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König J, Blusch A, Fatoba O, Gold R, Saft C, Ellrichmann-Wilms G. Examination of Anti-Inflammatory Effects After Propionate Supplementation in the R6/2 Mouse Model of Huntington's Disease. Int J Mol Sci 2025; 26:3318. [PMID: 40244185 PMCID: PMC11989372 DOI: 10.3390/ijms26073318] [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: 01/27/2025] [Revised: 03/23/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Huntington's disease is a progressive, untreatable neurodegenerative disorder caused by a mutation in the Huntingtin gene. Next to neurodegeneration, altered immune activation is involved in disease progression. Since central nervous system inflammation and dysfunction of immune cells are recognized as driving characteristics, immunomodulation might represent an additional therapeutic strategy. Short-chain fatty acids were known to have immunomodulatory effects in neuroinflammatory diseases, such as multiple sclerosis. In this study, R6/2 mice were treated daily with 150 mM propionate. Survival range, body weight, and motor abilities were monitored. In striatal and cortical samples, neuronal survival was analyzed by immunofluorescence staining of NeuN-positive cells and expression levels of BDNF mRNA by real-time polymerase chain reaction. As inflammatory marker TNFα mRNA and IL-6 mRNA were quantified by rtPCR, iNOS-expressing cells were counted in immunologically stained brain slides. Microglial activation was evaluated by immunofluorescent staining of IBA1-positive cells and total IBA1 protein by Western Blot, in addition, SPI1 mRNA expression was quantified by rtPCR. Except for clasping behavior, propionate treatment did neither improve the clinical course nor mediated neuronal protection in R6/2 mice. Yet there was a mild anti-inflammatory effect in the CNS, with (i) reduction in SPI1-mRNA levels, (ii) reduced iNOS positive cells in the motor cortex, and (iii) normalized TNFα-mRNA in the motor cortex of propionate-treated R6/2 mice. Thus, Short-chain fatty acids, as an environmental factor in the diet, may slightly alleviate symptoms by down-regulating inflammatory factors in the central nervous system. However, they cannot prevent clinical disease progression or neuronal loss.
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Affiliation(s)
- Jennifer König
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
- Department of Physiology and Pathophysiology, Center of Biomedical Education and Research (ZBAF), Faculty of Health, School of Medicine, Witten/Herdecke University, 58453 Witten, Germany
| | - Alina Blusch
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
- Brain Disease Biomarker Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, 221 84 Lund, Sweden
| | - Oluwaseun Fatoba
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan
| | - Ralf Gold
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Carsten Saft
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Gisa Ellrichmann-Wilms
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
- Faculty of Health, School of Medicine, Chair of Neurology II, Witten/Herdecke University, 58448 Witten, Germany
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Simmons DA, Selvaraj S, Chen T, Cao G, Camelo TS, McHugh TL, Gonzalez S, Martin RM, Simanauskaite J, Uchida N, Porteus MH, Longo FM. Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington's disease phenotypes. Mol Ther Methods Clin Dev 2025; 33:101415. [PMID: 39995448 PMCID: PMC11848452 DOI: 10.1016/j.omtm.2025.101415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 01/20/2025] [Indexed: 02/26/2025]
Abstract
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by striatal atrophy. Reduced trophic support due to decreased striatal levels of neurotrophins (NTs), mainly brain-derived neurotrophic factor (BDNF), contributes importantly to HD pathogenesis; restoring NTs has significant therapeutic potential. Human pluripotent stem cells (hPSCs) offer a scalable platform for NT delivery but have potential safety risks including teratoma formation. We engineered hPSCs to constitutively produce BDNF and contain inducible safeguards to eliminate these cells if safety concerns arise. This study examined the efficacy of intrastriatally transplanted striatal progenitor cells (STRpcs) derived from these hPSCs against HD phenotypes in R6/2 mice. Engrafted STRpcs overexpressing BDNF alleviated motor and cognitive deficits and reduced mutant huntingtin aggregates. Activating the inducible safety switch with rapamycin safely eliminated the engrafted cells. These results demonstrate that BDNF delivery via a novel hPSC-based platform incorporating safety switches could be a safe and effective HD therapeutic.
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Affiliation(s)
- Danielle A. Simmons
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sridhar Selvaraj
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tingshuo Chen
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Gloria Cao
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Talita Souto Camelo
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tyne L.M. McHugh
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Selena Gonzalez
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Renata M. Martin
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Juste Simanauskaite
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Nobuko Uchida
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Matthew H. Porteus
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Frank M. Longo
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
- Wu Tsai Neuroscience Institute, Stanford University, Stanford, CA 94305, USA
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Mi XQ, Liu BC, Qu L, Yuan Y, Li H, Xu AY, Zhang YL, Xie JX, Song N. Intranasal iron administration induces iron deposition, immunoactivation, and cell-specific vulnerability in the olfactory bulb of C57BL/6 mice. Zool Res 2025; 46:209-224. [PMID: 39846197 PMCID: PMC11891001 DOI: 10.24272/j.issn.2095-8137.2024.240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 10/14/2024] [Indexed: 01/24/2025] Open
Abstract
Iron is the most abundant transition metal in the brain and is essential for brain development and neuronal function; however, its abnormal accumulation is also implicated in various neurological disorders. The olfactory bulb (OB), an early target in neurodegenerative diseases, acts as a gateway for environmental toxins and contains diverse neuronal populations with distinct roles. This study explored the cell-specific vulnerability to iron in the OB using a mouse model of intranasal administration of ferric ammonium citrate (FAC). Olfactory function was assessed through olfactory discrimination tests, while iron levels in OB tissues, cerebrospinal fluid (CSF), and serum were quantified using inductively coupled plasma mass spectrometry (ICP-MS), immunohistochemical staining, and iron assays. Transcriptomic changes and immune responses were assessed using RNA sequencing and immune cell infiltration analysis. Results showed that intranasal FAC administration impaired olfactory function, accompanied by iron deposition in the olfactory mucosa and OB, as well as damage to olfactory sensory neurons. Notably, these effects occurred without elevations in CSF or serum iron levels. OB iron accumulation activated multiple immune cells, including microglia and astrocytes, but did not trigger ferroptosis. Spatial transcriptomic sequencing of healthy adult mouse OBs revealed significant cellular heterogeneity, with an abundance of neuroglia and neurons. Among neurons, GABAergic neurons were the most prevalent, followed by glutamatergic and dopaminergic neurons, while cholinergic and serotonergic neurons were sparsely distributed. Under iron-stressed conditions, oligodendrocytes, dopaminergic neurons, and glutamatergic neurons exhibited significant damage, while GABAergic neurons remained unaffected. These findings highlight the selective vulnerability of neuronal and glial populations to iron-induced stress, offering novel insights into the loss of specific cell types in the OB during iron dysregulation.
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Affiliation(s)
- Xiao-Qing Mi
- School of Basic Medicine, Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases, Qingdao University, Qingdao, Shandong, 266071, China
| | - Bao-Chen Liu
- School of Basic Medicine, Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases, Qingdao University, Qingdao, Shandong, 266071, China
| | - Le Qu
- School of Basic Medicine, Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases, Qingdao University, Qingdao, Shandong, 266071, China
| | - Yu Yuan
- School of Basic Medicine, Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases, Qingdao University, Qingdao, Shandong, 266071, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Hui Li
- School of Basic Medicine, Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases, Qingdao University, Qingdao, Shandong, 266071, China
| | - Ao-Yang Xu
- School of Basic Medicine, Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases, Qingdao University, Qingdao, Shandong, 266071, China
| | - Yu-Lin Zhang
- School of Basic Medicine, Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases, Qingdao University, Qingdao, Shandong, 266071, China
| | - Jun-Xia Xie
- School of Basic Medicine, Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases, Qingdao University, Qingdao, Shandong, 266071, China. E-mail:
| | - Ning Song
- School of Basic Medicine, Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases, Qingdao University, Qingdao, Shandong, 266071, China. E-mail:
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Ghanbari A, Rad F, Shahraki MH, Hosseini E, Barmak MJ, Zibara K. Human mesenchymal stem cells-derived microvesicles increase oligodendrogenesis and neurogenesis of cultured adult neural stem cells. Neurosci Lett 2024; 841:137951. [PMID: 39191299 DOI: 10.1016/j.neulet.2024.137951] [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: 04/22/2024] [Revised: 08/21/2024] [Accepted: 08/23/2024] [Indexed: 08/29/2024]
Abstract
Mesenchymal stem cells (MSCs) are involved in tissue repair and anti-inflammatory activities and have shown promising therapeutic efficiency in different animal models of neurodegenerative disorders. Microvesicles (MVs), implicated in cellular communication, are secreted from MSCs and play a key role in determining the fate of cell differentiation. Our study examines the effect of human umbilical cord MSC-derived MVs (hUC-MSC MVs) on the proliferation and differentiation potential of adult neural stem cells (NSCs). Results showed that 0.2 μg MSC derived MVs significantly increased the viability of NSCs and their proliferation, as demonstrated by an increase in the number of neurospheres and their derived cells, compared to controls. In addition, all hUC-MSC MVs concentrations (0.1, 0.2 and 0.4 µg) induced the differentiation of NSCs toward precursors (Olig2 + ) and mature oligodendrocytes (MBP+). This increase in mature oligodendrocytes was inversely proportional to the dose of MVs. Moreover, hUC-MSC MVs induced the differentiation of NSCs into neurons (β-tubulin + ), in a dose-dependent manner, but had no effect on astrocytes (GFAP+). Furthermore, treatment of NSCs with hUC-MSC MVs (0.1 and 0.2 μg) significantly increased the expression levels of the proliferation marker Ki67 gene, compared to controls. Finally, hUC-MSC MVs (0.1 μg) significantly increased the expression level of Sox10 transcripts; but not Pax6 gene, demonstrating an increased NSC ability to differentiate into oligodendrocytes. In conclusion, our study showed that hUC-MSC MVs increased NSC proliferation in vitro and induced NSC differentiation into oligodendrocytes and neurons, but not astrocytes.
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Affiliation(s)
- Amir Ghanbari
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Fariba Rad
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
| | | | - Ebrahim Hosseini
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mehrzad Jafari Barmak
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Kazem Zibara
- PRASE and Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.
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Lombardo MT, Gabrielli M, Julien-Marsollier F, Faivre V, Le Charpentier T, Bokobza C, D’Aliberti D, Pelizzi N, Halimi C, Spinelli S, Van Steenwinckel J, Verderio EAM, Gressens P, Piazza R, Verderio C. Human Umbilical Cord-Mesenchymal Stem Cells Promote Extracellular Matrix Remodeling in Microglia. Cells 2024; 13:1665. [PMID: 39404427 PMCID: PMC11475221 DOI: 10.3390/cells13191665] [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: 09/13/2024] [Revised: 10/02/2024] [Accepted: 10/05/2024] [Indexed: 10/19/2024] Open
Abstract
Human mesenchymal stem cells modulate the immune response and are good candidates for cell therapy in neuroinflammatory brain disorders affecting both adult and premature infants. Recent evidence indicates that through their secretome, mesenchymal stem cells direct microglia, brain-resident immune cells, toward pro-regenerative functions, but the mechanisms underlying microglial phenotypic transition are still under investigation. Using an in vitro coculture approach combined with transcriptomic analysis, we identified the extracellular matrix as the most relevant pathway altered by the human mesenchymal stem cell secretome in the response of microglia to inflammatory cytokines. We confirmed extracellular matrix remodeling in microglia exposed to the mesenchymal stem cell secretome via immunofluorescence analysis of the matrix component fibronectin and the extracellular crosslinking enzyme transglutaminase-2. Furthermore, an analysis of hallmark microglial functions revealed that changes in the extracellular matrix enhance ruffle formation by microglia and cell motility. These findings point to extracellular matrix changes, associated plasma membrane remodeling, and enhanced microglial migration as novel mechanisms by which mesenchymal stem cells contribute to the pro-regenerative microglial transition.
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Affiliation(s)
- Marta Tiffany Lombardo
- Institute of Neuroscience, National Research Council of Italy, Via Raoul Follereau 3, 20854 Vedano al Lambro, Italy; (M.T.L.); (M.G.); (C.H.)
- School of Medicine and Surgery, University of Milano-Bicocca, Piazza dell’ Ateneo Nuovo 1, 20126 Milan, Italy
| | - Martina Gabrielli
- Institute of Neuroscience, National Research Council of Italy, Via Raoul Follereau 3, 20854 Vedano al Lambro, Italy; (M.T.L.); (M.G.); (C.H.)
| | - Florence Julien-Marsollier
- Inserm, NeuroDiderot, Université Paris Cité, 75019 Paris, France; (F.J.-M.); (V.F.); (T.L.C.); (C.B.); (J.V.S.); (P.G.)
| | - Valérie Faivre
- Inserm, NeuroDiderot, Université Paris Cité, 75019 Paris, France; (F.J.-M.); (V.F.); (T.L.C.); (C.B.); (J.V.S.); (P.G.)
| | - Tifenn Le Charpentier
- Inserm, NeuroDiderot, Université Paris Cité, 75019 Paris, France; (F.J.-M.); (V.F.); (T.L.C.); (C.B.); (J.V.S.); (P.G.)
| | - Cindy Bokobza
- Inserm, NeuroDiderot, Université Paris Cité, 75019 Paris, France; (F.J.-M.); (V.F.); (T.L.C.); (C.B.); (J.V.S.); (P.G.)
| | - Deborah D’Aliberti
- Department of Medicine and Surgery, University of Milan-Bicocca, 20900 Monza, Italy; (D.D.); (S.S.); (R.P.)
| | - Nicola Pelizzi
- CARE Franchise, Chiesi Farmaceutici S.p.A., 43122 Parma, Italy;
| | - Camilla Halimi
- Institute of Neuroscience, National Research Council of Italy, Via Raoul Follereau 3, 20854 Vedano al Lambro, Italy; (M.T.L.); (M.G.); (C.H.)
| | - Silvia Spinelli
- Department of Medicine and Surgery, University of Milan-Bicocca, 20900 Monza, Italy; (D.D.); (S.S.); (R.P.)
| | - Juliette Van Steenwinckel
- Inserm, NeuroDiderot, Université Paris Cité, 75019 Paris, France; (F.J.-M.); (V.F.); (T.L.C.); (C.B.); (J.V.S.); (P.G.)
| | - Elisabetta A. M. Verderio
- School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK;
- Department of Biological Sciences (BIGEA), University of Bologna, Via Francesco Selmi 3, 40126 Bologna, Italy
| | - Pierre Gressens
- Inserm, NeuroDiderot, Université Paris Cité, 75019 Paris, France; (F.J.-M.); (V.F.); (T.L.C.); (C.B.); (J.V.S.); (P.G.)
| | - Rocco Piazza
- Department of Medicine and Surgery, University of Milan-Bicocca, 20900 Monza, Italy; (D.D.); (S.S.); (R.P.)
| | - Claudia Verderio
- Institute of Neuroscience, National Research Council of Italy, Via Raoul Follereau 3, 20854 Vedano al Lambro, Italy; (M.T.L.); (M.G.); (C.H.)
