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Sullivan MA, Lane SD, McKenzie ADJ, Ball SR, Sunde M, Neely GG, Moreno CL, Maximova A, Werry EL, Kassiou M. iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype. J Neuroinflammation 2024; 21:7. [PMID: 38178159 PMCID: PMC10765839 DOI: 10.1186/s12974-023-02951-2] [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: 11/11/2022] [Accepted: 11/07/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer's disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells. METHODS iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and Aβ42 and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently-labelled fibrillar Aβ42. RESULTS AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100β and increased secretion and phagocytosis of Aβ42 while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells showed exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia. CONCLUSION Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a 'primed' phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered Aβ42 production and phagocytosis.
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Affiliation(s)
- Michael A Sullivan
- School of Medical Sciences, The Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
| | - Samuel D Lane
- School of Medical Sciences, The Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
| | - André D J McKenzie
- School of Medical Sciences, The Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
| | - Sarah R Ball
- School of Medical Sciences, The Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
| | - Margaret Sunde
- School of Medical Sciences, The Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
| | - G Gregory Neely
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camperdown, Australia
| | - Cesar L Moreno
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camperdown, Australia
| | - Alexandra Maximova
- School of Medical Sciences, The Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
| | - Eryn L Werry
- School of Medical Sciences, The Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.
- School of Chemistry, The Faculty of Science, The University of Sydney, Camperdown, Australia.
- Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.
| | - Michael Kassiou
- School of Chemistry, The Faculty of Science, The University of Sydney, Camperdown, Australia.
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2
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Tu YH, Juan HF, Huang HC. Identification of cell states using super-enhancer RNA. BMC Genomics 2021; 22:787. [PMID: 34727867 PMCID: PMC8564956 DOI: 10.1186/s12864-021-08092-1] [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: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND A new class of regulatory elements called super-enhancers, comprised of multiple neighboring enhancers, have recently been reported to be the key transcriptional drivers of cellular, developmental, and disease states. RESULTS Here, we defined super-enhancer RNAs as highly expressed enhancer RNAs that are transcribed from a cluster of localized genomic regions. Using the cap analysis of gene expression sequencing data from FANTOM5, we systematically explored the enhancer and messenger RNA landscapes in hundreds of different cell types in response to various environments. Applying non-negative matrix factorization (NMF) to super-enhancer RNA profiles, we found that different cell types were well classified. In addition, through the NMF of individual time-course profiles from a single cell-type, super-enhancer RNAs were clustered into several states with progressive patterns. We further investigated the enriched biological functions of the proximal genes involved in each pattern, and found that they were associated with the corresponding developmental process. CONCLUSIONS The proposed super-enhancer RNAs can act as a good alternative, without the complicated measurement of histone modifications, for identifying important regulatory elements of cell type specification and identifying dynamic cell states.
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Affiliation(s)
- Yueh-Hua Tu
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, 106, Taiwan.,Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei, 115, Taiwan.,Institute of Biomedical Informatics, National Yang-Ming University, Taipei, 112, Taiwan
| | - Hsueh-Fen Juan
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, 106, Taiwan. .,Department of Life Science, Center for Computational and Systems Biology, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei, 106, Taiwan.
| | - Hsuan-Cheng Huang
- Institute of Biomedical Informatics, National Yang-Ming University, Taipei, 112, Taiwan. .,Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong Street, Taipei, 112, Taiwan.
