scholarly journals Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation

2020 ◽  
Vol 6 (46) ◽  
pp. eabc1428
Author(s):  
A. Nakano-Kobayashi ◽  
A. Fukumoto ◽  
A. Morizane ◽  
D. T. Nguyen ◽  
T. M. Le ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Neuronal Survival ◽  
Disease Model ◽  
Neuronal Loss ◽  
Induced Pluripotent Stem Cell ◽  
Related Factor ◽  
Induced Pluripotent ◽  
Novel Therapeutic

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced Parkinson’s disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell–derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

scholarly journals ACVR1R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages

Bone ◽  
2021 ◽  
pp. 116129
Author(s):  
Koji Matsuo ◽  
Abigail Lepinski ◽  
Robert D. Chavez ◽  
Emilie Barruet ◽  
Ashley Pereira ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Inflammatory Responses ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Correction to: Current and future applications of induced pluripotent stem cell-based models to study pathological proteins in neurodegenerative disorders

2021 ◽  
Author(s):  
Aurélie de Rus Jacquet ◽  
Hélèna L. Denis ◽  
Francesca Cicchetti ◽  
Melanie Alpaugh
Keyword(s):  
Stem Cell ◽  
Neurodegenerative Disorders ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

A Correction to this paper has been published: https://doi.org/10.1038/s41380-021-01055-8

scholarly journals GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Alondra Schweizer Burguete ◽  
Sandra Almeida ◽  
Fen-Biao Gao ◽  
Robert Kalb ◽  
Michael R Akins ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Fragile X ◽  
Disease Model ◽  
Induced Pluripotent Stem Cell ◽  
Spinal Cord Neurons ◽  
Human Orthologs ◽  
Dendritic Branching ◽  
Mental Retardation Protein ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Microsatellite expansions are the leading cause of numerous neurodegenerative disorders. Here we demonstrate that GGGGCC and CAG microsatellite repeat RNAs associated with C9orf72 in amyotrophic lateral sclerosis/frontotemporal dementia and with polyglutamine diseases, respectively, localize to neuritic granules that undergo active transport into distal neuritic segments. In cultured mammalian spinal cord neurons, the presence of neuritic GGGGCC repeat RNA correlates with neuronal branching defects, and the repeat RNA localizes to granules that label with fragile X mental retardation protein (FMRP), a transport granule component. Using a Drosophila GGGGCC expansion disease model, we characterize dendritic branching defects that are modulated by FMRP and Orb2. The human orthologs of these modifiers are misregulated in induced pluripotent stem cell-differentiated neurons (iPSNs) from GGGGCC expansion carriers. These data suggest that expanded repeat RNAs interact with the messenger RNA transport and translation machinery, causing transport granule dysfunction. This could be a novel mechanism contributing to the neuronal defects associated with C9orf72 and other microsatellite expansion diseases.

scholarly journals “Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

2020 ◽  
Vol 21 (19) ◽  
pp. 6997 ◽  
Author(s):  
Davide Rovina ◽  
Elisa Castiglioni ◽  
Francesco Niro ◽  
Sara Mallia ◽  
Giulio Pompilio ◽  
...  
Keyword(s):  
Stem Cell ◽  
Muscular Dystrophy ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Disease Model ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Great Promise ◽  
Cord Injury ◽  
Induced Pluripotent

The ultimate goal of precision disease modeling is to artificially recreate the disease of affected people in a highly controllable and adaptable external environment. This field has rapidly advanced which is evident from the application of patient-specific pluripotent stem-cell-derived precision therapies in numerous clinical trials aimed at a diverse set of diseases such as macular degeneration, heart disease, spinal cord injury, graft-versus-host disease, and muscular dystrophy. Despite the existence of semi-adequate treatments for tempering skeletal muscle degeneration in dystrophic patients, nonischemic cardiomyopathy remains one of the primary causes of death. Therefore, cardiovascular cells derived from muscular dystrophy patients’ induced pluripotent stem cells are well suited to mimic dystrophin-associated cardiomyopathy and hold great promise for the development of future fully effective therapies. The purpose of this article is to convey the realities of employing precision disease models of dystrophin-associated cardiomyopathy. This is achieved by discussing, as suggested in the title echoing William Shakespeare’s words, the settlements (or “leagues”) made by researchers to manage the constraints (“betwixt mine eye and heart”) distancing them from achieving a perfect precision disease model.

scholarly journals ML277 regulates KCNQ1 single-channel amplitudes and kinetics, modified by voltage sensor state