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Anvarinia Y, Del Mar NA, Awad AM, Hossain S, Seetharaman AT, Ravindran S, Roth S, Gangaraju R. MicroRNA-based engineered mesenchymal stem cell extracellular vesicles to treat visual deficits after blast-induced trauma. Exp Eye Res 2024; 247:110031. [PMID: 39128668 PMCID: PMC11392619 DOI: 10.1016/j.exer.2024.110031] [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: 04/29/2024] [Revised: 07/19/2024] [Accepted: 08/07/2024] [Indexed: 08/13/2024]
Abstract
Our previous studies have shown the benefit of intravitreal injection of a mesenchymal stem cell (MSC)- derived secretome to treat visual deficits in a mild traumatic brain injury (mTBI) mouse model. In this study, we have addressed whether MSC-derived extracellular vesicles (EV) overexpressing miR424, which particularly targets neuroinflammation, show similar benefits in the mTBI model. Adult C57BL/6 mice were subjected to a 50-psi air pulse on the left side, overlying the forebrain, resulting in mTBI. Sham-blast mice were controls. Within an hour of blast injury, 3 μl (∼7.5 × 108 particles) of miR424-EVs, native-EVs, or saline was delivered intravitreally. One month later, retinal morphology was observed through optical coherence tomography (OCT); visual function was assessed using optokinetic nystagmus (OKN) and electroretinogram (ERG), followed by immunohistological analysis. A separate study in adult mice tested the dose-response of EVs for safety. Blast injury mice with saline showed decreased visual acuity compared with the sham group (0.30 ± 0.03 vs. 0.39 ± 0.01 c/d, p < 0.02), improved with miR424-EVs (0.39 ± 0.02 c/d, p < 0.01) but not native-EVs (0.33 ± 0.04 c/d, p > 0.05). Contrast sensitivity thresholds of blast mice receiving saline increased compared with the sham group (85.3 ± 5.9 vs. 19.9 ± 4.8, %, p < 0.001), rescued by miR424-EVs (23.6 ± 7.3 %, p < 0.001) and native-EVs (45.6 ± 10.7 %, p < 0.01). Blast injury decreased "b" wave amplitude compared to sham mice (94.6 ± 24.0 vs. 279.2 ± 25.3 μV, p < 0.001), improved with miR424-EVs (173.0 ± 27.2 μV, p < 0.03) and native-EVs (230.2 ± 37.2 μV, p < 0.01) with a similar decrease in a-wave amplitude in blast mice improved with both miR424-EVs and native-EVs. Immunohistology showed increased GFAP and IBA1 in blast mice with saline compared with sham (GFAP: 11.9 ± 1.49 vs. 9.1 ± 0.8, mean intensity/100,000 μm2 area, p < 0.03; IBA1: 36.08 ± 4.3 vs. 24.0 ± 1.54, mean intensity/100,000 μm2 area, p < 0.01), with no changes with native-EVs (GFAP: 12.6 ± 0.79, p > 0.05; IBA1: 32.8 ± 2.9, p > 0.05), and miR424-EV (GFAP: 13.14 ± 0.76, p > 0.05; IBA1: 31.4 ± 2.7, p > 0.05). Both native-EVs and miR424-EVs exhibited vitreous aggregation, as evidenced by particulates in the vitreous by OCT, and increased vascular structures, as evidenced by αSMA and CD31 immunostainings. The number of capillary lumens in the ganglion cell layer increased with increased particles in the eye, with native EVs showing the worst effects. In conclusion, our study highlights the promise of EV-based therapies for treating visual dysfunction caused by mTBI, with miR424-EVs showing particularly strong neuroprotective benefits. Both miR424-EVs and native-EVs provided similar protection, but issues with EV aggregation and astrogliosis or microglial/macrophage activation at the current dosage call for improved delivery methods and dosage adjustments. Future research should investigate the mechanisms behind EVs' effects and optimize miR424 delivery strategies to enhance therapeutic outcomes and reduce complications.
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Affiliation(s)
- Yasaman Anvarinia
- Department of Ophthalmology, University of Tennessee Health Science Center, 930 Madison Ave, Suite 769, Memphis, TN, 38163, USA.
| | - Nobel A Del Mar
- Department of Ophthalmology, University of Tennessee Health Science Center, 930 Madison Ave, Suite 769, Memphis, TN, 38163, USA.
| | - Ahmed M Awad
- Department of Ophthalmology, University of Tennessee Health Science Center, 930 Madison Ave, Suite 769, Memphis, TN, 38163, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, 7731168, Mansoura, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt.
| | - Shahadat Hossain
- Department of Ophthalmology, University of Tennessee Health Science Center, 930 Madison Ave, Suite 769, Memphis, TN, 38163, USA.
| | - Amritha Tm Seetharaman
- Department of Ophthalmology, University of Tennessee Health Science Center, 930 Madison Ave, Suite 769, Memphis, TN, 38163, USA.
| | - Sriram Ravindran
- Department of Oral Biology, College of Dentistry, University of Illinois-Chicago, USA.
| | - Steven Roth
- Department of Anesthesiology, College of Medicine, University of Illinois-Chicago, USA.
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, Anatomy & Neurobiology, Neuroscience Institute, University of Tennessee Health Science Center, 930 Madison Ave, Suite 768, Memphis, TN, 38163, USA.
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7
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Rahimi Darehbagh R, Seyedoshohadaei SA, Ramezani R, Rezaei N. Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives. Eur J Med Res 2024; 29:386. [PMID: 39054501 PMCID: PMC11270957 DOI: 10.1186/s40001-024-01987-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 07/17/2024] [Indexed: 07/27/2024] Open
Abstract
Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise.
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Affiliation(s)
- Ramyar Rahimi Darehbagh
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Nanoclub Elites Association, Tehran, Iran
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Universal Scientific Education and Research Network (USERN), Sanandaj, Kurdistan, Iran
| | | | - Rojin Ramezani
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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8
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Zhao D, Hu M, Liu S. Glial cells in the mammalian olfactory bulb. Front Cell Neurosci 2024; 18:1426094. [PMID: 39081666 PMCID: PMC11286597 DOI: 10.3389/fncel.2024.1426094] [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: 04/30/2024] [Accepted: 06/24/2024] [Indexed: 08/02/2024] Open
Abstract
The mammalian olfactory bulb (OB), an essential part of the olfactory system, plays a critical role in odor detection and neural processing. Historically, research has predominantly focused on the neuronal components of the OB, often overlooking the vital contributions of glial cells. Recent advancements, however, underscore the significant roles that glial cells play within this intricate neural structure. This review discus the diverse functions and dynamics of glial cells in the mammalian OB, mainly focused on astrocytes, microglia, oligodendrocytes, olfactory ensheathing cells, and radial glia cells. Each type of glial contributes uniquely to the OB's functionality, influencing everything from synaptic modulation and neuronal survival to immune defense and axonal guidance. The review features their roles in maintaining neural health, their involvement in neurodegenerative diseases, and their potential in therapeutic applications for neuroregeneration. By providing a comprehensive overview of glial cell types, their mechanisms, and interactions within the OB, this article aims to enhance our understanding of the olfactory system's complexity and the pivotal roles glial cells play in both health and disease.
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Affiliation(s)
| | | | - Shaolin Liu
- Isakson Center for Neurological Disease Research, Department of Physiology and Pharmacology, Department of Biomedical Sciences, University of Georgia College of Veterinary Medicine, Athens, GA, United States
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Yu-Taeger L, El-Ayoubi A, Qi P, Danielyan L, Nguyen HHP. Intravenous MSC-Treatment Improves Impaired Brain Functions in the R6/2 Mouse Model of Huntington's Disease via Recovered Hepatic Pathological Changes. Cells 2024; 13:469. [PMID: 38534313 PMCID: PMC10969189 DOI: 10.3390/cells13060469] [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: 01/31/2024] [Revised: 03/02/2024] [Accepted: 03/06/2024] [Indexed: 03/28/2024] Open
Abstract
Huntington's disease (HD), a congenital neurodegenerative disorder, extends its pathological damages beyond the nervous system. The systematic manifestation of HD has been extensively described in numerous studies, including dysfunction in peripheral organs and peripheral inflammation. Gut dysbiosis and the gut-liver-brain axis have garnered greater emphasis in neurodegenerative research, and increased plasma levels of pro-inflammatory cytokines have been identified in HD patients and various in vivo models, correlating with disease progression. In the present study, we investigated hepatic pathological markers in the liver of R6/2 mice which convey exon 1 of the human mutant huntingtin gene. Furthermore, we evaluated the impact of intravenously administered Mesenchymal Stromal Cells (MSCs) on the liver enzymes, changes in hepatic inflammatory markers, as well as brain pathology and behavioral deficits in R6/2 mice. Our results revealed altered enzyme expression and increased levels of inflammatory mediators in the liver of R6/2 mice, which were significantly attenuated in the MSC-treated R6/2 mice. Remarkably, neuronal pathology and altered motor activities in the MSC-treated R6/2 mice were significantly ameliorated, despite the absence of MSCs in the postmortem brain. Our data highlight the importance of hepatic pathological changes in HD, providing a potential therapeutic approach. Moreover, the data open new perspectives for the search in blood biomarkers correlating with liver pathology in HD.
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Affiliation(s)
- Libo Yu-Taeger
- Department of Human Genetics, Ruhr University of Bochum, D-44801 Bochum, Germany
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
| | - Ali El-Ayoubi
- Department of Human Genetics, Ruhr University of Bochum, D-44801 Bochum, Germany
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
| | - Pengfei Qi
- Department of Human Genetics, Ruhr University of Bochum, D-44801 Bochum, Germany
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, D-72076 Tuebingen, Germany
| | - Lusine Danielyan
- Department of Clinical Pharmacology, University Hospital of Tuebingen, D-72076 Tuebingen, Germany
- Departments of Biochemistry and Clinical Pharmacology, and Neuroscience Laboratory, Yerevan State Medical University, Yerevan 0025, Armenia
| | - Hoa Huu Phuc Nguyen
- Department of Human Genetics, Ruhr University of Bochum, D-44801 Bochum, Germany
- Department of Medical Chemistry, Yerevan State Medical University, Yerevan 0025, Armenia
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10
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El‐Ayoubi A, Arakelyan A, Klawitter M, Merk L, Hakobyan S, Gonzalez‐Menendez I, Quintanilla Fend L, Holm PS, Mikulits W, Schwab M, Danielyan L, Naumann U. Development of an optimized, non-stem cell line for intranasal delivery of therapeutic cargo to the central nervous system. Mol Oncol 2024; 18:528-546. [PMID: 38115217 PMCID: PMC10920084 DOI: 10.1002/1878-0261.13569] [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: 05/30/2023] [Revised: 10/23/2023] [Accepted: 12/13/2023] [Indexed: 12/21/2023] Open
Abstract
Neural stem cells (NSCs) are considered to be valuable candidates for delivering a variety of anti-cancer agents, including oncolytic viruses, to brain tumors. However, owing to the previously reported tumorigenic potential of NSC cell lines after intranasal administration (INA), here we identified the human hepatic stellate cell line LX-2 as a cell type capable of longer resistance to replication of oncolytic adenoviruses (OAVs) as a therapeutic cargo, and that is non-tumorigenic after INA. Our data show that LX-2 cells can longer withstand the OAV XVir-N-31 replication and oncolysis than NSCs. By selecting the highly migratory cell population out of LX-2, an offspring cell line with a higher and more stable capability to migrate was generated. Additionally, as a safety backup, we applied genomic herpes simplex virus thymidine kinase (HSV-TK) integration into LX-2, leading to high vulnerability to ganciclovir (GCV). Histopathological analyses confirmed the absence of neoplasia in the respiratory tracts and brains of immuno-compromised mice 3 months after INA of LX-2 cells. Our data suggest that LX-2 is a novel, robust, and safe cell line for delivering anti-cancer and other therapeutic agents to the brain.