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Yu JZ, Wang J, Sheridan SD, Perlis RH, Rasenick MM. N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells. Mol Psychiatry 2021; 26:4605-4615. [PMID: 32504049 PMCID: PMC10034857 DOI: 10.1038/s41380-020-0786-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 05/01/2020] [Accepted: 05/13/2020] [Indexed: 12/24/2022]
Abstract
Evidence from epidemiological and laboratory studies, as well as randomized placebo-controlled trials, suggests supplementation with n-3 polyunsaturated fatty acids (PUFAs) may be efficacious for treatment of major depressive disorder (MDD). The mechanisms underlying n-3 PUFAs potential therapeutic properties remain unknown. There are suggestions in the literature that glial hypofunction is associated with depressive symptoms and that antidepressants may normalize glial function. In this study, induced pluripotent stem cells (iPSC)-derived neuronal stem cell lines were generated from individuals with MDD. Astrocytes differentiated from patient-derived neuronal stem cells (iNSCs) were verified by GFAP. Cells were treated with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or stearic acid (SA). During astrocyte differentiation, we found that n-3 PUFAs increased GFAP expression and GFAP positive cell formation. BDNF and GDNF production were increased in the astrocytes derived from patients subsequent to n-3 PUFA treatment. Stearic Acid (SA) treatment did not have this effect. CREB activity (phosphorylated CREB) was also increased by DHA and EPA but not by SA. Furthermore, when these astrocytes were treated with n-3 PUFAs, the cAMP antagonist, RP-cAMPs did not block n-3 PUFA CREB activation. However, the CREB specific inhibitor (666-15) diminished BDNF and GDNF production induced by n-3 PUFA, suggesting CREB dependence. Together, these results suggested that n-3 PUFAs facilitate astrocyte differentiation, and may mimic effects of some antidepressants by increasing production of neurotrophic factors. The CREB-dependence and cAMP independence of this process suggests a manner in which n-3 PUFA could augment antidepressant effects. These data also suggest a role for astrocytes in both MDD and antidepressant action.
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Affiliation(s)
- Jiang-Zhou Yu
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA.
| | - Jennifer Wang
- Center for Experimental Drugs and Diagnostics and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Steven D Sheridan
- Center for Experimental Drugs and Diagnostics and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Roy H Perlis
- Center for Experimental Drugs and Diagnostics and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
- Division of Clinical Research, Massachusetts General Hospital, Boston, 02114, USA
| | - Mark M Rasenick
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA.
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, 60612, USA.
- Jesse Brown VA Medical Center, Chicago, IL, 60612, USA.
- Pax Neuroscience, Glenview, IL, 60025, USA.
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4
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Sax JL, Hubler Z, Allimuthu D, Adams DJ. Screening Reveals Sterol Derivatives with Pro-Differentiation, Pro-Survival, or Potent Cytotoxic Effects on Oligodendrocyte Progenitor Cells. ACS Chem Biol 2021; 16:1288-1297. [PMID: 34232635 DOI: 10.1021/acschembio.1c00461] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inducing the formation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs) represents a potential approach to repairing the loss of myelin observed in multiple sclerosis and other diseases. Recently, we demonstrated that accumulation of specific cholesterol precursors, 8,9-unsaturated sterols, is a dominant mechanism by which dozens of small molecules enhance oligodendrocyte formation. Here, we evaluated a library of 56 sterols and steroids to evaluate whether other classes of bioactive sterol derivatives may also influence mouse oligodendrocyte precursor cell (OPC) differentiation or survival. From this library, we identified U-73343 as a potent enhancer of oligodendrocyte formation that induces 8,9-unsaturated sterol accumulation by inhibition of the cholesterol biosynthesis enzyme sterol 14-reductase. In contrast, we found that mouse OPCs are remarkably vulnerable to treatment with the glycosterol OSW-1, an oxysterol-binding protein (OSBP) modulator that induces Golgi stress and OPC death in the low picomolar range. A subsequent small-molecule suppressor screen identified mTOR signaling as a key effector pathway mediating OSW-1's cytotoxic effects in mouse OPCs. Finally, evaluation of a panel of ER and Golgi stress-inducing small molecules revealed that mouse OPCs are highly sensitive to these perturbations, more so than closely related neural progenitor cells. Together, these studies highlight the wide-ranging influence of sterols and steroids on OPC cell fate, with 8,9-unsaturated sterols positively enhancing differentiation to oligodendrocytes and OSW-1 able to induce lethal Golgi stress with remarkable potency.
