Publications by authors named "Anne E Rosser"

70 Publications

Delayed diagnosis of spinal cord injuries in Huntington's disease.

Authors:
Hamish D Morrison Dafydd Morgan Duncan J McLauchlan Catherine Clenaghan Anne E Rosser

Pract Neurol 2021 Feb 4. Epub 2021 Feb 4.

Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.

Huntington's disease is a neurodegenerative disorder, characterised by progressive cognitive, motor and psychiatric symptoms. Patients with advanced disease presenting to emergency medical services can pose a diagnostic and management challenge for physicians unfamiliar with the condition. We describe two patients with Huntington's disease in whom the diagnosis of traumatic spinal cord injury was delayed, discuss the role that cognitive bias and other factors played in this delay, and the lessons we can learn.
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http://dx.doi.org/10.1136/practneurol-2020-002854DOI Listing
February 2021

Induced pluripotent stem cells derived from the developing striatum as a potential donor source for cell replacement therapy for Huntington disease.

Authors:
Narawadee Choompoo Oliver J M Bartley Sophie V Precious Ngoc-Nga Vinh Christian Schnell Ana Garcia Victoria H Roberton Nigel M Williams Paul J Kemp Claire M Kelly Anne E Rosser

Cytotherapy 2021 Feb 25;23(2):111-118. Epub 2020 Nov 25.

Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK; MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK; Wales Brain Repair and Intracranial Neurotherapeutics Unit, School of Medicine, Cardiff University, Cardiff, UK. Electronic address:

Background: Cell replacement therapy (CRT) for Huntington disease (HD) requires a source of striatal (STR) progenitors capable of restoring the function lost due to STR degeneration. Authentic STR progenitors can be collected from the fetal putative striatum, or whole ganglionic eminence (WGE), but these tissues remain impractical for widespread clinical application, and alternative donor sources are required. Here we begin exploring the possibility that induced pluripotent stem cells (iPSC) derived from WGE may retain an epigenetic memory of their tissue of origin, which could enhance their ability to differentiate into STR cells.

Results: We generate four iPSC lines from human WGE (hWGE) and establish that they have a capacity similar to human embryonic stem cells with regard to their ability to differentiate toward an STR phenotype, as measured by expression and demethylation of key STR genes, while maintaining an overall different methylome. Finally, we demonstrate that these STR-differentiated hWGE iPSCs share characteristics with hWGE (i.e., authentic STR tissues) both in vitro and following transplantation into an HD model. Overall, iPSCs derived from human WGE show promise as a donor source for CRT for HD.
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http://dx.doi.org/10.1016/j.jcyt.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822401PMC
February 2021

Heparin-based, injectable microcarriers for controlled delivery of interleukin-13 to the brain.

Authors:
Lucas Schirmer Chloé Hoornaert Debbie Le Blon Dimitri Eigel Catia Neto Mark Gumbleton Petra B Welzel Anne E Rosser Carsten Werner Peter Ponsaerts Ben Newland

Biomater Sci 2020 Sep;8(18):4997-5004

Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Str. 6, 01069 Dresden, Germany. and School of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF10 3NB, Cardiff, UK.

Interleukin-13 (IL-13) drives cells of myeloid origin towards a more anti-inflammatory phenotype, but delivery to the brain remains problematic. Herein, we show that heparin-based cryogel microcarriers load high amounts of IL-13, releasing it slowly. Intra-striatal injection of loaded microcarriers caused local up-regulation of ARG1 in myeloid cells for pro-regenerative immunomodulation in the brain.
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http://dx.doi.org/10.1039/d0bm01249aDOI Listing
September 2020

Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases?

Authors:
Cristina Salado-Manzano Unai Perpiña Marco Straccia Francisco J Molina-Ruiz Emanuele Cozzi Anne E Rosser Josep M Canals

Front Cell Neurosci 2020 11;14:250. Epub 2020 Aug 11.

Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain.

Neurodegenerative disorders such as Parkinson's (PD) and Huntington's disease (HD) are characterized by a selective detrimental impact on neurons in a specific brain area. Currently, these diseases have no cures, although some promising trials of therapies that may be able to slow the loss of brain cells are underway. Cell therapy is distinguished by its potential to replace cells to compensate for those lost to the degenerative process and has shown a great potential to replace degenerated neurons in animal models and in clinical trials in PD and HD patients. Fetal-derived neural progenitor cells, embryonic stem cells or induced pluripotent stem cells are the main cell sources that have been tested in cell therapy approaches. Furthermore, new strategies are emerging, such as the use of adult stem cells, encapsulated cell lines releasing trophic factors or cell-free products, containing an enriched secretome, which have shown beneficial preclinical outcomes. One of the major challenges for these potential new treatments is to overcome the host immune response to the transplanted cells. Immune rejection can cause significant alterations in transplanted and endogenous tissue and requires immunosuppressive drugs that may produce adverse effects. T-, B-lymphocytes and microglia have been recognized as the main effectors in striatal graft rejection. This review aims to summarize the preclinical and clinical studies of cell therapies in PD and HD. In addition, the precautions and strategies to ensure the highest quality of cell grafts, the lowest risk during transplantation and the reduction of a possible immune rejection will be outlined. Altogether, the wide-ranging possibilities of advanced therapy medicinal products (ATMPs) could make therapeutic treatment of these incurable diseases possible in the near future.
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http://dx.doi.org/10.3389/fncel.2020.00250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433375PMC
August 2020

A randomised feasibility study of computerised cognitive training as a therapeutic intervention for people with Huntington's disease (CogTrainHD).

