ORCID Profile
0000-0002-4005-1203
Current Organisations
University of Cambridge
,
University of York
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Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.BIOMATERIALS.2018.11.020
Abstract: Ischemic stroke results in a loss of neurons for which there are no available clinical strategies to stimulate regeneration. While preclinical studies have demonstrated that functional recovery can be obtained by transplanting an exogenous source of neural progenitors into the brain, it remains unknown at which stage of neuronal maturity cells will provide the most benefit. We investigated the role of neuronal maturity on cell survival, differentiation, and long-term sensorimotor recovery in stroke-injured rats using a population of human cortically-specified neuroepithelial progenitor cells (cNEPs) delivered in a biocompatible, bioresorbable hyaluronan/methylcellulose hydrogel. We demonstrate that transplantation of immature cNEPs result in the greatest tissue and functional repair, relative to transplantation of more mature neurons. The transplantation process itself resulted in the least cell death and phenotypic changes in the immature cNEPs, and the greatest acute cell death in the mature cells. The latter negatively impacted host tissue and negated any potential positive effects associated with cell maturity and the hydrogel vehicle, which itself showed some functional and tissue benefit. Moreover, we show that more mature cell populations are drastically altered during the transplantation process itself. The phenotype of the cells before and after transplantation had an enormous impact on their survival and the consequent tissue and behavioral response, emphasizing the importance of characterizing injected cells in transplantation studies more broadly.
Publisher: IOP Publishing
Date: 26-09-2013
Publisher: Frontiers Media SA
Date: 29-04-2021
DOI: 10.3389/FNCEL.2021.654290
Abstract: Stroke is a leading cause of death and long-term disability worldwide. Current therapeutic options are limited in terms of their time for implementation and efficacy in promoting recovery. Cell transplantation has been shown to have promise in several animal models however significant challenges remain, including the optimal source of cells to promote neural repair. Here, we report on the use of a population of human ESC derived, cortically specified, neuroepithelial precursor cells (cNEPs) that are neurally restricted in their lineage potential. CNEPs have the potential to give rise to mature neural cell types following transplantation, including neurons, astrocytes and oligodendrocytes. With a view towards translation, we sought to determine whether this human cell source was effective in promoting improved functional outcomes following stroke. Undifferentiated cNEPs were transplanted in a pre-clinical endothelin-1 (ET-1) model of ischemic motor cortical stroke in immunocompromised SCID-beige mice and cellular and functional outcomes were assessed. We demonstrate that cNEP transplantation in the acute phase (4 days post-stroke) improves motor function as early as 20 days post-stroke, compared to stroke-injured, non-transplanted mice. At the time of recovery, a small fraction (& %) of the transplanted cNEPs are observed within the stroke injury site. The surviving cells expressed the immature neuronal marker, doublecortin, with no differentiation into mature neural phenotypes. At longer survival times (40 days), the majority of recovered, transplanted mice had a complete absence of surviving cNEPS. Hence, human cNEPs grafted at early times post-stroke support the observed functional recovery following ET-1 stroke but their persistence is not required, thereby supporting a by-stander effect rather than cell replacement.
Publisher: IOP Publishing
Date: 15-10-2008
Publisher: Elsevier BV
Date: 2020
Publisher: Cold Spring Harbor Laboratory
Date: 27-03-2021
DOI: 10.1101/2021.03.27.437311
Abstract: The cerebral cortex develops from dorsal forebrain neuroepithelial progenitor cells. Initial expansion of the progenitor cell pool is followed by the generation of neurons of all the cortical layers and later, astrocytes and oligodendrocytes. However, the regulatory pathways that control the expansion and maintenance of the neuroepithelial progenitor cell pool are currently unknown. Here we define six basic pathway components that regulate proliferation of cortically specified human neuroepithelial stem cells (cNESCs) in vitro without the loss of developmental potential. We show that activation of FGF and inhibition of BMP and ACTIVIN A signalling are required for long-term cNESC proliferation. We also demonstrate that cNESCs preserve dorsal telencephalon-specific potential when GSK3, AKT and nuclear CATENIN-β1 activity are low. Remarkably, regulation of these six pathway components supports the clonal expansion of cNESCs. Moreover, cNESCs differentiate to lower and upper layer cortical neurons both in vitro and in vivo . Identifying the mechanisms that drive the self-renewal and fate of cNESCs decision of neuroepithelial stem cells is key to developing new stem cell-based therapeutic approaches to treat neurological conditions.