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Affiliation(s)
- Joel L. Sax
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States
| | - Zita Hubler
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States
| | - Dharmaraja Allimuthu
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States
| | - Drew J. Adams
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States
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5
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Direct and selective lineage conversion of human fibroblasts to dopaminergic precursors. Neurosci Lett 2019; 699:16-23. [PMID: 30664902 DOI: 10.1016/j.neulet.2019.01.033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 01/16/2019] [Accepted: 01/17/2019] [Indexed: 01/23/2023]
Abstract
Transplantation of dopaminergic precursors (DPs) is a promising therapeutic strategy of Parkinson's disease (PD). However, limited cell source for dopaminergic precursors has become a major obstacle for transplantation therapy. Our group demonstrated previously that mouse fibroblasts can be reprogrammed into induced dopaminergic precursors (iDPs) with high differentiation efficiency. In the current study, we hypothesized that a similar strategy can be applied to generate human iDPs for future cell therapy of PD. We overexpressed transcription factors Brn2, Sox2, and Foxa2 in human fibroblasts and observed formation of neurospheres. Subsequent characterization of the precursor colonies confirmed the generation of human induced dopaminergic precursors (hiDPs). These hiDPs were capable of self-renewal, proliferation, and differentiation. The hiDPs demonstrated high immunoreactivity for neural progenitor markers and high levels of gene expression for ventral mesencephalon-related neural progenitor markers such as Lmx1a, NIKX6.1, Corin, Otx2 and Mash1. Furthermore, the hiDPs could be differentiated into dopaminergic neurons with ˜80% efficiency, which significantly increased major functionally relevant proteins such as TH, DAT, AADC, Lmx1B, and VMAT2 compared to hiDPs. Additionally, hiDPs are more dopaminergic progenitor-restricted compare to those hiDP-like cells reprogrammed only by Brn2 and Sox2. Together, these results suggest that hiDPs with high differentiation efficiency can be generated by direct lineage reprogramming of fibroblasts with transcription factors Brn2, Sox2, and Foxa2. These hiDPs may serve as a safe and effective cell source for transplantation treatment of PD.
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6
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Guo W, Fumagalli L, Prior R, Van Den Bosch L. Current Advances and Limitations in Modeling ALS/FTD in a Dish Using Induced Pluripotent Stem Cells. Front Neurosci 2017; 11:671. [PMID: 29326542 PMCID: PMC5733489 DOI: 10.3389/fnins.2017.00671] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/20/2017] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two age-dependent multifactorial neurodegenerative disorders, which are typically characterized by the selective death of motor neurons and cerebral cortex neurons, respectively. These two diseases share many clinical, genetic and pathological aspects. During the past decade, cell reprogramming technologies enabled researchers to generate human induced pluripotent stem cells (iPSCs) from somatic cells. This resulted in the unique opportunity to obtain specific neuronal and non-neuronal cell types from patients which could be used for basic research. Moreover, these in vitro models can mimic not only the familial forms of ALS/FTD, but also sporadic cases without known genetic cause. At present, there have been extensive technical advances in the generation of iPSCs, as well as in the differentiation procedures to obtain iPSC-derived motor neurons, cortical neurons and non-neuronal cells. The major challenge at this moment is to determine whether these iPSC-derived cells show relevant phenotypes that recapitulate complex diseases. In this review, we will summarize the work related to iPSC models of ALS and FTD. In addition, we will discuss potential drawbacks and solutions for establishing more trustworthy iPSC models for both ALS and FTD.
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Affiliation(s)
- Wenting Guo
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
| | - Laura Fumagalli
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
| | - Robert Prior
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
| | - Ludo Van Den Bosch
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
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7
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Playne R, Connor B. Understanding Parkinson's Disease through the Use of Cell Reprogramming. Stem Cell Rev Rep 2017; 13:151-169. [PMID: 28083784 DOI: 10.1007/s12015-017-9717-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Recent progress in the field of somatic cell reprogramming offers exciting new possibilities for the study and treatment of Parkinson's disease (PD). Reprogramming technology offers the ability to untangle the diverse contributing risk factors for PD, such as ageing, genetics and environmental toxins. In order to gain novel insights into such a complex disease, cell-based models of PD should represent, as closely as possible, aged human dopaminergic neurons of the substantia nigra. However, the generation of high yields of functionally mature, authentic ventral midbrain dopamine (vmDA) neurons has not been easy to achieve. Furthermore, ensuring cells represent aged rather than embryonic neurons has presented a significant challenge. To date, induced pluripotent stem (iPS) cells have received much attention for modelling PD. Nonetheless, direct reprogramming strategies (either to a neuronal or neural stem/progenitor fate) represent a valid alternative that are yet to be extensively explored. Direct reprogramming is faster and more efficient than iPS cell reprogramming, and appears to conserve age-related markers. At present, however, protocols aiming to derive authentic, mature vmDA neurons by direct reprogramming of adult human somatic cells are sorely lacking. This review will discuss the strategies that have been employed to generate vmDA neurons and their potential for the study and treatment of PD.