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Affiliation(s)
- Ali El‐Ayoubi
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center NeurologyUniversity Hospital of TübingenGermany
| | - Arsen Arakelyan
- Research Group of BioinformaticsInstitute of Molecular Biology NAS RAYerevanArmenia
| | - Moritz Klawitter
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center NeurologyUniversity Hospital of TübingenGermany
| | - Luisa Merk
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center NeurologyUniversity Hospital of TübingenGermany
| | - Siras Hakobyan
- Research Group of BioinformaticsInstitute of Molecular Biology NAS RAYerevanArmenia
- Armenian Institute of BioinformaticsYerevanArmenia
| | - Irene Gonzalez‐Menendez
- Institute for Pathology, Department of General and Molecular PathologyUniversity Hospital TübingenGermany
- Cluster of Excellence iFIT (EXC 2180) "Image‐Guided and Functionally Instructed Tumor Therapies"Eberhard Karls University of TübingenGermany
| | - Leticia Quintanilla Fend
- Institute for Pathology, Department of General and Molecular PathologyUniversity Hospital TübingenGermany
- Cluster of Excellence iFIT (EXC 2180) "Image‐Guided and Functionally Instructed Tumor Therapies"Eberhard Karls University of TübingenGermany
| | - Per Sonne Holm
- Department of Urology, Klinikum rechts der IsarTechnical University of MunichGermany
- Department of Oral and Maxillofacial SurgeryMedical University InnsbruckAustria
- XVir Therapeutics GmbHMunichGermany
| | - Wolfgang Mikulits
- Center for Cancer Research, Comprehensive Cancer CenterMedical University of ViennaAustria
| | - Matthias Schwab
- Cluster of Excellence iFIT (EXC 2180) "Image‐Guided and Functionally Instructed Tumor Therapies"Eberhard Karls University of TübingenGermany
- Dr. Margarete Fischer‐Bosch Institute of Clinical PharmacologyStuttgartGermany
- Department of Pharmacy and BiochemistryUniversity of TübingenGermany
- Department of Clinical PharmacologyUniversity Hospital TübingenGermany
- Neuroscience Laboratory and Departments of Biochemistry and Clinical PharmacologyYerevan State Medical UniversityArmenia
| | - Lusine Danielyan
- Department of Pharmacy and BiochemistryUniversity of TübingenGermany
- Department of Clinical PharmacologyUniversity Hospital TübingenGermany
- Neuroscience Laboratory and Departments of Biochemistry and Clinical PharmacologyYerevan State Medical UniversityArmenia
| | - Ulrike Naumann
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center NeurologyUniversity Hospital of TübingenGermany
- Gene and RNA Therapy Center (GRTC)Faculty of Medicine University TübingenGermany
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11
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Xu Y, Gao W, Sun Y, Wu M. New insight on microglia activation in neurodegenerative diseases and therapeutics. Front Neurosci 2023; 17:1308345. [PMID: 38188026 PMCID: PMC10770846 DOI: 10.3389/fnins.2023.1308345] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 12/06/2023] [Indexed: 01/09/2024] Open
Abstract
Microglia are immune cells within the central nervous system (CNS) closely linked to brain health and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In response to changes in the surrounding environment, microglia activate and change their state and function. Several factors, example for circadian rhythm disruption and the development of neurodegenerative diseases, influence microglia activation. In this review, we explore microglia's function and the associated neural mechanisms. We elucidate that circadian rhythms are essential factors influencing microglia activation and function. Circadian rhythm disruption affects microglia activation and, consequently, neurodegenerative diseases. In addition, we found that abnormal microglia activation is a common feature of neurodegenerative diseases and an essential factor of disease development. Here we highlight the importance of microglia activation in neurodegenerative diseases. Targeting microglia for neurodegenerative disease treatment is a promising direction. We introduce the progress of methods targeting microglia for the treatment of neurodegenerative diseases and summarize the progress of drugs developed with microglia as targets, hoping to provide new ideas for treating neurodegenerative diseases.
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Affiliation(s)
- Yucong Xu
- Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Wei Gao
- Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yingnan Sun
- Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Minghua Wu
- Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
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12
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Alizadeh R, Asghari A, Taghizadeh-Hesary F, Moradi S, Farhadi M, Mehdizadeh M, Simorgh S, Nourazarian A, Shademan B, Susanabadi A, Kamrava K. Intranasal delivery of stem cells labeled by nanoparticles in neurodegenerative disorders: Challenges and opportunities. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023; 15:e1915. [PMID: 37414546 DOI: 10.1002/wnan.1915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 05/05/2023] [Accepted: 06/11/2023] [Indexed: 07/08/2023]
Abstract
Neurodegenerative disorders occur through progressive loss of function or structure of neurons, with loss of sensation and cognition values. The lack of successful therapeutic approaches to solve neurologic disorders causes physical disability and paralysis and has a significant socioeconomic impact on patients. In recent years, nanocarriers and stem cells have attracted tremendous attention as a reliable approach to treating neurodegenerative disorders. In this regard, nanoparticle-based labeling combined with imaging technologies has enabled researchers to survey transplanted stem cells and fully understand their fate by monitoring their survival, migration, and differentiation. For the practical implementation of stem cell therapies in the clinical setting, it is necessary to accurately label and follow stem cells after administration. Several approaches to labeling and tracking stem cells using nanotechnology have been proposed as potential treatment strategies for neurological diseases. Considering the limitations of intravenous or direct stem cell administration, intranasal delivery of nanoparticle-labeled stem cells in neurological disorders is a new method of delivering stem cells to the central nervous system (CNS). This review describes the challenges and limitations of stem cell-based nanotechnology methods for labeling/tracking, intranasal delivery of cells, and cell fate regulation as theragnostic labeling. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.
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Affiliation(s)
- Rafieh Alizadeh
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alimohamad Asghari
- Skull Base Research Center, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farzad Taghizadeh-Hesary
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Salah Moradi
- Department of Life Science Engineering, Faculty of New Science and Technology, University of Tehran, Tehran, Iran
| | - Mohammad Farhadi
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Mehdizadeh
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Simorgh
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Nourazarian
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - Behrouz Shademan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Susanabadi
- Department of Anesthesia and Pain Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Kamran Kamrava
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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13
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El-Ayoubi A, Klawitter M, Rüttinger J, Wellhäusser G, Holm PS, Danielyan L, Naumann U. Intranasal Delivery of Oncolytic Adenovirus XVir-N-31 via Optimized Shuttle Cells Significantly Extends Survival of Glioblastoma-Bearing Mice. Cancers (Basel) 2023; 15:4912. [PMID: 37894279 PMCID: PMC10605419 DOI: 10.3390/cancers15204912] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/05/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
A glioblastoma (GBM) is an aggressive and lethal primary brain tumor with restricted treatment options and a dismal prognosis. Oncolytic virotherapy (OVT) has developed as a promising approach for GBM treatment. However, reaching invasive GBM cells may be hindered by tumor-surrounding, non-neoplastic cells when the oncolytic virus (OV) is applied intratumorally. Using two xenograft GBM mouse models and immunofluorescence analyses, we investigated the intranasal delivery of the oncolytic adenovirus (OAV) XVir-N-31 via virus-loaded, optimized shuttle cells. Intranasal administration (INA) was selected due to its non-invasive nature and the potential to bypass the blood-brain barrier (BBB). Our findings demonstrate that the INA of XVir-N-31-loaded shuttle cells successfully delivered OAVs to the core tumor and invasive GBM cells, significantly prolonged the survival of the GBM-bearing mice, induced immunogenic cell death and finally reduced the tumor burden, all this highlighting the therapeutic potential of this innovative approach. Overall, this study provides compelling evidence for the effectiveness of the INA of XVir-N-31 via shuttle cells as a promising therapeutic strategy for GBM. The non-invasive nature of the INA of OV-loaded shuttle cells holds great promise for future clinical translation. However, further research is required to assess the efficacy of this approach to ultimately progress in human clinical trials.
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Affiliation(s)
- Ali El-Ayoubi
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany; (A.E.-A.); (M.K.); (J.R.); (G.W.)
| | - Moritz Klawitter
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany; (A.E.-A.); (M.K.); (J.R.); (G.W.)
| | - Jakob Rüttinger
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany; (A.E.-A.); (M.K.); (J.R.); (G.W.)
| | - Giulia Wellhäusser
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany; (A.E.-A.); (M.K.); (J.R.); (G.W.)
| | - Per Sonne Holm
- Department of Urology, Klinikum Rechts der Isar, Technical University of Munich, D-81675 Munich, Germany;
- Department of Oral and Maxillofacial Surgery, Medical University Innsbruck, A-6020 Innsbruck, Austria
- XVir Therapeutics GmbH, D-80331 Munich, Germany
| | - Lusine Danielyan
- Department of Clinical Pharmacology, University Hospital Tübingen, D-72076 Tübingen, Germany;
- Neuroscience Laboratory and Departments of Biochemistry and Clinical Pharmacology, Yerevan State Medical University, Yerevan 0025, Armenia
| | - Ulrike Naumann
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany; (A.E.-A.); (M.K.); (J.R.); (G.W.)
- Gene and RNA Therapy Center (GRTC), Faculty of Medicine, University of Tübingen, D-72076 Tübingen, Germany
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14
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Du L, Chen L, Liu F, Wang W, Huang H. Nose-to-brain drug delivery for the treatment of CNS disease: New development and strategies. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 171:255-297. [PMID: 37783558 DOI: 10.1016/bs.irn.2023.05.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
Abstract
Delivering drugs to the brain has always been a challenging task due to the restrictive properties of the blood-brain barrier (BBB). Intranasal delivery is therefore emerging as an efficient method of administration, making it easy to self-administration and thus provides a non-invasive and painless alternative to oral and parenteral administration for delivering therapeutics to the central nervous system (CNS). Recently, drug formulations have been developed to further enhance this nose-to-brain transport, primarily using nanoparticles (NPs). Therefore, the purposes of this review are to highlight and describe the anatomical basis of nasal-brain pathway and provide an overview of drug formulations and current drugs for intranasal administration in CNS disease.
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Affiliation(s)
- Li Du
- Biotherapeutic Research Center, Beijing Tsinghua Changgung Hospital, Beijing, P.R. China
| | - Lin Chen
- Department of Neurosurgery, Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine, Beijing, P.R. China
| | - Fangfang Liu
- Department of Neurology, Jilin City Central Hospital, Jilin, China
| | - Wenya Wang
- Biotherapeutic Research Center, Beijing Tsinghua Changgung Hospital, Beijing, P.R. China,.
| | - Hongyun Huang
- Institute of Neurorestoratology, Third Medical Center of General Hospital of PLA, Beijing, P.R. China; Beijing Hongtianji Neuroscience Academy, Beijing, P.R. China.
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15
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Elzayat EM, Shahien SA, El-Sherif AA, Hosney M. Therapeutic potential of stem cells and acitretin on inflammatory signaling pathway-associated genes regulated by miRNAs 146a and 155 in AD-like rats. Sci Rep 2023; 13:9613. [PMID: 37311848 DOI: 10.1038/s41598-023-36772-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 06/09/2023] [Indexed: 06/15/2023] Open
Abstract
Alzheimer's disease (AD) is one of the most common causes of dementia. Several drugs are used to improve the symptoms, but do not stop AD progression. There are more promising treatments that may have a significant role in AD diagnosis and treatment such as miRNAs and stem cells. The present study aims to develop a new approach for AD treatment by mesenchymal stem cells (MSCs) and/or acitretin with special reference to inflammatory signaling pathway as NF-kB and its regulator miRNAs in AD-like rat model. Fourty-five male albino rats were allotted for the present study. The experimental periods were divided into induction, withdrawal, and therapeutic phases. Expression levels of miR-146a, miR-155, necrotic, growth and inflammatory genes were assessed using RT-qPCR. Histopathological examination of brain tissues was performed in different rat groups. The normal physiological, molecular, and histopathological levels were restored after treatment with MSCs and/or acitretin. The present study demonstrates that the miR-146a and miR-155 might be used as promising biomarkers for AD. MSCs and/or acitretin proved their therapeutic potential in restoring the expression levels of targeted miRNAs and their related genes concerning NF-kB signaling pathway.
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Affiliation(s)
- Emad M Elzayat
- Zoology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Sherif A Shahien
- Biotechnology/Bimolecular Chemistry Program, Faculty of Science, Helwan University, Cairo, Egypt
| | - Ahmed A El-Sherif
- Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Mohamed Hosney
- Zoology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt.
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16
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Usman Khan M, Cai X, Shen Z, Mekonnen T, Kourmatzis A, Cheng S, Gholizadeh H. Challenges in the Development and Application of Organ-on-Chips for Intranasal Drug Delivery Studies. Pharmaceutics 2023; 15:pharmaceutics15051557. [PMID: 37242799 DOI: 10.3390/pharmaceutics15051557] [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: 04/10/2023] [Revised: 05/12/2023] [Accepted: 05/14/2023] [Indexed: 05/28/2023] Open
Abstract
With the growing demand for the development of intranasal (IN) products, such as nasal vaccines, which has been especially highlighted during the COVID-19 pandemic, the lack of novel technologies to accurately test the safety and effectiveness of IN products in vitro so that they can be delivered promptly to the market is critically acknowledged. There have been attempts to manufacture anatomically relevant 3D replicas of the human nasal cavity for in vitro IN drug tests, and a couple of organ-on-chip (OoC) models, which mimic some key features of the nasal mucosa, have been proposed. However, these models are still in their infancy, and have not completely recapitulated the critical characteristics of the human nasal mucosa, including its biological interactions with other organs, to provide a reliable platform for preclinical IN drug tests. While the promising potential of OoCs for drug testing and development is being extensively investigated in recent research, the applicability of this technology for IN drug tests has barely been explored. This review aims to highlight the importance of using OoC models for in vitro IN drug tests and their potential applications in IN drug development by covering the background information on the wide usage of IN drugs and their common side effects where some classical examples of each area are pointed out. Specifically, this review focuses on the major challenges of developing advanced OoC technology and discusses the need to mimic the physiological and anatomical features of the nasal cavity and nasal mucosa, the performance of relevant drug safety assays, as well as the fabrication and operational aspects, with the ultimate goal to highlight the much-needed consensus, to converge the effort of the research community in this area of work.