2021 ◽  
Vol 153 (12) ◽  
Author(s):  
Jodene Eldstrom ◽  
Donald A. McAfee ◽  
Ying Dou ◽  
Yundi Wang ◽  
David Fedida
Keyword(s):  
Single Channel ◽  
Therapeutic Potential ◽  
Induced Pluripotent Stem Cell ◽  
Voltage Sensor ◽  
K Channel ◽  
Cardiac Repolarization ◽  
Wild Type ◽  
Mutant Channel ◽  
Induced Pluripotent ◽  
Sensor State

KCNQ1 is a pore-forming K+ channel subunit critically important to cardiac repolarization at high heart rates. (2R)-N-[4-(4-methoxyphenyl)-2-thiazolyl]-1-[(4-methylphenyl)sulfonyl]-2 piperidinecarboxamide, or ML277, is an activator of this channel that rescues function of pathophysiologically important mutant channel complexes in human induced pluripotent stem cell–derived cardiomyocytes, and that therefore may have therapeutic potential. Here we extend our understanding of ML277 actions through cell-attached single-channel recordings of wild-type and mutant KCNQ1 channels with voltage sensor domains fixed in resting, intermediate, and activated states. ML277 has profound effects on KCNQ1 single-channel kinetics, eliminating the flickering nature of the openings, converting them to discrete opening bursts, and increasing their amplitudes approximately threefold. KCNQ1 single-channel behavior after ML277 treatment most resembles IO state-locked channels (E160R/R231E) rather than AO state channels (E160R/R237E), suggesting that at least during ML277 treatment, KCNQ1 does not frequently visit the AO state. Introduction of KCNE1 subunits reduces the effectiveness of ML277, but some enhancement of single-channel openings is still observed.

scholarly journals Pluripotency and Immunomodulatory Signatures of Canine Induced Pluripotent Stem Cell-derived Mesenchymal Stromal Cells Are Similar to Harvested Mesenchymal Stromal Cells

2020 ◽  
Author(s):  
Arash Shahsavari ◽  
Prasanna Weeratunga ◽  
Dmitry A. Ovchinnikov ◽  
Deanne Whitworth
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Induced Pluripotent Stem Cell ◽  
Interferon Γ ◽  
Mesenchymal Transition ◽  
Cox 2 ◽  
Induced Pluripotent ◽  
Tgf Β1

Abstract Background: With a view towards harnessing the therapeutic potential of canine mesenchymal stromal cells (cMSCs) as modulators of inflammation and the immune response, and to avoid the issues of the variable quality and quantity of harvested cMSCs, we examined the immunomodulatory properties of cMSCs derived from canine induced pluripotent stem cells (ciMSCs), and compared them to cMSCsharvested from adipose tissue (cAT-MSC) and bone marrow (cBM-MSC).Methods and results: Deep sequencing of the ciMSC transcriptome confirmed that ciMSCsexpress more genes in common with cBM-MSCsthan with the ciPSCs from which they were derived. Both ciMSCs and cBM-MSCsexpress a range of pluripotency factors in common withthe ciPSCsincluding NANOG, POU5F1 (OCT-4), SOX-2, KLF-4, LIN-28A, MYC, LIF, LIFR, and TERT. However, ESRRB and PRDM-14, both factors associated with naïve, rather than primed, pluripotency were expressed only in the ciPSCs. LOXL-2, which is involved in epithelial to mesenchymal transition (EMT), is also expressed in ciMSCs and cBM-MSCs but notciPSCs. ciMSCsconstitutively express the immunomodulatory factors iNOS, GAL-9, TGF-β1, PTGER-2αand VEGF, and the pro-inflammatory mediators COX-2,IL-1βand IL-8.When stimulated with the canine pro-inflammatory cytokines tumor necrosis factor-α (cTNF-α), interferon-γ (cIFN-γ), or a combination of both, ciMSCsupregulated their expression ofIDO,iNOS, GAL-9,HGF, TGF-β1, PTGER-2α, VEGF, COX-2, IL-1β andIL-8.When co-cultured with mitogen-stimulated lymphocytes, ciMSCsdownregulated their expression of iNOS, HGF, TGF-β1andPTGER-2α, while increasing their expression of COX-2, IDO and IL-1β. Conclusions: Taken together, these findings suggest that ciMSCs possess similar immunomodulatory capabilities as harvested cMSCs and support further investigation into the potential use ofciMSCsfor the management of canine immune-mediated and inflammatory disorders.

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