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Affiliation(s)
- Rebecca Playne
- Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, FMHS, University of Auckland, Auckland, 1023, New Zealand
| | - Bronwen Connor
- Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, FMHS, University of Auckland, Auckland, 1023, New Zealand.
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8
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Smith DK, He M, Zhang CL, Zheng JC. The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders. Prog Neurobiol 2017; 157:212-229. [PMID: 26844759 PMCID: PMC5848468 DOI: 10.1016/j.pneurobio.2016.01.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 11/25/2015] [Accepted: 01/04/2016] [Indexed: 12/12/2022]
Abstract
Neural cell identity reprogramming strategies aim to treat age-related neurodegenerative disorders with newly induced neurons that regenerate neural architecture and functional circuits in vivo. The isolation and neural differentiation of pluripotent embryonic stem cells provided the first in vitro models of human neurodegenerative disease. Investigation into the molecular mechanisms underlying stem cell pluripotency revealed that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs) and these cells could be used to model Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Additional neural precursor and direct transdifferentiation strategies further enabled the induction of diverse neural linages and neuron subtypes both in vitro and in vivo. In this review, we highlight neural induction strategies that utilize stem cells, iPSCs, and lineage reprogramming to model or treat age-related neurodegenerative diseases, as well as, the clinical challenges related to neural transplantation and in vivo reprogramming strategies.
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Affiliation(s)
- Derek K Smith
- Department of Molecular Biology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA
| | - Miao He
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Physical Therapy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chun-Li Zhang
- Department of Molecular Biology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
| | - Jialin C Zheng
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Family Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; Center for Translational Neurodegeneration and Regenerative Therapy, the Collaborative Innovation Center for Brain Science, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.
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9
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Renal epithelial miR-205 expression correlates with disease severity in a mouse model of congenital obstructive nephropathy. Pediatr Res 2016; 80:602-9. [PMID: 27384406 PMCID: PMC5506548 DOI: 10.1038/pr.2016.121] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 04/07/2016] [Indexed: 11/08/2022]
Abstract
BACKGROUND Congenital obstructive nephropathy (CON) is a leading cause of pediatric chronic kidney disease (CKD). Despite optimal surgical and medical care, there is a high rate of CKD progression. Better understanding of molecular and cellular changes is needed to facilitate development of improved biomarkers and novel therapeutic approaches in CON. METHODS The megabladder (mgb) mouse is an animal model of CKD with impaired bladder emptying, hydronephrosis, and progressive renal injury. In this study, we characterize a particular microRNA, miR-205, whose expression changes with the degree of hydronephrosis in the mgb(-/-) kidney. RESULTS Expression of miR-205 is progressively increased in the adult mgb(-/-) mouse with worsening severity of hydronephrosis. miR-205 expression is correlated with altered expression of cytokeratins and uroplakins, which are markers of cellular differentiation in urothelium. We describe the spatial pattern of miR-205 expression, including increased expression in renal urothelium and novel miR-205 expression in medullary collecting duct epithelium in the congenitally obstructed kidney. CONCLUSION miR-205 is increased with severity of CON and CKD in the mgb(-/-) mouse and may regulate urothelial differentiation.