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Affiliation(s)
| | - Xinyu Cai
- School of Engineering, Macquarie University, Sydney, NSW 2113, Australia
| | - Zhiwei Shen
- School of Engineering, Macquarie University, Sydney, NSW 2113, Australia
| | - Taye Mekonnen
- School of Aerospace, Mechanical and Mechatronic Engineering, The University of Sydney, Sydney, NSW 2006, Australia
| | - Agisilaos Kourmatzis
- School of Aerospace, Mechanical and Mechatronic Engineering, The University of Sydney, Sydney, NSW 2006, Australia
| | - Shaokoon Cheng
- School of Engineering, Macquarie University, Sydney, NSW 2113, Australia
| | - Hanieh Gholizadeh
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
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17
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Choi BY, Hong DK, Kang BS, Lee SH, Choi S, Kim HJ, Lee SM, Suh SW. Engineered Mesenchymal Stem Cells Over-Expressing BDNF Protect the Brain from Traumatic Brain Injury-Induced Neuronal Death, Neurological Deficits, and Cognitive Impairments. Pharmaceuticals (Basel) 2023; 16:ph16030436. [PMID: 36986535 PMCID: PMC10054459 DOI: 10.3390/ph16030436] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Traumatic brain injury (TBI) causes transitory or permanent neurological and cognitive impairments, which can intensify over time due to secondary neuronal death. However, no therapy currently exists that can effectively treat brain injury following TBI. Here, we evaluate the therapeutic potential of irradiated engineered human mesenchymal stem cells over-expressing brain-derived neurotrophic factor (BDNF), which we denote by BDNF-eMSCs, in protecting the brain against neuronal death, neurological deficits, and cognitive impairment in TBI rats. BDNF-eMSCs were administered directly into the left lateral ventricle of the brain in rats that received TBI damage. A single administration of BDNF-eMSCs reduced TBI-induced neuronal death and glial activation in the hippocampus, while repeated administration of BDNF-eMSCs reduced not only glial activation and delayed neuronal loss but also enhanced hippocampal neurogenesis in TBI rats. In addition, BDNF-eMSCs reduced the lesion area in the damaged brain of the rats. Behaviorally, BDNF-eMSC treatment improved the neurological and cognitive functions of the TBI rats. The results presented in this study demonstrate that BDNF-eMSCs can attenuate TBI-induced brain damage through the suppression of neuronal death and increased neurogenesis, thus enhancing functional recovery after TBI, indicating the significant therapeutic potential of BDNF-eMSCs in the treatment of TBI.
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Affiliation(s)
- Bo Young Choi
- Department of Physical Education, Hallym University, Chuncheon 24252, Republic of Korea
- Institute of Sports Science, Hallym University, Chuncheon 24252, Republic of Korea
| | - Dae Ki Hong
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Beom Seok Kang
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
| | - Si Hyun Lee
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
| | - Seunghyuk Choi
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
| | - Hyo-Jin Kim
- SL BiGen, Inc., SL BIGEN Research Hall, 85, Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Soon Min Lee
- SL BiGen, Inc., SL BIGEN Research Hall, 85, Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
- Correspondence: (S.M.L.); (S.W.S.)
| | - Sang Won Suh
- Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
- Correspondence: (S.M.L.); (S.W.S.)
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18
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Turano E, Scambi I, Virla F, Bonetti B, Mariotti R. Extracellular Vesicles from Mesenchymal Stem Cells: Towards Novel Therapeutic Strategies for Neurodegenerative Diseases. Int J Mol Sci 2023; 24:ijms24032917. [PMID: 36769247 PMCID: PMC9917806 DOI: 10.3390/ijms24032917] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/26/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Neurodegenerative diseases are fatal disorders of the central nervous system (CNS) which currently lack effective treatments. The application of mesenchymal stem cells (MSCs) represents a new promising approach for treating these incurable disorders. Growing evidence suggest that the therapeutic effects of MSCs are due to the secretion of neurotrophic molecules through extracellular vesicles. The extracellular vesicles produced by MSCs (MSC-EVs) have valuable innate properties deriving from parental cells and could be exploited as cell-free treatments for many neurological diseases. In particular, thanks to their small size, they are able to overcome biological barriers and reach lesion sites inside the CNS. They have a considerable pharmacokinetic and safety profile, avoiding the critical issues related to the fate of cells following transplantation. This review discusses the therapeutic potential of MSC-EVs in the treatment of neurodegenerative diseases, focusing on the strategies to further enhance their beneficial effects such as tracking methods, bioengineering applications, with particular attention to intranasal delivery as a feasible strategy to deliver MSC-EVs directly to the CNS in an effective and minimally invasive way. Current progresses and limiting issues to the extent of the use of MSC-EVs treatment for human neurodegenerative diseases will be also revised.
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Affiliation(s)
- Ermanna Turano
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
| | - Ilaria Scambi
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
| | - Federica Virla
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
| | - Bruno Bonetti
- Neurology Unit, Azienda Ospedaliera Universitaria Integrata Verona, 37124 Verona, Italy
| | - Raffaella Mariotti
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
- Correspondence: ; Tel.: +39-045-802-7164
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Zamorano M, Alexander JF, Catania D, Dharmaraj S, Kavelaars A, Heijnen CJ. Nasal administration of mesenchymal stem cells prevents accelerated age-related tauopathy after chemotherapy in mice. Immun Ageing 2023; 20:5. [PMID: 36698170 PMCID: PMC9874182 DOI: 10.1186/s12979-023-00328-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 01/12/2023] [Indexed: 01/26/2023]
Abstract
BACKGROUND There is increasing concern that cancer and cancer treatment accelerate aging and the associated cognitive decline. We showed recently that treatment of 9-month-old male mice with cisplatin causes cognitive deficits that are associated with formation of tau deposits in the hippocampus. Here we explored the capacity of mesenchymal stem cells (MSC) given via the nose to prevent age-related brain tau deposits. Moreover, we more closely examined the cellular distribution of this hallmark of accelerated brain aging in response to treatment of 9-month-old female and male mice with cisplatin. RESULTS We show that cisplatin induces tau deposits in the entorhinal cortex and hippocampus in both sexes. The tau deposits colocalize with syndecan-2. Astrocytes surrounding tau deposits have increased glial fibrillary acidic protein glial fibrillary acidic protein (GFAP) expression. Most of the cisplatin-induced tau deposits were located in microtubule associated protein-2 (MAP-2)+ neurons that were surrounded by aquaporin 4+ (AQP4)+ neuron-facing membrane domains of astrocytes. In addition, some tau deposits were detected in the perinuclear region of GFAP+ astrocytes and in CD31+ endothelial cells. There were no morphological signs of activation of ionized calcium binding adaptor molecule-1+ (Iba-1)+ microglia and no increases in brain cytokine production. Nasal administration of MSC at 48 and 96 hours after cisplatin prevented formation of tau deposits and normalized syndecan-2 and GFAP expression. Behaviorally, cisplatin-induced tau cluster formation was associated with reduced executive functioning and working/spatial memory and nasal administration of MSC at 48 and 96 hours after cisplatin prevented these cognitive deficits. Notably, delayed MSC administration (1 month after cisplatin) also prevented tau cluster formation and cognitive deficits, in both sexes. CONCLUSION In summary, nasal administration of MSC to older mice at 2 days or 1 month after completion of cisplatin treatment prevents the accelerated development of tau deposits in entorhinal cortex and hippocampus and the associated cognitive deficits. Since MSC are already in clinical use for many other clinical indications, developing nasal MSC administration for treatment of accelerated brain aging and cognitive deficits in cancer survivors should be feasible and would greatly improve their quality of life.
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Affiliation(s)
- Miriam Zamorano
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA ,grid.267308.80000 0000 9206 2401Department of Pediatric Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX USA
| | - Jenolyn F. Alexander
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA ,grid.410718.b0000 0001 0262 7331Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr, 55 Essen, Germany
| | - Desiree Catania
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA
| | - Shruti Dharmaraj
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA
| | - Annemieke Kavelaars
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA
| | - Cobi J. Heijnen
- grid.240145.60000 0001 2291 4776Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, TX USA
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Saade-Lemus S, Videnovic A. Sleep Disorders and Circadian Disruption in Huntington's Disease. J Huntingtons Dis 2023; 12:121-131. [PMID: 37424473 PMCID: PMC10473087 DOI: 10.3233/jhd-230576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2023] [Indexed: 07/11/2023]
Abstract
Sleep and circadian alterations are common in patients with Huntington's disease (HD). Understanding the pathophysiology of these alterations and their association with disease progression and morbidity can guide HD management. We provide a narrative review of the clinical and basic-science studies centered on sleep and circadian function on HD. Sleep/wake disturbances among HD patients share many similarities with other neurodegenerative diseases. Overall, HD patients and animal models of the disease present with sleep changes early in the clinical course of the disease, including difficulties with sleep initiation and maintenance leading to decreased sleep efficiency, and progressive deterioration of normal sleep architecture. Despite this, sleep alterations remain frequently under-reported by patients and under-recognized by health professionals. The degree of sleep and circadian alterations has not consistently shown to be CAG dose-dependent. Evidence based treatment recommendations are insufficient due to lack of well-designed intervention trials. Approaches aimed at improving circadian entrainment, such as including light therapy, and time-restricted feeding have demonstrated a potential to delay symptom progression in some basic HD investigations. Larger study cohorts, comprehensive assessment of sleep and circadian function, and reproducibility of findings are needed in future in order to better understand sleep and circadian function in HD and to develop effective treatments.
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Affiliation(s)
- Sandra Saade-Lemus
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Aleksandar Videnovic
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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21
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Aslan A, Yuka SA. Stem Cell-Based Therapeutic Approaches in Genetic Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1436:19-53. [PMID: 36735185 DOI: 10.1007/5584_2023_761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Stem cells, which can self-renew and differentiate into different cell types, have become the keystone of regenerative medicine due to these properties. With the achievement of superior clinical results in the therapeutic approaches of different diseases, the applications of these cells in the treatment of genetic diseases have also come to the fore. Foremost, conventional approaches of stem cells to genetic diseases are the first approaches in this manner, and they have brought safety issues due to immune reactions caused by allogeneic transplantation. To eliminate these safety issues and phenotypic abnormalities caused by genetic defects, firstly, basic genetic engineering practices such as vectors or RNA modulators were combined with stem cell-based therapeutic approaches. However, due to challenges such as immune reactions and inability to target cells effectively in these applications, advanced molecular methods have been adopted in ZFN, TALEN, and CRISPR/Cas genome editing nucleases, which allow modular designs in stem cell-based genetic diseases' therapeutic approaches. Current studies in genetic diseases are in the direction of creating permanent treatment regimens by genomic manipulation of stem cells with differentiation potential through genome editing tools. In this chapter, the stem cell-based therapeutic approaches of various vital genetic diseases were addressed wide range from conventional applications to genome editing tools.
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Affiliation(s)
- Ayça Aslan
- Department of Bioengineering, Yildiz Technical University, Istanbul, Turkey
| | - Selcen Arı Yuka
- Department of Bioengineering, Yildiz Technical University, Istanbul, Turkey.
- Health Biotechnology Joint Research and Application Center of Excellence, Istanbul, Turkey.
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Liang XS, Sun ZW, Thomas AM, Li S. Mesenchymal Stem Cell Therapy for Huntington Disease: A Meta-Analysis. Stem Cells Int 2023; 2023:1109967. [PMID: 37168444 PMCID: PMC10164866 DOI: 10.1155/2023/1109967] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 12/06/2022] [Accepted: 04/11/2023] [Indexed: 05/13/2023] Open
Abstract
Objective Mesenchymal stem cell (MSC) therapy has been explored in Huntington disease (HD) as a potential therapeutic approach; however, a complete synthesis of these results is lacking. We conducted a meta-analysis to evaluate the effects of MSCs on HD. Method Eligible studies published before November 2022 were screened from Embase, PubMed, Web of Science, Medline, and Cochrane in accordance with PRISMA guidelines. ClinicalTrial.gov and the World Health Organization International Clinical Trials Registry Platform were also searched for registered clinical trials. The outcomes in rodent studies evaluated included morphological changes (striatal volume and ventricular volume), motor function (rotarod test, wire hang test, grip strength test, limb-clasping test, apomorphine-induced rotation test, and neuromuscular electromyography activity), cognition (Morris water maze test), and body weight. Result The initial search returned 362 records, of which 15 studies incorporating 346 HD rodents were eligible for meta-analysis. Larger striatal and smaller ventricular volumes were observed in MSC-treated animals compared to controls. MSCs transplanted before the occurrence of motor dysfunction rescued the motor incoordination of HD. Among different MSC sources, bone marrow mesenchymal stem cells were the most investigated cells and were effective in improving motor coordination. MSC therapy improved muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed. The body weight of male HD rodents increased after MSC transplantation, while that of females was not affected. Conclusion Meta-analysis showed a positive effect of MSCs on HD rodents overall, as reflected in morphological changes, motor coordination, muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed by MSC therapy.
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Affiliation(s)
- Xue-Song Liang
- Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
| | - Zheng-Wu Sun
- Department of Clinical Pharmacy, Dalian Municipal Central Hospital, Dalian, China
| | - Aline M. Thomas
- The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shen Li
- Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
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Alteration of Autophagy and Glial Activity in Nilotinib-Treated Huntington's Disease Patients. Metabolites 2022; 12:metabo12121225. [PMID: 36557263 PMCID: PMC9781133 DOI: 10.3390/metabo12121225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/03/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
Nilotinib is a tyrosine kinase inhibitor that is safe and tolerated in neurodegeneration, it achieves CSF concentration that is adequate to inhibit discoidin domain receptor (DDR)-1. Nilotinib significantly affects dopamine metabolites, including Homovanillic acid (HVA), resulting in an increase in brain dopamine. HD is a hereditary disease caused by mutations in the Huntingtin's (HTT) gene and characterized by neurodegeneration and motor and behavioral symptoms that are associated with activation of dopamine receptors. We explored the effects of a low dose of nilotinib (150 mg) on behavioral changes and motor symptoms in manifest HD patients and examined the effects of nilotinib on several brain mechanisms, including dopamine transmission and gene expression via cerebrospinal fluid (CSF) miRNA sequencing. Nilotinib, 150 mg, did not result in any behavioral changes, although it significantly attenuated HVA levels, suggesting reduction of dopamine catabolism. There was no significant change in HTT, phosphorylated neuro-filament and inflammatory markers in the CSF and plasma via immunoassays. Whole miRNA genome sequencing of the CSF revealed significant longitudinal changes in miRNAs that control specific genes associated with autophagy, inflammation, microglial activity and basal ganglia neurotransmitters, including dopamine and serotonin.
