scholarly journals Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons

2021 ◽  
Author(s):  
Jason P. Chua ◽  
Karan Bedi ◽  
Michelle T. Paulsen ◽  
Mats Ljungman ◽  
Elizabeth M.H. Tank ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Live Cells ◽  
Nascent Transcript ◽  
Critical Determinant ◽  
Autophagy Induction ◽  
A Cell ◽  
Lysosome Degradation ◽  
Induced Pluripotent

Autophagy is a conserved, multi-step process of capturing proteolytic cargo in autophagosomes for lysosome degradation. The capacity to remove toxic proteins that accumulate in neurodegenerative disorders attests to the disease-modifying potential of the autophagy pathway. However, neurons respond only marginally to conventional methods for inducing autophagy, limiting efforts to develop therapeutic autophagy modulators for neurodegenerative diseases. The determinants underlying poor autophagy induction in neurons and the degree to which neurons and other cell types are differentially sensitive to autophagy stimuli are incompletely defined. Accordingly, we sampled nascent transcript synthesis and stabilities in fibroblasts, induced pluripotent stem cells (iPSCs) and iPSC-derived neurons (iNeurons), thereby uncovering a neuron-specific stability of transcripts encoding myotubularin-related phosphatase 5 (MTMR5). MTMR5 is an autophagy suppressor that acts with its binding partner, MTMR2, to dephosphorylate phosphoinositides critical for autophagy initiation and autophagosome maturation. We found that MTMR5 is necessary and sufficient to suppress autophagy in iNeurons and undifferentiated iPSCs. Using optical pulse labeling to visualize the turnover of endogenously-encoded proteins in live cells, we observed that knockdown of MTMR5 or MTMR2, but not MTMR9, significantly enhances neuronal degradation of TDP-43, an autophagy substrate implicated in several neurodegenerative diseases. Accordingly, our findings establish a regulatory mechanism of autophagy intrinsic to neurons and targetable for clearing disease-related proteins in a cell type-specific manner. In so doing, our results not only unravel novel aspects of neuronal biology and proteostasis, but also elucidate a strategy for modulating neuronal autophagy that could be of high therapeutic potential for multiple neurodegenerative diseases.

scholarly journals Utilising Induced Pluripotent Stem Cells in Neurodegenerative Disease Research: Focus on Glia

2021 ◽  
Vol 22 (9) ◽  
pp. 4334
Author(s):  
Katrina Albert ◽  
Jonna Niskanen ◽  
Sara Kälvälä ◽  
Šárka Lehtonen
Keyword(s):  
Stem Cells ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Induced Pluripotent Stem Cells ◽  
Glial Cells ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Human Ipscs ◽  
Induced Pluripotent

Induced pluripotent stem cells (iPSCs) are a self-renewable pool of cells derived from an organism’s somatic cells. These can then be programmed to other cell types, including neurons. Use of iPSCs in research has been two-fold as they have been used for human disease modelling as well as for the possibility to generate new therapies. Particularly in complex human diseases, such as neurodegenerative diseases, iPSCs can give advantages over traditional animal models in that they more accurately represent the human genome. Additionally, patient-derived cells can be modified using gene editing technology and further transplanted to the brain. Glial cells have recently become important avenues of research in the field of neurodegenerative diseases, for example, in Alzheimer’s disease and Parkinson’s disease. This review focuses on using glial cells (astrocytes, microglia, and oligodendrocytes) derived from human iPSCs in order to give a better understanding of how these cells contribute to neurodegenerative disease pathology. Using glia iPSCs in in vitro cell culture, cerebral organoids, and intracranial transplantation may give us future insight into both more accurate models and disease-modifying therapies.

scholarly journals Defining stem cell types: understanding the therapeutic potential of ESCs, ASCs, and iPS cells

2012 ◽  
Vol 49 (2) ◽  
pp. R89-R111 ◽  
Author(s):  
Clara V Alvarez ◽  
Montserrat Garcia-Lavandeira ◽  
Maria E R Garcia-Rendueles ◽  
Esther Diaz-Rodriguez ◽  
Angela R Garcia-Rendueles ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Main Property ◽  
Cell Types ◽  
Functional Behavior ◽  
Dna Alterations ◽  
Human Therapy ◽  
Induced Pluripotent ◽  
Models Of Disease

Embryonic, adult, artificially reprogrammed, and cancer…– there are various types of cells associated with stemness. Do they have something fundamental in common? Are we applying a common name to very different entities? In this review, we will revisit the characteristics that define ‘pluripotency’, the main property of stem cells (SCs). For each main type of physiological (embryonic and adult) or synthetic (induced pluripotent) SCs, markers and functional behavior in vitro and in vivo will be described. We will review the pioneering work that has led to obtaining human SC lines, together with the problems that have arisen, both in a biological context (DNA alterations, heterogeneity, tumors, and immunogenicity) and with regard to ethical concerns. Such problems have led to proposals for new operative procedures for growing human SCs of sufficiently high quality for use as models of disease and in human therapy. Finally, we will review the data from the first clinical trials to use various types of SCs.