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10
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Lardenoije R, Iatrou A, Kenis G, Kompotis K, Steinbusch HWM, Mastroeni D, Coleman P, Lemere CA, Hof PR, van den Hove DLA, Rutten BPF. The epigenetics of aging and neurodegeneration. Prog Neurobiol 2015; 131:21-64. [PMID: 26072273 PMCID: PMC6477921 DOI: 10.1016/j.pneurobio.2015.05.002] [Citation(s) in RCA: 246] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 05/13/2015] [Accepted: 05/13/2015] [Indexed: 12/14/2022]
Abstract
Epigenetics is a quickly growing field encompassing mechanisms regulating gene expression that do not involve changes in the genotype. Epigenetics is of increasing relevance to neuroscience, with epigenetic mechanisms being implicated in brain development and neuronal differentiation, as well as in more dynamic processes related to cognition. Epigenetic regulation covers multiple levels of gene expression; from direct modifications of the DNA and histone tails, regulating the level of transcription, to interactions with messenger RNAs, regulating the level of translation. Importantly, epigenetic dysregulation currently garners much attention as a pivotal player in aging and age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, where it may mediate interactions between genetic and environmental risk factors, or directly interact with disease-specific pathological factors. We review current knowledge about the major epigenetic mechanisms, including DNA methylation and DNA demethylation, chromatin remodeling and non-coding RNAs, as well as the involvement of these mechanisms in normal aging and in the pathophysiology of the most common neurodegenerative diseases. Additionally, we examine the current state of epigenetics-based therapeutic strategies for these diseases, which either aim to restore the epigenetic homeostasis or skew it to a favorable direction to counter disease pathology. Finally, methodological challenges of epigenetic investigations and future perspectives are discussed.
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Affiliation(s)
- Roy Lardenoije
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands
| | - Artemis Iatrou
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands
| | - Gunter Kenis
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands
| | - Konstantinos Kompotis
- Center for Integrative Genomics, University of Lausanne, Genopode Building, 1015 Lausanne-Dorigny, Switzerland
| | - Harry W M Steinbusch
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands
| | - Diego Mastroeni
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands; L.J. Roberts Alzheimer's Disease Center, Banner Sun Health Research Institute, 10515 W. Santa Fe Drive, Sun City, AZ 85351, USA
| | - Paul Coleman
- L.J. Roberts Alzheimer's Disease Center, Banner Sun Health Research Institute, 10515 W. Santa Fe Drive, Sun City, AZ 85351, USA
| | - Cynthia A Lemere
- Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Patrick R Hof
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Daniel L A van den Hove
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands; Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstrasse 15, 97080 Wuerzburg, Germany
| | - Bart P F Rutten
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands.
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11
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Bradford AB, McNutt PM. Importance of being Nernst: Synaptic activity and functional relevance in stem cell-derived neurons. World J Stem Cells 2015; 7:899-921. [PMID: 26240679 PMCID: PMC4515435 DOI: 10.4252/wjsc.v7.i6.899] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 02/28/2015] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
Functional synaptogenesis and network emergence are signature endpoints of neurogenesis. These behaviors provide higher-order confirmation that biochemical and cellular processes necessary for neurotransmitter release, post-synaptic detection and network propagation of neuronal activity have been properly expressed and coordinated among cells. The development of synaptic neurotransmission can therefore be considered a defining property of neurons. Although dissociated primary neuron cultures readily form functioning synapses and network behaviors in vitro, continuously cultured neurogenic cell lines have historically failed to meet these criteria. Therefore, in vitro-derived neuron models that develop synaptic transmission are critically needed for a wide array of studies, including molecular neuroscience, developmental neurogenesis, disease research and neurotoxicology. Over the last decade, neurons derived from various stem cell lines have shown varying ability to develop into functionally mature neurons. In this review, we will discuss the neurogenic potential of various stem cells populations, addressing strengths and weaknesses of each, with particular attention to the emergence of functional behaviors. We will propose methods to functionally characterize new stem cell-derived neuron (SCN) platforms to improve their reliability as physiological relevant models. Finally, we will review how synaptically active SCNs can be applied to accelerate research in a variety of areas. Ultimately, emphasizing the critical importance of synaptic activity and network responses as a marker of neuronal maturation is anticipated to result in in vitro findings that better translate to efficacious clinical treatments.