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24
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Nose-to-Brain: The Next Step for Stem Cell and Biomaterial Therapy in Neurological Disorders. Cells 2022; 11:cells11193095. [PMID: 36231058 PMCID: PMC9564248 DOI: 10.3390/cells11193095] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/28/2022] [Accepted: 09/29/2022] [Indexed: 11/18/2022] Open
Abstract
Neurological disorders are a leading cause of morbidity worldwide, giving rise to a growing need to develop treatments to revert their symptoms. This review highlights the great potential of recent advances in cell therapy for the treatment of neurological disorders. Through the administration of pluripotent or stem cells, this novel therapy may promote neuroprotection, neuroplasticity, and neuroregeneration in lesion areas. The review also addresses the administration of these therapeutic molecules by the intranasal route, a promising, non-conventional route that allows for direct access to the central nervous system without crossing the blood–brain barrier, avoiding potential adverse reactions and enabling the administration of large quantities of therapeutic molecules to the brain. Finally, we focus on the need to use biomaterials, which play an important role as nutrient carriers, scaffolds, and immune modulators in the administration of non-autologous cells. Little research has been conducted into the integration of biomaterials alongside intranasally administered cell therapy, a highly promising approach for the treatment of neurological disorders.
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25
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Intranasal delivery of biotechnology-based therapeutics. Drug Discov Today 2022; 27:103371. [PMID: 36174965 DOI: 10.1016/j.drudis.2022.103371] [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: 04/23/2022] [Revised: 08/09/2022] [Accepted: 09/21/2022] [Indexed: 11/21/2022]
Abstract
Biotechnology-based therapeutics include a wide range of products, such as recombinant hormones, stem cells, therapeutic enzymes, monoclonal antibodies, genes, vaccines, among others. The administration of these macromolecules has been studied via various routes. The nasal route is one of the promising routes of administration for biotechnology products owing to its easy delivery, the rich vascularity of the nasal mucosa, high absorption and targeted action. Several preclinical studies have been reported for nasal delivery of these products and many are at the clinical stage. This review focuses on biotechnology-based therapeutics administered via the intranasal route for treating various diseases.
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Rahbaran M, Zekiy AO, Bahramali M, Jahangir M, Mardasi M, Sakhaei D, Thangavelu L, Shomali N, Zamani M, Mohammadi A, Rahnama N. Therapeutic utility of mesenchymal stromal cell (MSC)-based approaches in chronic neurodegeneration: a glimpse into underlying mechanisms, current status, and prospects. Cell Mol Biol Lett 2022; 27:56. [PMID: 35842587 PMCID: PMC9287902 DOI: 10.1186/s11658-022-00359-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 06/30/2022] [Indexed: 12/11/2022] Open
Abstract
Recently, mesenchymal stromal cell (MSC)-based therapy has become an appreciated therapeutic approach in the context of neurodegenerative disease therapy. Accordingly, a myriad of studies in animal models and also some clinical trials have evinced the safety, feasibility, and efficacy of MSC transplantation in neurodegenerative conditions, most importantly in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). The MSC-mediated desired effect is mainly a result of secretion of immunomodulatory factors in association with release of various neurotrophic factors (NTFs), such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Thanks to the secretion of protein-degrading molecules, MSC therapy mainly brings about the degradation of pathogenic protein aggregates, which is a typical appearance of chronic neurodegenerative disease. Such molecules, in turn, diminish neuroinflammation and simultaneously enable neuroprotection, thereby alleviating disease pathological symptoms and leading to cognitive and functional recovery. Also, MSC differentiation into neural-like cells in vivo has partially been evidenced. Herein, we focus on the therapeutic merits of MSCs and also their derivative exosome as an innovative cell-free approach in AD, HD, PD, and ALS conditions. Also, we give a brief glimpse into novel approaches to potentiate MSC-induced therapeutic merits in such disorders, most importantly, administration of preconditioned MSCs.
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Affiliation(s)
- Mohaddeseh Rahbaran
- Biotechnology Department, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Angelina Olegovna Zekiy
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Mahta Bahramali
- Biotechnology Department, University of Tehran, Tehran, Iran
| | | | - Mahsa Mardasi
- Biotechnology Department, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Delaram Sakhaei
- School of Medicine, Sari Branch, Islamic Azad University, Sari, Iran
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Ali Mohammadi
- Department of Neurology, Imam Khomeini Hospital, Urmia University of Medical Sciences, Urmia, Iran.
| | - Negin Rahnama
- Department of Internal Medicine and Health Services, Semnan University of Medical Sciences, Semnan, Iran.
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27
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Yadav D, Kumar P. Restoration and targeting of aberrant neurotransmitters in Parkinson's disease therapeutics. Neurochem Int 2022; 156:105327. [PMID: 35331828 DOI: 10.1016/j.neuint.2022.105327] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/18/2022] [Accepted: 03/17/2022] [Indexed: 12/13/2022]
Abstract
Neurotransmitters are considered as a fundamental regulator in the process of neuronal growth, differentiation and survival. Parkinson's Disease (PD) occurs due to extensive damage of dopamine-producing neurons; this causes dopamine deficits in the midbrain, followed by the alternation of various other neurotransmitters (glutamate, GABA, serotonin, etc.). It has been observed that fluctuation of neurotransmission in the basal ganglia exhibits a great impact on the pathophysiology of PD. Dopamine replacement therapy, such as the use of L-DOPA, can increase the dopamine level, but it majorly ameliorates the motor symptoms and is also associated with long-term complications (for e.g., LID). While the non-dopaminergic system can efficiently target non-motor symptoms, for instance, the noradrenergic system regulates the synthesis of BDNF via the MAPK pathway, which is important in learning and memory. Herein, we briefly discuss the role of different neurotransmitters, implementation of neurotransmitter receptors in PD. We also illustrate the recent advances of neurotransmitter-based drugs, which are currently under in vivo and clinical studies. Reinstating normal neurotransmitter levels has been believed to be advantageous in the treatment of PD. Thus, there is an increasing demand for drugs that can specifically target the neurotransmission system and reinstate the normal levels of neurotransmitters, which might prevent or delay neurodegeneration in PD.
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Affiliation(s)
- Divya Yadav
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi, India; Delhi Technological University (Formerly Delhi College of Engineering), Delhi, 110042, India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi, India; Delhi Technological University (Formerly Delhi College of Engineering), Delhi, 110042, India.
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Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions. Nat Rev Neurol 2022; 18:145-157. [PMID: 35022573 DOI: 10.1038/s41582-021-00612-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2021] [Indexed: 02/07/2023]
Abstract
Non-coding CGG repeat expansions cause multiple neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukodystrophy, and oculopharyngodistal myopathy. The underlying genetic causes of several of these diseases have been identified only in the past 2-3 years. These expansion disorders have substantial overlapping clinical, neuroimaging and histopathological features. The shared features suggest common mechanisms that could have implications for the development of therapies for this group of diseases - similar therapeutic strategies or drugs may be effective for various neurodegenerative disorders induced by non-coding CGG expansions. In this Review, we provide an overview of clinical and pathological features of these CGG repeat expansion diseases and consider the likely pathological mechanisms, including RNA toxicity, CGG repeat-associated non-AUG-initiated translation, protein aggregation and mitochondrial impairment. We then discuss future research needed to improve the identification and diagnosis of CGG repeat expansion diseases, to improve modelling of these diseases and to understand their pathogenesis. We also consider possible therapeutic strategies. Finally, we propose that CGG repeat expansion diseases may represent manifestations of a single underlying neuromyodegenerative syndrome in which different organs are affected to different extents depending on the gene location of the repeat expansion.
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Abstract
Endogenous biological clocks, orchestrated by the suprachiasmatic nucleus, time the circadian rhythms that synchronize physiological and behavioural functions in humans. The circadian system influences most physiological processes, including sleep, alertness and cognitive performance. Disruption of circadian homeostasis has deleterious effects on human health. Neurodegenerative disorders involve a wide range of symptoms, many of which exhibit diurnal variations in frequency and intensity. These disorders also disrupt circadian homeostasis, which in turn has negative effects on symptoms and quality of life. Emerging evidence points to a bidirectional relationship between circadian homeostasis and neurodegeneration, suggesting that circadian function might have an important role in the progression of neurodegenerative disorders. Therefore, the circadian system has become an attractive target for research and clinical care innovations. Studying circadian disruption in neurodegenerative disorders could expand our understanding of the pathophysiology of neurodegeneration and facilitate the development of novel, circadian-based interventions for these disabling disorders. In this Review, we discuss the alterations to the circadian system that occur in movement (Parkinson disease and Huntington disease) and cognitive (Alzheimer disease and frontotemporal dementia) neurodegenerative disorders and provide directions for future investigations in this field.
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Jeon S, Park SH, Kim E, Kim J, Kim SW, Choi H. A Magnetically Powered Stem Cell-Based Microrobot for Minimally Invasive Stem Cell Delivery via the Intranasal Pathway in a Mouse Brain. Adv Healthc Mater 2021; 10:e2100801. [PMID: 34160909 DOI: 10.1002/adhm.202100801] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/03/2021] [Indexed: 12/12/2022]
Abstract
Targeted stem cell delivery with microrobots has emerged as a potential alternative therapeutic strategy in regenerative medicine, and intranasal administration is an effective approach for minimally invasive delivery of therapeutic agents into the brain. In this study, a magnetically powered stem cell-based microrobot ("Cellbot") is used for minimally invasive targeted stem cell delivery to the brain through the intranasal passage. The Cellbot is developed by internalizing superparamagnetic iron oxide nanoparticles (SPIONs) into human nasal turbinate stem cells. The SPIONs have no influence on hNTSC characteristics, including morphology, cell viability, and neuronal differentiation. The Cellbots are capable of proliferation and differentiation into neurons, neural precursor cells, and neurogliocytes. The Cellbots in the microfluidic channel can be reliably manipulated by an external magnetic field for orientation and position control. Using an ex vivo model based on brain organoids, it is determined that the Cellbots can be transplanted into brain tissue. Using a murine model, it is demonstrated that the Cellbots can be intranasally administered and magnetically guided to the target tissue in vivo. This approach has the potential to effectively treat central nervous system disorders in a minimally invasive manner.
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Affiliation(s)
- Sungwoong Jeon
- Department of Robotics Engineering DGIST‐ETH Microrobotics Research Center Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu 42988 Republic of Korea
| | - Sun Hwa Park
- Department of Otolaryngology‐Head and Neck Surgery Seoul St. Mary's Hospital The Catholic University Seoul 06591 Republic of Korea
| | - Eunhee Kim
- Department of Robotics Engineering DGIST‐ETH Microrobotics Research Center Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu 42988 Republic of Korea
| | - Jin‐young Kim
- Department of Robotics Engineering DGIST‐ETH Microrobotics Research Center Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu 42988 Republic of Korea
| | - Sung Won Kim
- Department of Otolaryngology‐Head and Neck Surgery Seoul St. Mary's Hospital The Catholic University Seoul 06591 Republic of Korea
| | - Hongsoo Choi
- Department of Robotics Engineering DGIST‐ETH Microrobotics Research Center Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu 42988 Republic of Korea
- Robotics Research Center DGIST Daegu 42988 Republic of Korea
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Kim IK, Park JH, Kim B, Hwang KC, Song BW. Recent advances in stem cell therapy for neurodegenerative disease: Three dimensional tracing and its emerging use. World J Stem Cells 2021; 13:1215-1230. [PMID: 34630859 PMCID: PMC8474717 DOI: 10.4252/wjsc.v13.i9.1215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/20/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative disease is a brain disorder caused by the loss of structure and function of neurons that lowers the quality of human life. Apart from the limited potential for endogenous regeneration, stem cell-based therapies hold considerable promise for maintaining homeostatic tissue regeneration and enhancing plasticity. Despite many studies, there remains insufficient evidence for stem cell tracing and its correlation with endogenous neural cells in brain tissue with three-dimensional structures. Recent advancements in tissue optical clearing techniques have been developed to overcome the existing shortcomings of cross-sectional tissue analysis in thick and complex tissues. This review focuses on recent progress of stem cell treatments to improve neurodegenerative disease, and introduces tissue optical clearing techniques that can implement a three-dimensional image as a proof of concept. This review provides a more comprehensive understanding of stem cell tracing that will play an important role in evaluating therapeutic efficacy and cellular interrelationship for regeneration in neurodegenerative diseases.
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Affiliation(s)
- Il-Kwon Kim
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea
| | - Jun-Hee Park
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
| | - Bomi Kim
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea.