Publisher: Springer Science and Business Media LLC
Date: 23-05-2022
DOI: 10.1038/S41467-022-29839-8
Abstract: The cerebral cortex develops from dorsal forebrain neuroepithelial progenitor cells. Following the initial expansion of the progenitor cell pool, these cells generate neurons of all the cortical layers and then astrocytes and oligodendrocytes. Yet, the regulatory pathways that control the expansion and maintenance of the progenitor cell pool are currently unknown. Here we define six basic pathway components that regulate proliferation of cortically specified human neuroepithelial stem cells (cNESCs) in vitro without the loss of cerebral cortex developmental potential. We show that activation of FGF and inhibition of BMP and ACTIVIN A signalling are required for long-term cNESC proliferation. We also demonstrate that cNESCs preserve dorsal telencephalon-specific potential when GSK3, AKT and nuclear CATENIN-β1 activity are low. Remarkably, regulation of these six pathway components supports the clonal expansion of cNESCs. Moreover, cNESCs differentiate into lower- and upper-layer cortical neurons in vitro and in vivo. The identification of mechanisms that drive the neuroepithelial stem cell self-renewal and differentiation and preserve this potential in vitro is key to developing regenerative and cell-based therapeutic approaches to treat neurological conditions.
Publisher: IOP Publishing
Date: 10-09-2009
DOI: 10.1088/0029-5515/49/10/104017
Abstract: Several improvements to the MAST plant and diagnostics have facilitated new studies advancing the physics basis for ITER and DEMO, as well as for future spherical tokamaks (STs). Using the increased heating capabilities P NBI ⩽ 3.8 MW H-mode at I p = 1.2 MA was accessed showing that the energy confinement on MAST scales more weakly with I p and more strongly with B t than in the ITER IPB98( y , 2) scaling. Measurements of the fuel retention of shallow pellets extrapolate to an ITER particle throughput of 70% of its original designed total throughput capacity. The anomalous momentum diffusion, χ ϕ , is linked to the ion diffusion, χ i , with a Prandtl number close to P ϕ ≈ χ ϕ /χ i ≈ 1, although χ i approaches neoclassical values. New high spatial resolution measurements of the edge radial electric field, E r , show that the position of steepest gradients in electron pressure and E r (i.e. shearing rate) are coincident, but their magnitudes are not linked. The T e pedestal width on MAST scales with rather than ρ pol . The edge localized mode (ELM) frequency for type-IV ELMs, new in MAST, was almost doubled using n = 2 resonant magnetic perturbations from a set of four external coils ( n = 1, 2). A new internal 12 coil set ( n ⩽ 3) has been commissioned. The filaments in the inter-ELM and L-mode phase are different from ELM filaments, and the characteristics in L-mode agree well with turbulence calculations. A variety of fast particle driven instabilities were studied from 10 kHz saturated fishbone like activity up to 3.8 MHz compressional Alfvén eigenmodes. Fast particle instabilities also affect the off-axis NBI current drive, leading to fast ion diffusion of the order of 0.5 m 2 s −1 and a reduction in the driven current fraction from 40% to 30%. EBW current drive start-up is demonstrated for the first time in a ST generating plasma currents up to 55 kA. Many of these studies contributed to the physics basis of a planned upgrade to MAST.
Publisher: IOP Publishing
Date: 02-02-2018
Publisher: Mary Ann Liebert Inc
Date: 02-2018
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Balazs Varga.