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12
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Lai S, Zhang M, Xu D, Zhang Y, Qiu L, Tian C, Zheng JC. Direct reprogramming of induced neural progenitors: a new promising strategy for AD treatment. Transl Neurodegener 2015; 4:7. [PMID: 25949812 PMCID: PMC4422611 DOI: 10.1186/s40035-015-0028-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Accepted: 04/03/2015] [Indexed: 12/23/2022] Open
Abstract
Alzheimer's disease (AD) is a prominent form of dementia, characterized by aggregation of the amyloid β-peptide (Aβ) plaques and neurofibrillary tangles, loss of synapses and neurons, and degeneration of cognitive functions. Currently, although a variety of medications can relieve some of the symptoms, there is no cure for AD. Recent breakthroughs in the stem cell field provide promising strategies for AD treatment. Stem cells including embryonic stem cells (ESCs), neural stem cells (NSCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs) are potentials for AD treatment. However, the limitation of cell sources, safety issues, and ethical issues restrict their applications in AD. Recently, the direct reprogramming of induced neural progenitor cells (iNPCs) has shed light on the treatment of AD. In this review, we will discuss the latest progress, challenges, and potential applications of direct reprogramming in AD treatment.
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Affiliation(s)
- Siqiang Lai
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
| | - Min Zhang
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
| | - Dongsheng Xu
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
- />University of Nebraska Medical Center, Omaha, NE 68198-5930 USA
| | - Yiying Zhang
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
| | - Lisha Qiu
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
| | - Changhai Tian
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
- />University of Nebraska Medical Center, Omaha, NE 68198-5930 USA
| | - Jialin Charlie Zheng
- />Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, 200072 China
- />University of Nebraska Medical Center, Omaha, NE 68198-5930 USA
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13
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Fitzsimons CP, van Bodegraven E, Schouten M, Lardenoije R, Kompotis K, Kenis G, van den Hurk M, Boks MP, Biojone C, Joca S, Steinbusch HWM, Lunnon K, Mastroeni DF, Mill J, Lucassen PJ, Coleman PD, van den Hove DLA, Rutten BPF. Epigenetic regulation of adult neural stem cells: implications for Alzheimer's disease. Mol Neurodegener 2014; 9:25. [PMID: 24964731 PMCID: PMC4080757 DOI: 10.1186/1750-1326-9-25] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2014] [Accepted: 06/06/2014] [Indexed: 01/27/2023] Open
Abstract
Experimental evidence has demonstrated that several aspects of adult neural stem cells (NSCs), including their quiescence, proliferation, fate specification and differentiation, are regulated by epigenetic mechanisms. These control the expression of specific sets of genes, often including those encoding for small non-coding RNAs, indicating a complex interplay between various epigenetic factors and cellular functions.Previous studies had indicated that in addition to the neuropathology in Alzheimer's disease (AD), plasticity-related changes are observed in brain areas with ongoing neurogenesis, like the hippocampus and subventricular zone. Given the role of stem cells e.g. in hippocampal functions like cognition, and given their potential for brain repair, we here review the epigenetic mechanisms relevant for NSCs and AD etiology. Understanding the molecular mechanisms involved in the epigenetic regulation of adult NSCs will advance our knowledge on the role of adult neurogenesis in degeneration and possibly regeneration in the AD brain.
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Affiliation(s)
- Carlos P Fitzsimons
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH Amsterdam, The Netherlands
| | - Emma van Bodegraven
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH Amsterdam, The Netherlands
| | - Marijn Schouten
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH Amsterdam, The Netherlands
| | - Roy Lardenoije
- Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, the Netherlands
| | - Konstantinos Kompotis
- Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, the Netherlands
| | - Gunter Kenis
- Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, the Netherlands
| | - Mark van den Hurk
- Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, the Netherlands
| | - Marco P Boks
- Department Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Caroline Biojone
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Samia Joca
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Harry WM Steinbusch
- Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, the Netherlands
| | - Katie Lunnon
- University of Exeter Medical School, RILD Level 4, Barrack Road, University of Exeter, Devon, UK
| | - Diego F Mastroeni
- University of Exeter Medical School, RILD Level 4, Barrack Road, University of Exeter, Devon, UK
| | - Jonathan Mill
- University of Exeter Medical School, RILD Level 4, Barrack Road, University of Exeter, Devon, UK
| | - Paul J Lucassen
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH Amsterdam, The Netherlands
| | - Paul D Coleman
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH Amsterdam, The Netherlands
| | - Daniel LA van den Hove
- Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, the Netherlands
| | - Bart PF Rutten
- Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, the Netherlands
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, P.O. Box 616, 6200 MD Maastricht, The Netherlands
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