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Lee DY, Lee SE, Kwon DH, Nithiyanandam S, Lee MH, Hwang JS, Basith S, Ahn JH, Shin TH, Lee G. Strategies to Improve the Quality and Freshness of Human Bone Marrow-Derived Mesenchymal Stem Cells for Neurological Diseases. Stem Cells Int 2021; 2021:8444599. [PMID: 34539792 PMCID: PMC8445711 DOI: 10.1155/2021/8444599] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/26/2021] [Indexed: 12/14/2022] Open
Abstract
Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) have been studied for their application to manage various neurological diseases, owing to their anti-inflammatory, immunomodulatory, paracrine, and antiapoptotic ability, as well as their homing capacity to specific regions of brain injury. Among mesenchymal stem cells, such as BM-MSCs, adipose-derived MSCs, and umbilical cord MSCs, BM-MSCs have many merits as cell therapeutic agents based on their widespread availability and relatively easy attainability and in vitro handling. For stem cell-based therapy with BM-MSCs, it is essential to perform ex vivo expansion as low numbers of MSCs are obtained in bone marrow aspirates. Depending on timing, before hBM-MSC transplantation into patients, after detaching them from the culture dish, cell viability, deformability, cell size, and membrane fluidity are decreased, whereas reactive oxygen species generation, lipid peroxidation, and cytosolic vacuoles are increased. Thus, the quality and freshness of hBM-MSCs decrease over time after detachment from the culture dish. Especially, for neurological disease cell therapy, the deformability of BM-MSCs is particularly important in the brain for the development of microvessels. As studies on the traditional characteristics of hBM-MSCs before transplantation into the brain are very limited, omics and machine learning approaches are needed to evaluate cell conditions with indepth and comprehensive analyses. Here, we provide an overview of hBM-MSCs, the application of these cells to various neurological diseases, and improvements in their quality and freshness based on integrated omics after detachment from the culture dish for successful cell therapy.
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Affiliation(s)
- Da Yeon Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Sung Eun Lee
- Department of Emergency Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Do Hyeon Kwon
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | | | - Mi Ha Lee
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | - Ji Su Hwang
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
| | - Shaherin Basith
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jung Hwan Ahn
- Department of Emergency Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Tae Hwan Shin
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Gwang Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea
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Skok M. Mesenchymal stem cells as a potential therapeutic tool to cure cognitive impairment caused by neuroinflammation. World J Stem Cells 2021; 13:1072-1083. [PMID: 34567426 PMCID: PMC8422935 DOI: 10.4252/wjsc.v13.i8.1072] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/28/2021] [Accepted: 07/29/2021] [Indexed: 02/06/2023] Open
Abstract
An established contribution of neuroinflammation to multiple brain pathologies has raised the requirement for therapeutic strategies to overcome it in order to prevent age- and disease-dependent cognitive decline. Mesenchymal stem cells (MSCs) produce multiple growth and neurotrophic factors and seem to evade immune rejection due to low expression of major histocompatibility complex class I molecules. Therefore, MSCs are widely used in experiments and clinical trials of regenerative medicine. This review summarizes recent data concerning the optimization of MSC use for therapeutic purposes with the emphasis on the achievements of the last 2 years. Specific attention is paid to extracellular vesicles secreted by MSCs and to the role of α7 nicotinic acetylcholine receptors. The reviewed data demonstrate that MSCs have a significant therapeutic potential in treating neuroinflammation-related cognitive disfunctions including age-related neurodegenerative diseases. The novel data demonstrate that maximal therapeutic effect is being achieved when MSCs penetrate the brain and produce their stimulating factors in situ. Consequently, therapeutic application using MSCs should include measures to facilitate their homing to the brain, support the survival in the brain microenvironment, and stimulate the production of neurotrophic and anti-inflammatory factors. These measures include but are not limited to genetic modification of MSCs and pre-conditioning before transplantation.
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Affiliation(s)
- Maryna Skok
- Department of Molecular Immunology, Palladin Institute of Biochemistry NAS of Ukraine, Kyiv 01054, Ukraine
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Tung CW, Huang PY, Chan SC, Cheng PH, Yang SH. The regulatory roles of microRNAs toward pathogenesis and treatments in Huntington's disease. J Biomed Sci 2021; 28:59. [PMID: 34412645 PMCID: PMC8375176 DOI: 10.1186/s12929-021-00755-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 08/12/2021] [Indexed: 12/21/2022] Open
Abstract
Huntington's disease (HD) is one of neurodegenerative diseases, and is defined as a monogenetic disease due to the mutation of Huntingtin gene. This disease affects several cellular functions in neurons, and further influences motor and cognitive ability, leading to the suffering of devastating symptoms in HD patients. MicroRNA (miRNA) is a non-coding RNA, and is responsible for gene regulation at post-transcriptional levels in cells. Since one miRNA targets to several downstream genes, it may regulate different pathways simultaneously. As a result, it raises a potential therapy for different diseases using miRNAs, especially for inherited diseases. In this review, we will not only introduce the update information of HD and miRNA, but also discuss the development of potential miRNA-based therapy in HD. With the understanding toward the progression of miRNA studies in HD, we anticipate it may provide an insight to treat this devastating disease, even applying to other genetic diseases.
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Affiliation(s)
- Chih-Wei Tung
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Pin-Yu Huang
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Siew Chin Chan
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Pei-Hsun Cheng
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Shang-Hsun Yang
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan. .,Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 70101, Taiwan.
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Mukai T, Sei K, Nagamura-Inoue T. Mesenchymal Stromal Cells Perspective: New Potential Therapeutic for the Treatment of Neurological Diseases. Pharmaceutics 2021; 13:pharmaceutics13081159. [PMID: 34452120 PMCID: PMC8401282 DOI: 10.3390/pharmaceutics13081159] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/23/2021] [Accepted: 07/24/2021] [Indexed: 12/13/2022] Open
Abstract
Several studies have shown that mesenchymal stromal/stem cells (MSCs) exert their neuroprotective and neurorestorative efficacy via the secretion of neurotrophic factors. Based on these studies, many clinical trials using MSCs for the treatment of neurological disorders have been conducted, and results regarding their feasibility and efficacy have been reported. The present review aims to highlight the characteristics and basic research regarding the role of MSCs in neurological disease and to discuss the recent progress in clinical trials using MSCs to treat various neurological disorders.
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Affiliation(s)
- Takeo Mukai
- Department of Pediatrics, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; (K.S.); (T.N.-I.)
- Correspondence: ; Tel.: +81-3-3815-5411; Fax: 81-3-5449-5452
| | - Kenshi Sei
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; (K.S.); (T.N.-I.)
| | - Tokiko Nagamura-Inoue
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; (K.S.); (T.N.-I.)
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Parajuli B, Saito H, Shinozaki Y, Shigetomi E, Miwa H, Yoneda S, Tanimura M, Omachi S, Asaki T, Takahashi K, Fujita M, Nakashima K, Koizumi S. Transnasal transplantation of human induced pluripotent stem cell-derived microglia to the brain of immunocompetent mice. Glia 2021; 69:2332-2348. [PMID: 34309082 DOI: 10.1002/glia.23985] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/15/2021] [Accepted: 02/19/2021] [Indexed: 01/26/2023]
Abstract
Microglia are the resident immune cells of the brain, and play essential roles in neuronal development, homeostatic function, and neurodegenerative disease. Human microglia are relatively different from mouse microglia. However, most research on human microglia is performed in vitro, which does not accurately represent microglia characteristics under in vivo conditions. To elucidate the in vivo characteristics of human microglia, methods have been developed to generate and transplant induced pluripotent or embryonic stem cell-derived human microglia into neonatal or adult mouse brains. However, its widespread use remains limited by the technical difficulties of generating human microglia, as well as the need to use immune-deficient mice and conduct invasive surgeries. To address these issues, we developed a simplified method to generate induced pluripotent stem cell-derived human microglia and transplant them into the brain via a transnasal route in immunocompetent mice, in combination with a colony stimulating factor 1 receptor antagonist. We found that human microglia were able to migrate through the cribriform plate to different regions of the brain, proliferate, and become the dominant microglia in a region-specific manner by occupying the vacant niche when exogenous human cytokine is administered, for at least 60 days.
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Affiliation(s)
- Bijay Parajuli
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.,GLIA Center, University of Yamanashi, Yamanashi, Japan
| | - Hiroki Saito
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Youichi Shinozaki
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.,GLIA Center, University of Yamanashi, Yamanashi, Japan
| | - Eiji Shigetomi
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.,GLIA Center, University of Yamanashi, Yamanashi, Japan
| | - Hiroto Miwa
- Laboratory for Innovative Therapy Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Sosuke Yoneda
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Miki Tanimura
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Shigeki Omachi
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Toshiyuki Asaki
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Koji Takahashi
- Laboratory for Innovative Therapy Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Masahide Fujita
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Kinichi Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Schuichi Koizumi
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.,GLIA Center, University of Yamanashi, Yamanashi, Japan
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Andrzejewska A, Dabrowska S, Lukomska B, Janowski M. Mesenchymal Stem Cells for Neurological Disorders. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2002944. [PMID: 33854883 PMCID: PMC8024997 DOI: 10.1002/advs.202002944] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 11/23/2020] [Indexed: 05/13/2023]
Abstract
Neurological disorders are becoming a growing burden as society ages, and there is a compelling need to address this spiraling problem. Stem cell-based regenerative medicine is becoming an increasingly attractive approach to designing therapies for such disorders. The unique characteristics of mesenchymal stem cells (MSCs) make them among the most sought after cell sources. Researchers have extensively studied the modulatory properties of MSCs and their engineering, labeling, and delivery methods to the brain. The first part of this review provides an overview of studies on the application of MSCs to various neurological diseases, including stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and other less frequently studied clinical entities. In the second part, stem cell delivery to the brain is focused. This fundamental but still understudied problem needs to be overcome to apply stem cells to brain diseases successfully. Here the value of cell engineering is also emphasized to facilitate MSC diapedesis, migration, and homing to brain areas affected by the disease to implement precision medicine paradigms into stem cell-based therapies.
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Affiliation(s)
- Anna Andrzejewska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Sylwia Dabrowska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Barbara Lukomska
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
| | - Miroslaw Janowski
- NeuroRepair DepartmentMossakowski Medical Research CentrePASWarsaw02‐106Poland
- Center for Advanced Imaging ResearchDepartment of Diagnostic Radiology and Nuclear MedicineUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
- Tumor Immunology and Immunotherapy ProgramUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of MarylandBaltimoreMD21201‐1595USA
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White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies. Nat Rev Neurol 2021; 17:199-214. [PMID: 33504979 PMCID: PMC8880688 DOI: 10.1038/s41582-020-00447-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2020] [Indexed: 01/31/2023]
Abstract
Intraventricular haemorrhage (IVH) continues to be a major complication of prematurity that can result in cerebral palsy and cognitive impairment in survivors. No optimal therapy exists to prevent IVH or to treat its consequences. IVH varies in severity and can present as a bleed confined to the germinal matrix, small-to-large IVH or periventricular haemorrhagic infarction. Moderate-to-severe haemorrhage dilates the ventricle and damages the periventricular white matter. This white matter injury results from a constellation of blood-induced pathological reactions, including oxidative stress, glutamate excitotoxicity, inflammation, perturbed signalling pathways and remodelling of the extracellular matrix. Potential therapies for IVH are currently undergoing investigation in preclinical models and evidence from clinical trials suggests that stem cell treatment and/or endoscopic removal of clots from the cerebral ventricles could transform the outcome of infants with IVH. This Review presents an integrated view of new insights into the mechanisms underlying white matter injury in premature infants with IVH and highlights the importance of early detection of disability and immediate intervention in optimizing the outcomes of IVH survivors.
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Zhang YT, He KJ, Zhang JB, Ma QH, Wang F, Liu CF. Advances in intranasal application of stem cells in the treatment of central nervous system diseases. Stem Cell Res Ther 2021; 12:210. [PMID: 33762014 PMCID: PMC7992869 DOI: 10.1186/s13287-021-02274-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cells are characterized by their self-renewal and multipotency and have great potential in the therapy of various disorders. However, the blood-brain barrier (BBB) limits the application of stem cells in the therapy of neurological disorders, especially in a noninvasive way. It has been shown that small molecular substances, macromolecular proteins, and even stem cells can bypass the BBB and reach the brain parenchyma following intranasal administration. Here, we review the possible brain-entry routes of transnasal treatment, the cell types, and diseases involved in intranasal stem cell therapy, and discuss its advantages and disadvantages in the treatment of central nervous system diseases, to provide a reference for the application of intranasal stem cell therapy.
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Affiliation(s)
- Yu-Ting Zhang
- Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.,Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Kai-Jie He
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Jin-Bao Zhang
- Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.,Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Quan-Hong Ma
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China
| | - Fen Wang
- Institute of Neuroscience, Soochow University, Suzhou, 215123, China.
| | - Chun-Feng Liu
- Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China. .,Institute of Neuroscience, Soochow University, Suzhou, 215123, China.
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Aguilera Y, Mellado-Damas N, Olmedo-Moreno L, López V, Panadero-Morón C, Benito M, Guerrero-Cázares H, Márquez-Vega C, Martín-Montalvo A, Capilla-González V. Preclinical Safety Evaluation of Intranasally Delivered Human Mesenchymal Stem Cells in Juvenile Mice. Cancers (Basel) 2021; 13:cancers13051169. [PMID: 33803160 PMCID: PMC7963187 DOI: 10.3390/cancers13051169] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/03/2021] [Accepted: 03/05/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The concept of utilizing mesenchymal stem cells for the treatment of central nervous system disorders has progressed from preclinical studies to clinical trials. While promising, the effectiveness of cell therapy is hampered by the route used to deliver cells into the brain. In this context, intranasal cell administration has boomed over the past few years as an effective cell delivery method. However, comprehensive safety studies are required before translation to the clinic. Our study shed light on how intranasally administrated mesenchymal stem cells may be used to safely treat neurological disorders. Abstract Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a non-invasive delivery method. However, a comprehensive investigation of the safety of intranasal MSC treatment should be performed before clinical applications. Here, we cultured human MSCs in compliance with quality control standards and administrated repeated doses of cells into the nostrils of juvenile immunodeficient mice, mimicking the design of a subsequent clinical trial. Short- and long-term effects of cell administration were evaluated by in vivo and ex vivo studies. No serious adverse events were reported on mouse welfare, behavioral performances, and blood plasma analysis. Magnetic resonance study and histological analysis did not reveal tumor formation or other abnormalities in the examined organs of mice receiving MSCs. Biodistribution study reveals a progressive disappearance of transplanted cells that was further supported by an absent expression of human GAPDH gene in the major organs of transplanted mice. Our data indicate that the intranasal application of MSCs is a safe, simple and non-invasive strategy and encourage its use in future clinical trials.
