also modulates many physiological and pathological processes ranging from aging and cancer to fracture healing. During these different physiological activities and pathological changes, stem cells usually play a core role. Thus, many studies have investigated the effects of metformin on stem cells. Metformin affects cell differentiation and has promising applications in stem cell medicine. It exerts anti-aging effects and can be applied to gerontology and regenerative medicine. The potential anti-cancer stem cell effect of metformin indicates that it can be an adjuvant therapy for cancers. Furthermore, metformin has beneficial effects against many other diseases including cardiovascular and autoimmune diseases. In this review, we summarize the effects of metformin on stem cells and provide an overview of its molecular mechanisms and clinical prospects.
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Affiliation(s)
- Lin-Li Jiang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China.
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47
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Kosaraju J, Seegobin M, Gouveia A, Syal C, Sarma SN, Lu KJ, Ilin J, He L, Wondisford FE, Lagace D, De Repentigny Y, Kothary R, Wang J. Metformin promotes CNS remyelination and improves social interaction following focal demyelination through CBP Ser436 phosphorylation. Exp Neurol 2020; 334:113454. [PMID: 32877653 DOI: 10.1016/j.expneurol.2020.113454] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 08/15/2020] [Accepted: 08/26/2020] [Indexed: 02/04/2023]
Abstract
Individuals with demyelinating diseases often experience difficulties during social interactions that are not well studied in preclinical models. Here, we describe a novel juvenile focal corpus callosum demyelination murine model exhibiting a social interaction deficit. Using this preclinical murine demyelination model, we discover that application of metformin, an FDA-approved drug, in this model promotes oligodendrocyte regeneration and remyelination and improves the social interaction. This beneficial effect of metformin acts through stimulating Ser436 phosphorylation in CBP, a histone acetyltransferase. In addition, we found that metformin acts through two distinct molecular pathways to enhance oligodendrocyte precursor (OPC) proliferation and differentiation, respectively. Metformin enhances OPC proliferation through early-stage autophagy inhibition, while metformin promotes OPC differentiation into mature oligodendrocytes through activating CBP Ser436 phosphorylation. In summary, we identify that metformin is a promising remyelinating agent to improve juvenile demyelination-associated social interaction deficits by promoting oligodendrocyte regeneration and remyelination.
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Affiliation(s)
- Jayasankar Kosaraju
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Matthew Seegobin
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Ayden Gouveia
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Charvi Syal
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Sailendra Nath Sarma
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Kevin Jiaqi Lu
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Julius Ilin
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Ling He
- Department of Pediatrics and Medicine, Johns Hopkins Medical School, Baltimore, MD 21287, USA
| | - Fredric E Wondisford
- Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Diane Lagace
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada; Canadian Partnership for Stroke Recovery, Ottawa, ON K1G 5Z3, Canada
| | - Yves De Repentigny
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Rashmi Kothary
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Jing Wang
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada; Canadian Partnership for Stroke Recovery, Ottawa, ON K1G 5Z3, Canada.
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48
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Ahuja CS, Mothe A, Khazaei M, Badhiwala JH, Gilbert EA, van der Kooy D, Morshead CM, Tator C, Fehlings MG. The leading edge: Emerging neuroprotective and neuroregenerative cell-based therapies for spinal cord injury. Stem Cells Transl Med 2020; 9:1509-1530. [PMID: 32691994 PMCID: PMC7695641 DOI: 10.1002/sctm.19-0135] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/01/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022] Open
Abstract
Spinal cord injuries (SCIs) are associated with tremendous physical, social, and financial costs for millions of individuals and families worldwide. Rapid delivery of specialized medical and surgical care has reduced mortality; however, long-term functional recovery remains limited. Cell-based therapies represent an exciting neuroprotective and neuroregenerative strategy for SCI. This article summarizes the most promising preclinical and clinical cell approaches to date including transplantation of mesenchymal stem cells, neural stem cells, oligodendrocyte progenitor cells, Schwann cells, and olfactory ensheathing cells, as well as strategies to activate endogenous multipotent cell pools. Throughout, we emphasize the fundamental biology of cell-based therapies, critical features in the pathophysiology of spinal cord injury, and the strengths and limitations of each approach. We also highlight salient completed and ongoing clinical trials worldwide and the bidirectional translation of their findings. We then provide an overview of key adjunct strategies such as trophic factor support to optimize graft survival and differentiation, engineered biomaterials to provide a support scaffold, electrical fields to stimulate migration, and novel approaches to degrade the glial scar. We also discuss important considerations when initiating a clinical trial for a cell therapy such as the logistics of clinical-grade cell line scale-up, cell storage and transportation, and the delivery of cells into humans. We conclude with an outlook on the future of cell-based treatments for SCI and opportunities for interdisciplinary collaboration in the field.
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Affiliation(s)
- Christopher S. Ahuja
- Division of Neurosurgery, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
- Institute of Medical ScienceUniversity of TorontoTorontoOntarioCanada
- Department of Genetics and DevelopmentKrembil Research Institute, UHNTorontoOntarioCanada
| | - Andrea Mothe
- Department of Genetics and DevelopmentKrembil Research Institute, UHNTorontoOntarioCanada
| | - Mohamad Khazaei
- Department of Genetics and DevelopmentKrembil Research Institute, UHNTorontoOntarioCanada
| | - Jetan H. Badhiwala
- Division of Neurosurgery, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
| | - Emily A. Gilbert
- Division of Anatomy, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
| | - Derek van der Kooy
- Department of Molecular GeneticsUniversity of TorontoTorontoOntarioCanada
| | - Cindi M. Morshead
- Institute of Medical ScienceUniversity of TorontoTorontoOntarioCanada
- Division of Anatomy, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
- Institute of Biomaterials and Biomedical EngineeringUniversity of TorontoTorontoOntarioCanada
| | - Charles Tator
- Division of Neurosurgery, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
- Institute of Medical ScienceUniversity of TorontoTorontoOntarioCanada
- Department of Genetics and DevelopmentKrembil Research Institute, UHNTorontoOntarioCanada
| | - Michael G. Fehlings
- Division of Neurosurgery, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
- Institute of Medical ScienceUniversity of TorontoTorontoOntarioCanada
- Department of Genetics and DevelopmentKrembil Research Institute, UHNTorontoOntarioCanada
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Fan YY, Wang YJ, Guo J, Wu MN, Zhang MS, Niu BL, Li Y, Zhao J, Yang CH, Li Y, Chen M, Jiao XY. Delayed metformin treatment improves functional recovery following traumatic brain injury via central AMPK-dependent brain tissue repair. Brain Res Bull 2020; 164:146-156. [DOI: 10.1016/j.brainresbull.2020.08.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 08/16/2020] [Accepted: 08/19/2020] [Indexed: 11/15/2022]
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50
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Affiliation(s)
- Erin M Gibson
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Michelle Monje
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. .,Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
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