scholarly journals An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

2020 ◽  
Author(s):  
Jerome Robert ◽  
Nicholas Weilinger ◽  
Li-Ping Zao ◽  
Stefano Cataldi ◽  
Emily Button ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Cortical Neurons ◽  
Neurovascular Unit ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Experimental Models ◽  
Flow Conditions ◽  
Anatomy And Physiology ◽  
Induced Pluripotent

Abstract Introduction: The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently noin vitro3-dimensional (3D) perfusible model of the human cortical arterial NVU. Method: We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries. Results: This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It also reproduces key characteristics of cortical neurons and astrocytes, as well as the formation of a selective and functional endothelial barrier. We further provide proof-of-principle that our in vitro human arterial NVU may be suitable to study neurodegenerative diseases such as Alzheimer’s disease (AD), as we report both phosphorylated tau and beta-amyloid accumulation in our model over time. Finally, we show that our arterial NVU model enables the study of neuronal and glial fluid biomarkers. Conclusion: This model is a suitable tool to investigate arterial NVU functions such as neuronal electrophysiology in health and disease. Further the design of platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.

scholarly journals An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

2020 ◽  
Author(s):  
Jerome Robert ◽  
Nicholas Weilinger ◽  
Li-Ping Zao ◽  
Stefano Cataldi ◽  
Emily Button ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Cortical Neurons ◽  
Neurovascular Unit ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Experimental Models ◽  
Flow Conditions ◽  
Anatomy And Physiology ◽  
Induced Pluripotent

Abstract Introduction: The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU.Method: We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries.Results: This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer’s disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model.Conclusion: This model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.

scholarly journals Advances in Stem Cell Technologies for Disease Therapy: A Current Review

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Nadiya Patel
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Ethical Issues ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Cell Types ◽  
Current Review ◽  
Disease Therapy ◽  
Induced Pluripotent ◽  
A Current

Stem cells have the capability of differentiating into limitless cell types, alongside the function of exceptional proliferative capacity. There are three main types of stem cells: embryonic stem cells (ESCs), induced pluripotent stem cells (IPSCs) and mesenchymal stem cells (MSCs). ESCs are highly versatile and hold great therapeutic potential but have great ethical barriers and considerations that are yet to be overcome. IPSCs have become increasingly popular within research as they are not restrained by any ethical issues and do not require approval for their usage. The aim of this review was to expand on the background and therapeutic potential of ESCs and IPSCs whilst linking this to their use within disease therapy with a specific focus on ethics, tumorigenesis and survivability. The analysis found some conflicting results and a delay in the advance of overcoming the problems of tumorigenesis and survivability of stem cells. Both stem cells types have shown good efficacy but do also come with their disadvantages.

scholarly journals Elevated 4R-tau in Astrocytes From Asymptomatic Carriers of the MAPT 10+16 Mutation

2020 ◽  
Author(s):  
Nuria Seto-Salvia ◽  
Noemi Esteras ◽  
Rohan de Silva ◽  
Eduardo de Pablo-Fernandez ◽  
Charles Arber ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Potential Role ◽  
Cell Types ◽  
Protein Levels ◽  
Intronic Mutation ◽  
A Cell ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Induced Pluripotent ◽  
Pathogenic Process

Abstract The MAPT 10+16 intronic mutation causes frontotemporal lobar degeneration (FTLD) by increasing expression of four-repeat (4R)-tau isoforms. We investigated the potential role for astrocytes in the pathogenesis of FTLD by studying the expression of 4R-tau. We derived astrocytes and neurons from induced pluripotent stem cells from two asymptomatic 10+16 carriers and, compared to controls, showed persistently increased 4R:3R-tau transcript and protein ratios in both cell types. However, beyond 300 days culture, 10+16 neurons showed less marked increase of this 4R:3R-tau transcript ratio compared to astrocytes. Interestingly, throughout maturation, both 10+16 carriers consistently displayed different 4R:3R-tau ratios at transcript and protein levels. Our study shows elevated levels of 4R-tau in astrocytes implicating glial cells in the pathogenic process and also suggests a cell-type-specific regulation and may inform and help on treatment of preclinical tauopathies.

scholarly journals An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Jerome Robert ◽  
Nicholas L. Weilinger ◽  
Li-Ping Cao ◽  
Stefano Cataldi ◽  
Emily B. Button ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Cortical Neurons ◽  
Neurovascular Unit ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Experimental Models ◽  
Flow Conditions ◽  
Anatomy And Physiology ◽  
Induced Pluripotent

Abstract Introduction The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU. Method We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries. Results This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer’s disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model. Conclusion This model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.