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Affiliation(s)
- Yolanda Aguilera
- Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-CSIC-US-UPO, Department of Regeneration and Cell Therapy, 41092 Seville, Spain; (Y.A.); (N.M.-D.); (L.O.-M.); (V.L.); (C.P.-M.); (A.M.-M.)
| | - Nuria Mellado-Damas
- Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-CSIC-US-UPO, Department of Regeneration and Cell Therapy, 41092 Seville, Spain; (Y.A.); (N.M.-D.); (L.O.-M.); (V.L.); (C.P.-M.); (A.M.-M.)
| | - Laura Olmedo-Moreno
- Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-CSIC-US-UPO, Department of Regeneration and Cell Therapy, 41092 Seville, Spain; (Y.A.); (N.M.-D.); (L.O.-M.); (V.L.); (C.P.-M.); (A.M.-M.)
| | - Víctor López
- Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-CSIC-US-UPO, Department of Regeneration and Cell Therapy, 41092 Seville, Spain; (Y.A.); (N.M.-D.); (L.O.-M.); (V.L.); (C.P.-M.); (A.M.-M.)
| | - Concepción Panadero-Morón
- Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-CSIC-US-UPO, Department of Regeneration and Cell Therapy, 41092 Seville, Spain; (Y.A.); (N.M.-D.); (L.O.-M.); (V.L.); (C.P.-M.); (A.M.-M.)
| | - Marina Benito
- Research Magnetic Resonance Unit, Hospital Nacional de Parapléjicos, 45004 Toledo, Spain;
| | | | | | - Alejandro Martín-Montalvo
- Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-CSIC-US-UPO, Department of Regeneration and Cell Therapy, 41092 Seville, Spain; (Y.A.); (N.M.-D.); (L.O.-M.); (V.L.); (C.P.-M.); (A.M.-M.)
| | - Vivian Capilla-González
- Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-CSIC-US-UPO, Department of Regeneration and Cell Therapy, 41092 Seville, Spain; (Y.A.); (N.M.-D.); (L.O.-M.); (V.L.); (C.P.-M.); (A.M.-M.)
- Correspondence:
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Sarkar A, Saha S, Paul A, Maji A, Roy P, Maity TK. Understanding stem cells and its pivotal role in regenerative medicine. Life Sci 2021; 273:119270. [PMID: 33640402 DOI: 10.1016/j.lfs.2021.119270] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/06/2021] [Accepted: 02/14/2021] [Indexed: 02/07/2023]
Abstract
Stem cells (SCs) are clonogenic cells that develop into the specialized cells which later responsible for making up various types of tissue in the human body. SCs are not only the appropriate source of information for cell division, molecular and cellular processes, and tissue homeostasis but also one of the major putative biological aids to diagnose and cure various degenerative diseases. This study emphasises on various research outputs that occurred in the past two decades. This will give brief information on classification, differentiation, detection, and various isolation techniques of SCs. Here, the various signalling pathways which includes WNT, Sonic hedgehog, Notch, BMI1 and C-met pathways and how does it effect on the regeneration of various classes of SCs and factors that regulates the potency of the SCs are also been discussed. We also focused on the application of SCs in the area of regenerative medicine along with the cellular markers that are useful as salient diagnostic or curative tools or in both, by the process of reprogramming, which includes diabetes, cancer, cardiovascular disorders and neurological disorders. The biomarkers that are mentioned in various literatures and experiments include PDX1, FOXA2, HNF6, and NKX6-1 (for diabetes); CD33, CD24, CD133 (for cancer); c-Kit, SCA-1, Wilm's tumor 1 (for cardiovascular disorders); and OCT4, SOX2, c-MYC, EN1, DAT and VMAT2 (for neurological disorders). In this review, we come to know the advancements and scopes of potential SC-based therapies, its diverse applications in clinical fields that can be helpful in the near future.
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Affiliation(s)
- Arnab Sarkar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Sanjukta Saha
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Abhik Paul
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Avik Maji
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Puspita Roy
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Tapan Kumar Maity
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India.
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Keller LA, Merkel O, Popp A. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Deliv Transl Res 2021; 12:735-757. [PMID: 33491126 PMCID: PMC7829061 DOI: 10.1007/s13346-020-00891-5] [Citation(s) in RCA: 248] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2020] [Indexed: 02/06/2023]
Abstract
Over the past 10 years, the interest in intranasal drug delivery in pharmaceutical R&D has increased. This review article summarises information on intranasal administration for local and systemic delivery, as well as for CNS indications. Nasal delivery offers many advantages over standard systemic delivery systems, such as its non-invasive character, a fast onset of action and in many cases reduced side effects due to a more targeted delivery. There are still formulation limitations and toxicological aspects to be optimised. Intranasal drug delivery in the field of drug development is an interesting delivery route for the treatment of neurological disorders. Systemic approaches often fail to efficiently supply the CNS with drugs. This review paper describes the anatomical, histological and physiological basis and summarises currently approved drugs for administration via intranasal delivery. Further, the review focuses on toxicological considerations of intranasally applied compounds and discusses formulation aspects that need to be considered for drug development.
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Affiliation(s)
- Lea-Adriana Keller
- Preclinical Safety, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
- Department of Pharmacy, Pharmaceutical Technology and Biopharmacy, Ludwig-Maximilians-University, Butenandtstraße 5-13, 81337 Munich, Germany
| | - Olivia Merkel
- Department of Pharmacy, Pharmaceutical Technology and Biopharmacy, Ludwig-Maximilians-University, Butenandtstraße 5-13, 81337 Munich, Germany
| | - Andreas Popp
- Preclinical Safety, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
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Etxeberria-Rekalde E, Alzola-Aldamizetxebarria S, Flunkert S, Hable I, Daurer M, Neddens J, Hutter-Paier B. Quantification of Huntington's Disease Related Markers in the R6/2 Mouse Model. Front Mol Neurosci 2021; 13:617229. [PMID: 33505246 PMCID: PMC7831778 DOI: 10.3389/fnmol.2020.617229] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/10/2020] [Indexed: 12/12/2022] Open
Abstract
Huntington’s disease (HD) is caused by an expansion of CAG triplets in the huntingtin gene, leading to severe neuropathological changes that result in a devasting and lethal phenotype. Neurodegeneration in HD begins in the striatum and spreads to other brain regions such as cortex and hippocampus, causing motor and cognitive dysfunctions. To understand the signaling pathways involved in HD, animal models that mimic the human pathology are used. The R6/2 mouse as model of HD was already shown to present major neuropathological changes in the caudate putamen and other brain regions, but recently established biomarkers in HD patients were yet not analyzed in these mice. We therefore performed an in-depth analysis of R6/2 mice to establish new and highly translational readouts focusing on Ctip2 as biological marker for motor system-related neurons and translocator protein (TSPO) as a promising readout for early neuroinflammation. Our results validate already shown pathologies like mutant huntingtin aggregates, ubiquitination, and brain atrophy, but also provide evidence for decreased tyrosine hydroxylase and Ctip2 levels as indicators of a disturbed motor system, while vesicular acetyl choline transporter levels as marker for the cholinergic system barely change. Additionally, increased astrocytosis and activated microglia were observed by GFAP, Iba1 and TSPO labeling, illustrating, that TSPO is a more sensitive marker for early neuroinflammation compared to GFAP and Iba1. Our results thus demonstrate a high sensitivity and translational value of Ctip2 and TSPO as new marker for the preclinical evaluation of new compounds in the R6/2 mouse model of HD.
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Affiliation(s)
| | | | | | - Isabella Hable
- QPS Austria GmbH, Grambach, Austria.,Department of Health Studies, FH Joanneum University of Applied Sciences, Graz, Austria
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Alexander JF, Seua AV, Arroyo LD, Ray PR, Wangzhou A, Heiβ-Lückemann L, Schedlowski M, Price TJ, Kavelaars A, Heijnen CJ. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics 2021; 11:3109-3130. [PMID: 33537077 PMCID: PMC7847685 DOI: 10.7150/thno.53474] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 12/12/2020] [Indexed: 12/15/2022] Open
Abstract
Up to seventy-five percent of patients treated for cancer suffer from cognitive deficits which can persist for months to decades, severely impairing quality of life. Although the number of cancer survivors is increasing tremendously, no efficacious interventions exist. Cisplatin, most commonly employed for solid tumors, leads to cognitive impairment including deficits in memory and executive functioning. We recently proposed deficient neuronal mitochondrial function as its underlying mechanism. We hypothesized nasal administration of mitochondria isolated from human mesenchymal stem cells to mice, can reverse cisplatin-induced cognitive deficits. Methods: Puzzle box, novel object place recognition and Y-maze tests were used to assess the cognitive function of mice. Immunofluorescence and high-resolution confocal microscopy were employed to trace the nasally delivered mitochondria and evaluate their effect on synaptic loss. Black Gold II immunostaining was used to determine myelin integrity. Transmission electron microscopy helped determine mitochondrial and membrane integrity of brain synaptosomes. RNA-sequencing was performed to analyse the hippocampal transcriptome. Results: Two nasal administrations of mitochondria isolated from human mesenchymal stem cells to mice, restored executive functioning, working and spatial memory. Confocal imaging revealed nasally delivered mitochondria rapidly arrived in the meninges where they were readily internalized by macrophages. The administered mitochondria also accessed the rostral migratory stream and various other brain regions including the hippocampus where they colocalized with GFAP+ cells. The restoration of cognitive function was associated with structural repair of myelin in the cingulate cortex and synaptic loss in the hippocampus. Nasal mitochondrial donation also reversed the underlying synaptosomal mitochondrial defects. Moreover, transcriptome analysis by RNA-sequencing showed reversal of cisplatin-induced changes in the expression of about seven hundred genes in the hippocampus. Pathway analysis identified Nrf2-mediated response as the top canonical pathway. Conclusion: Our results provide key evidence on the therapeutic potential of isolated mitochondria - restoring both brain structure and function, their capability to enter brain meninges and parenchyma upon nasal delivery and undergo rapid cellular internalization and alter the hippocampal transcriptome. Our data identify nasal administration of mitochondria as an effective strategy for reversing chemotherapy-induced cognitive deficits and restoring brain health, providing promise for the growing population of both adult and pediatric cancer survivors.
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Affiliation(s)
- Jenolyn F. Alexander
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States
| | - Alexandre V. Seua
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States
| | - Luis D. Arroyo
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States
| | - Pradipta R. Ray
- School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, Texas, United States
| | - Andi Wangzhou
- School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, Texas, United States
| | - Laura Heiβ-Lückemann
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Theodore J. Price
- School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, Texas, United States
| | - Annemieke Kavelaars
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States
| | - Cobi J. Heijnen
- Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, United States
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He L, Chen Z, Peng L, Tang B, Jiang H. Human stem cell models of polyglutamine diseases: Sources for disease models and cell therapy. Exp Neurol 2020; 337:113573. [PMID: 33347831 DOI: 10.1016/j.expneurol.2020.113573] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 12/19/2022]
Abstract
Polyglutamine (polyQ) diseases are a group of neurodegenerative disorders involving expanded CAG repeats in pathogenic genes that are translated into extended polyQ tracts and lead to progressive neuronal degeneration in the affected brain. To date, there is no effective therapy for these diseases. Due to the complex pathologic mechanisms of these diseases, intensive research on the pathogenesis of their progression and potential treatment strategies is being conducted. However, animal models cannot recapitulate all aspects of neuronal degeneration. Pluripotent stem cells (PSCs), such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), can be used to study the pathological mechanisms of polyQ diseases, and the ability of autologous stem cell transplantation to treat these diseases. Differentiated PSCs, neuronal precursor cells/neural progenitor cells (NPCs) and mesenchymal stem cells (MSCs) are valuable resources for preclinical and clinical cell transplantation therapies. Here, we discuss diverse stem cell models and their ability to generate neurons involved in polyQ diseases, such as medium spiny neurons (MSNs), cortical neurons, cerebellar Purkinje cells (PCs) and motor neurons. In addition, we discuss potential therapeutic approaches, including stem cell replacement therapy and gene therapy.
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Affiliation(s)
- Lang He
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhao Chen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Diseases, Central South University, Changsha, Hunan, China
| | - Linliu Peng
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Beisha Tang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Diseases, Central South University, Changsha, Hunan, China; Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China
| | - Hong Jiang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Diseases, Central South University, Changsha, Hunan, China; Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
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Brain and Nasal Cavity Anatomy of the Cynomolgus Monkey: Species Differences from the Viewpoint of Direct Delivery from the Nose to the Brain. Pharmaceutics 2020; 12:pharmaceutics12121227. [PMID: 33352847 PMCID: PMC7766477 DOI: 10.3390/pharmaceutics12121227] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 11/17/2022] Open
Abstract
Based on structural data on the nasal cavity and brain of the cynomolgus monkey, species differences in the olfactory bulb and cribriform plate were discussed from the viewpoint of direct delivery from the nose to the brain. Structural 3D data on the cynomolgus monkey skull were obtained using X-ray computed tomography. The dimensions of the nasal cavity of the cynomolgus monkey were 5 mm width × 20 mm height × 60 mm depth. The nasal cavity was very narrow and the olfactory region was far from the nostrils, similar to rats and humans. The weight and size of the monkey brain were 70 g and 55 mm width × 40 mm height × 70 mm depth. The olfactory bulb of monkeys is plate-like, while that of humans and rats is bulbar, suggesting that the olfactory area connected with the brain of monkeys is narrow. Although the structure of the monkey nasal cavity is similar to that of humans, the size and shape of the olfactory bulb are different, which is likely to result in low estimation of direct delivery from the nose to the brain in monkeys.
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Barros I, Marcelo A, Silva TP, Barata J, Rufino-Ramos D, Pereira de Almeida L, Miranda CO. Mesenchymal Stromal Cells' Therapy for Polyglutamine Disorders: Where Do We Stand and Where Should We Go? Front Cell Neurosci 2020; 14:584277. [PMID: 33132851 PMCID: PMC7573388 DOI: 10.3389/fncel.2020.584277] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/03/2020] [Indexed: 12/16/2022] Open
Abstract
Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by the expansion of the cytosine-adenine-guanine (CAG) repeat. This mutation encodes extended glutamine (Q) tract in the disease protein, resulting in the alteration of its conformation/physiological role and in the formation of toxic fragments/aggregates of the protein. This group of heterogeneous disorders shares common molecular mechanisms, which opens the possibility to develop a pan therapeutic approach. Vast efforts have been made to develop strategies to alleviate disease symptoms. Nonetheless, there is still no therapy that can cure or effectively delay disease progression of any of these disorders. Mesenchymal stromal cells (MSC) are promising tools for the treatment of polyQ disorders, promoting protection, tissue regeneration, and/or modulation of the immune system in animal models. Accordingly, data collected from clinical trials have so far demonstrated that transplantation of MSC is safe and delays the progression of some polyQ disorders for some time. However, to achieve sustained phenotypic amelioration in clinics, several treatments may be necessary. Therefore, efforts to develop new strategies to improve MSC's therapeutic outcomes have been emerging. In this review article, we discuss the current treatments and strategies used to reduce polyQ symptoms and major pre-clinical and clinical achievements obtained with MSC transplantation as well as remaining flaws that need to be overcome. The requirement to cross the blood-brain-barrier (BBB), together with a short rate of cell engraftment in the lesioned area and low survival of MSC in a pathophysiological context upon transplantation may contribute to the transient therapeutic effects. We also review methods like pre-conditioning or genetic engineering of MSC that can be used to increase MSC survival in vivo, cellular-free approaches-i.e., MSC-conditioned medium (CM) or MSC-derived extracellular vesicles (EVs) as a way of possibly replacing the use of MSC and methods required to standardize the potential of MSC/MSC-derived products. These are fundamental questions that need to be addressed to obtain maximum MSC performance in polyQ diseases and therefore increase clinical benefits.
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Affiliation(s)
- Inês Barros
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,III-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Adriana Marcelo
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Teresa P Silva
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - João Barata
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - David Rufino-Ramos
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
| | - Luís Pereira de Almeida
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Viravector-Viral Vector for Gene Transfer Core Facility, University of Coimbra, Coimbra, Portugal
| | - Catarina O Miranda
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,III-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
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Danielyan L, Schwab M, Siegel G, Brawek B, Garaschuk O, Asavapanumas N, Buadze M, Lourhmati A, Wendel HP, Avci-Adali M, Krueger MA, Calaminus C, Naumann U, Winter S, Schaeffeler E, Spogis A, Beer-Hammer S, Neher JJ, Spohn G, Kretschmer A, Krämer-Albers EM, Barth K, Lee HJ, Kim SU, Frey WH, Claussen CD, Hermann DM, Doeppner TR, Seifried E, Gleiter CH, Northoff H, Schäfer R. Cell motility and migration as determinants of stem cell efficacy. EBioMedicine 2020; 60:102989. [PMID: 32920368 PMCID: PMC7494685 DOI: 10.1016/j.ebiom.2020.102989] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 08/13/2020] [Accepted: 08/20/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Stem cells` (SC) functional heterogeneity and its poorly understood aetiology impedes clinical development of cell-based therapies in regenerative medicine and oncology. Recent studies suggest a strong correlation between the SC migration potential and their therapeutic efficacy in humans. Designating SC migration as a denominator of functional SC heterogeneity, we sought to identify highly migrating subpopulations within different SC classes and evaluate their therapeutic properties in comparison to the parental non-selected cells. METHODS We selected highly migrating subpopulations from mesenchymal and neural SC (sMSC and sNSC), characterized their features including but not limited to migratory potential, trophic factor release and transcriptomic signature. To assess lesion-targeted migration and therapeutic properties of isolated subpopulations in vivo, surgical transplantation and intranasal administration of MSCs in mouse models of glioblastoma and Alzheimer's disease respectively were performed. FINDINGS Comparison of parental non-selected cells with isolated subpopulations revealed superior motility and migratory potential of sMSC and sNSC in vitro. We identified podoplanin as a major regulator of migratory features of sMSC/sNSC. Podoplanin engineering improved oncovirolytic activity of virus-loaded NSC on distantly located glioblastoma cells. Finally, sMSC displayed more targeted migration to the tumour site in a mouse glioblastoma model and remarkably higher potency to reduce pathological hallmarks and memory deficits in transgenic Alzheimer's disease mice. INTERPRETATION Functional heterogeneity of SC is associated with their motility and migration potential which can serve as predictors of SC therapeutic efficacy. FUNDING This work was supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and by the IZEPHA grant.
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Affiliation(s)
- Lusine Danielyan
- Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany; Neuroscience Laboratory and Departments of Biochemistry and Clinical Pharmacology, Yerevan State Medical University, Yerevan, Armenia.
| | - Matthias Schwab
- Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany; Neuroscience Laboratory and Departments of Biochemistry and Clinical Pharmacology, Yerevan State Medical University, Yerevan, Armenia; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany; Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany
| | - Georg Siegel
- Institute of Clinical and Experimental Transfusion Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Bianca Brawek
- Institute of Physiology, Department of Neurophysiology, University of Tübingen, Tübingen, Germany
| | - Olga Garaschuk
- Institute of Physiology, Department of Neurophysiology, University of Tübingen, Tübingen, Germany
| | - Nithi Asavapanumas
- Institute of Physiology, Department of Neurophysiology, University of Tübingen, Tübingen, Germany
| | - Marine Buadze
- Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany
| | - Ali Lourhmati
- Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany
| | - Hans-Peter Wendel
- Department of Thoracic, Cardiac and Vascular Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Meltem Avci-Adali
- Department of Thoracic, Cardiac and Vascular Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Marcel A Krueger
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Tübingen, Germany
| | - Carsten Calaminus
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Tübingen, Germany
| | - Ulrike Naumann
- Hertie Institute for Clinical Brain Research and Center Neurology, Department of Vascular Neurology, Tübingen Neuro-Campus (TNC), University of Tübingen, Tübingen, Germany
| | - Stefan Winter
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tübingen, Tübingen, Germany
| | - Annett Spogis
- Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany
| | - Sandra Beer-Hammer
- Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomic, and ICePhA, University Hospital Tübingen, Tübingen, Germany
| | - Jonas J Neher
- Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Tübingen, Germany
| | - Gabriele Spohn
- Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Donor Service Baden-Württemberg-Hessen gGmbH, Goethe-University Hospital, Frankfurt am Main, Germany
| | - Anja Kretschmer
- Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Donor Service Baden-Württemberg-Hessen gGmbH, Goethe-University Hospital, Frankfurt am Main, Germany
| | - Eva-Maria Krämer-Albers
- Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Kerstin Barth
- Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Hong Jun Lee
- College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea; Research Institute eBiogen Inc., Seoul, Republic of Korea
| | - Seung U Kim
- Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, BC, Canada
| | - William H Frey
- HealthPartners Center for Memory and Aging, HealthPartners Neurosciences, St. Paul, MN, U.S.A
| | - Claus D Claussen
- Department of Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Dirk M Hermann
- Department of Neurology, University of Duisburg-Essen, Essen, Germany
| | - Thorsten R Doeppner
- Department of Neurology, University of Duisburg-Essen, Essen, Germany; Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Erhard Seifried
- Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Donor Service Baden-Württemberg-Hessen gGmbH, Goethe-University Hospital, Frankfurt am Main, Germany
| | - Christoph H Gleiter
- Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany
| | - Hinnak Northoff
- Institute of Clinical and Experimental Transfusion Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Richard Schäfer
- Institute of Clinical and Experimental Transfusion Medicine, University Hospital Tübingen, Tübingen, Germany; Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Donor Service Baden-Württemberg-Hessen gGmbH, Goethe-University Hospital, Frankfurt am Main, Germany.
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Sultan MT, Choi BY, Ajiteru O, Hong DK, Lee SM, Kim HJ, Ryu JS, Lee JS, Hong H, Lee YJ, Lee H, Suh YJ, Lee OJ, Kim SH, Suh SW, Park CH. Reinforced-hydrogel encapsulated hMSCs towards brain injury treatment by trans-septal approach. Biomaterials 2020; 266:120413. [PMID: 33038593 DOI: 10.1016/j.biomaterials.2020.120413] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/11/2020] [Accepted: 09/18/2020] [Indexed: 12/14/2022]
Abstract
Encapsulated stem cells in various biomaterials have become a potentially promising cell transplantation strategy in the treatment of various neurologic disorders. However, there is no ideal cell delivery material and method for clinical application in brain diseases. Here we show silk fibroin (SF)-based hydrogel encapsulated engineered human mesenchymal stem cells (hMSCs) to overproduce brain-derived neurotrophic factor (BDNF) (BDNF-hMSC) is an effective approach to treat brain injury through trans-septal cell transplantation in the rat model. In this study, we observed SF induced sustained BDNF production by BDNF-hMSC both in 2D (9.367 ± 1.969 ng/ml) and 3D (7.319 ± 0.1025 ng/ml) culture conditions for 3 days. Through immunohistochemistry using α-tubulin, BDNF-hMSCs showed a significant increased average neurite length of co-cultured neuro 2a (N2a) cells, suggested that BDNF-hMSCs induced neurogenesis in vitro. Encapsulated BDNF-hMSC, pre-labeled with the red fluorescent dye PKH-26, exhibited intense fluorescence up to 14 days trans-septal transplantation, indicated excellent viability of the transplanted cells. Compared to the vehicle-treated, encapsulated BDNF- hMSC demonstrated significantly increased BDNF level both in the sham-operated and injured hippocampus (Hip) through immunoblot analysis after 7 days implantation. Transplantation of the encapsulated BDNF-hMSC promoted neurological functional recovery via significantly reduced neuronal death in the Hip 7 days post-injury. Using magnetic resonance imaging (MRI) analysis, we demonstrated that encapsulated BDNF-hMSC reduced lesion area significantly at 14 and 21 days in the damaged brain following trans-septal implantation. This stem cell transplantation approach represents a critical set up towards brain injury treatment for clinical application.
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Affiliation(s)
- Md Tipu Sultan
- Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Bo Young Choi
- Department of Physiology, Hallym University College of Medicine, Chuncheon, 24252, Republic of Korea
| | - Olatunji Ajiteru
- Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Dae Ki Hong
- Department of Physiology, Hallym University College of Medicine, Chuncheon, 24252, Republic of Korea
| | - Soon Min Lee
- SL BiGen, Inc. SL BIGEN Research Hall, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea
| | - Hyo-Jin Kim
- SL BiGen, Inc. SL BIGEN Research Hall, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea
| | - Jun Sun Ryu
- Department of Otorhinolaryngology-Head and Neck Surgery, National Cancer Center, Goyang, 10408, Republic of Korea
| | - Ji Seung Lee
- Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Heesun Hong
- Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Young Jin Lee
- Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Hanna Lee
- Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Ye Ji Suh
- Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Ok Joo Lee
- Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Soon Hee Kim
- Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Sang Won Suh
- Department of Physiology, Hallym University College of Medicine, Chuncheon, 24252, Republic of Korea
| | - Chan Hum Park
- Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital, School of Medicine, Hallym University, Chuncheon, 24253, Republic of Korea.
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50
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Veronesi MC, Alhamami M, Miedema SB, Yun Y, Ruiz-Cardozo M, Vannier MW. Imaging of intranasal drug delivery to the brain. AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2020; 10:1-31. [PMID: 32211216 PMCID: PMC7076302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 02/07/2020] [Indexed: 06/10/2023]
Abstract
Intranasal (IN) delivery is a rapidly developing area for therapies with great potential for the treatment of central nervous system (CNS) diseases. Moreover, in vivo imaging is becoming an important part of therapy assessment, both clinically in humans and translationally in animals. IN drug delivery is an alternative to systemic administration that uses the direct anatomic pathway between the olfactory/trigeminal neuroepithelium of the nasal mucosa and the brain. Several drugs have already been approved for IN application, while others are undergoing development and testing. To better understand which imaging modalities are being used to assess IN delivery of therapeutics, we performed a literature search with the key words "Intranasal delivery" and "Imaging" and summarized these findings in the current review. While this review does not attempt to be fully comprehensive, we intend for the examples provided to allow a well-rounded picture of the imaging tools available to assess IN delivery, with an emphasis on the nose-to-brain delivery route. Examples of in vivo imaging, for both humans and animals, include magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), gamma scintigraphy and computed tomography (CT). Additionally, some in vivo optical imaging modalities, including bioluminescence and fluorescence, have been used more in experimental testing in animals. In this review, we introduce each imaging modality, how it is being utilized and outline its strengths and weaknesses, specifically in the context of IN delivery of therapeutics to the brain.
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Affiliation(s)
- Michael C Veronesi
- Department of Radiology & Imaging Sciences, Indiana University School of MedicineUSA
| | - Mosa Alhamami
- Department of Radiology & Imaging Sciences, Indiana University School of MedicineUSA
| | - Shelby B Miedema
- Department of Radiology & Imaging Sciences, Indiana University School of MedicineUSA
- Department of Biomedical Engineering, Indiana University-Purdue University IndianapolisUSA
| | - Yeonhee Yun
- Department of Radiology & Imaging Sciences, Indiana University School of MedicineUSA
| | - Miguel Ruiz-Cardozo
- Clinical Research Institute, Universidad Nacional de Colombia School of MedicineUSA
| | - Michael W Vannier
- Department of Radiology, University of Chicago School of MedicineUSA
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