scholarly journals iPSC Therapy for Myocardial Infarction in Large Animal Models: Land of Hope and Dreams

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1836
Author(s):  
Daina Martínez-Falguera ◽  
Oriol Iborra-Egea ◽  
Carolina Gálvez-Montón
Keyword(s):  
Myocardial Infarction ◽  
Animal Models ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Large Animal ◽  
Technical Application ◽  
In Vivo Models ◽  
Large Animal Models ◽  
Induced Pluripotent

Myocardial infarction is the main driver of heart failure due to ischemia and subsequent cell death, and cell-based strategies have emerged as promising therapeutic methods to replace dead tissue in cardiovascular diseases. Research in this field has been dramatically advanced by the development of laboratory-induced pluripotent stem cells (iPSCs) that harbor the capability to become any cell type. Like other experimental strategies, stem cell therapy must meet multiple requirements before reaching the clinical trial phase, and in vivo models are indispensable for ensuring the safety of such novel therapies. Specifically, translational studies in large animal models are necessary to fully evaluate the therapeutic potential of this approach; to empirically determine the optimal combination of cell types, supplementary factors, and delivery methods to maximize efficacy; and to stringently assess safety. In the present review, we summarize the main strategies employed to generate iPSCs and differentiate them into cardiomyocytes in large animal species; the most critical differences between using small versus large animal models for cardiovascular studies; and the strategies that have been pursued regarding implanted cells’ stage of differentiation, origin, and technical application.

scholarly journals Nondestructive nanostraw intracellular sampling for longitudinal cell monitoring

2017 ◽  
Vol 114 (10) ◽  
pp. E1866-E1874 ◽  
Author(s):  
Yuhong Cao ◽  
Martin Hjort ◽  
Haodong Chen ◽  
Fikri Birey ◽  
Sergio A. Leal-Ortiz ◽  
...  
Keyword(s):  
Cell Types ◽  
Cell Extract ◽  
Cell Contact ◽  
Time Resolved ◽  
Induced Pluripotency ◽  
Native Cell ◽  
Dynamic Cell ◽  
Cell Monitoring ◽  
A Cell ◽  
Induced Pluripotent

Here, we report a method for time-resolved, longitudinal extraction and quantitative measurement of intracellular proteins and mRNA from a variety of cell types. Cytosolic contents were repeatedly sampled from the same cell or population of cells for more than 5 d through a cell-culture substrate, incorporating hollow 150-nm-diameter nanostraws (NS) within a defined sampling region. Once extracted, the cellular contents were analyzed with conventional methods, including fluorescence, enzymatic assays (ELISA), and quantitative real-time PCR. This process was nondestructive with >95% cell viability after sampling, enabling long-term analysis. It is important to note that the measured quantities from the cell extract were found to constitute a statistically significant representation of the actual contents within the cells. Of 48 mRNA sequences analyzed from a population of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs), 41 were accurately quantified. The NS platform samples from a select subpopulation of cells within a larger culture, allowing native cell-to-cell contact and communication even during vigorous activity such as cardiomyocyte beating. This platform was applied both to cell lines and to primary cells, including CHO cells, hiPSC-CMs, and human astrocytes derived in 3D cortical spheroids. By tracking the same cell or group of cells over time, this method offers an avenue to understand dynamic cell behavior, including processes such as induced pluripotency and differentiation.

scholarly journals Phosphoinositide 3 Kinase Signaling in Human Stem Cells from Reprogramming to Differentiation: A Tale in Cytoplasmic and Nuclear Compartments

2019 ◽  
Vol 20 (8) ◽  
pp. 2026 ◽  
Author(s):  
Ramazzotti ◽  
Ratti ◽  
Fiume ◽  
Yung Follo ◽  
Billi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Therapeutic Potential ◽  
Induced Pluripotent Stem Cell ◽  
Cellular Transformation ◽  
Cell Types ◽  
Human Stem Cells ◽  
Mesenchymal Differentiation ◽  
Induced Pluripotent ◽  
Phosphoinositide 3 Kinase

Stem cells are undifferentiated cells that can give rise to several different cell types and can self-renew. Given their ability to differentiate into different lineages, stem cells retain huge therapeutic potential for regenerative medicine. Therefore, the understanding of the signaling pathways involved in stem cell pluripotency maintenance and differentiation has a paramount importance in order to understand these biological processes and to develop therapeutic strategies. In this review, we focus on phosphoinositide 3 kinase (PI3K) since its signaling pathway regulates many cellular processes, such as cell growth, proliferation, survival, and cellular transformation. Precisely, in human stem cells, the PI3K cascade is involved in different processes from pluripotency and induced pluripotent stem cell (iPSC) reprogramming to mesenchymal and oral mesenchymal differentiation, through different and interconnected mechanisms.

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