Authors:
Emma Yhnell Hannah Furby Rachel S Lowe Lucy C Brookes-Howell Cheney J G Drew Rebecca Playle Gareth Watson Claudia Metzler-Baddeley Anne E Rosser Monica E Busse

Pilot Feasibility Stud 2020 19;6:88. Epub 2020 Jun 19.

Centre for Trials Research (CTR), Cardiff University, Neuadd Meironnydd, Heath Park, Cardiff, CF14 4YS UK.

Background: Huntington's disease (HD) is associated with a range of cognitive deficits including problems with executive function. In the absence of a disease modifying treatment, cognitive training has been proposed as a means of slowing cognitive decline; however, the impact of cognitive training in HD patient populations remains unclear. The CogTrainHD study assessed the feasibility and acceptability of home-based computerised executive function training, for people impacted by HD.

Methods: Thirty HD gene carriers were recruited and randomised to either executive function training or non-intervention control groups. Participants allocated to the intervention group were asked to complete executive function training three times a week for 30 min for 12 weeks in their own homes. Semi-structured interviews were conducted with participants and friends, family or carers, to determine their views on the study.

Results: 26 out of 30 participants completed the baseline assessments and were subsequently randomised: 13 to the control group and 13 to the intervention group. 23 of the 30 participants were retained until study completion: 10/13 in the intervention group and 13/13 in the control group. 4/10 participants fully adhered to the executive function training. All participants in the control group 13/13 completed the study as intended. Interview data suggested several key facilitators including participant determination, motivation, incorporation of the intervention into routine and support from friends and family members. Practical limitations, including lack of time, difficulty and frustration in completing the intervention, were identified as barriers to study completion.

Conclusions: The CogTrainHD feasibility study provides important evidence regarding the feasibility and acceptability of a home-based cognitive training intervention for people with HD. Variable adherence to the cognitive training implies that the intervention is not feasible to all participants in its current form. The study has highlighted important aspects in relation to both the study and intervention design that require consideration, and these include the design of games in the executive function training software, logistical considerations such as lack of time, the limited time participants had to complete the intervention and the number of study visits required. Further studies are necessary before computerised executive function training can be recommended routinely for people with HD.

Trial Registration: ClinicalTrials.gov, Registry number NCT02990676.
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http://dx.doi.org/10.1186/s40814-020-00623-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304172PMC
June 2020

Altered cerebrovascular response to acute exercise in patients with Huntington's disease.

Authors:
Jessica J Steventon Hannah Furby James Ralph Peter O'Callaghan Anne E Rosser Richard G Wise Monica Busse Kevin Murphy

Brain Commun 2020 16;2(1):fcaa044. Epub 2020 Apr 16.

Cardiff University Brain Research Imaging Centre, School of Physics and Astronomy, Cardiff University, Cardiff CF24 4HQ, UK.

The objective of this study was to determine whether a single session of exercise was sufficient to induce cerebral adaptations in individuals with Huntington's disease and to explore the time dynamics of any acute cerebrovascular response. In this case-control study, we employed arterial-spin labelling MRI in 19 Huntington's disease gene-positive participants (32-65 years, 13 males) and 19 controls (29-63 years, 10 males) matched for age, gender, body mass index and self-reported activity levels, to measure global and regional perfusion in response to 20 min of moderate-intensity cycling. Cerebral perfusion was measured at baseline and 15, 40 and 60 min after exercise cessation. Relative to baseline, we found that cerebral perfusion increased in patients with Huntington's disease yet was unchanged in control participants in the precentral gyrus ( = 0.016), middle frontal gyrus ( = 0.046) and hippocampus ( = 0.048) 40 min after exercise cessation (+15 to +32.5% change in Huntington's disease participants, -7.7 to 0.8% change in controls). The length of the disease-causing trinucleotide repeat expansion in the huntingtin gene predicted the change in the precentral gyrus ( = 0.03) and the intensity of the exercise intervention predicted hippocampal perfusion change in Huntington's disease participants ( < 0.001). In both groups, exercise increased hippocampal blood flow 60 min after exercise cessation ( = 0.039). These findings demonstrate the utility of acute exercise as a clinically sensitive experimental paradigm to modulate the cerebrovasculature. Twenty minutes of aerobic exercise induced transient cerebrovascular adaptations in the hippocampus and cortex selectively in Huntington's disease participants and likely represents latent neuropathology not evident at rest.
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http://dx.doi.org/10.1093/braincomms/fcaa044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293798PMC
April 2020

Dopaminergic Progenitors Derived From Epiblast Stem Cells Function Similarly to Primary VM-Derived Progenitors When Transplanted Into a Parkinson's Disease Model.

Authors:
Sophie V Precious Gaynor A Smith Andreas Heuer Ines Jaeger Emma L Lane Stephen B Dunnett Meng Li Claire M Kelly Anne E Rosser

Front Neurosci 2020 7;14:312. Epub 2020 Apr 7.

Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom.

Neural transplantation in neurodegenerative diseases such as Parkinson's disease (PD) offers to replace cells lost during the progression of the disease process. Primary fetal ventral mesencephalon (VM), the origin of midbrain dopaminergic (DAergic) precursors, is currently the gold standard source of cells for transplantation in PD. However, the use of tissue from this source raises ethical and logistical constraints necessitating the need for alternative supplies of donor cells. The requirement of any alternative donor cell source is to have the capability to generate authentic mature DAergic neurons, which could be utilized in cell-replacement strategies. Mouse pluripotent stem cells can efficiently generate electrochemically mature midbrain DAergic precursors using a stepwise control of FGF signaling. Here, we have compared DAergic transplants derived from two progenitor cell sources in an allograft system: mouse epiblast stem cells (EpiSC) and primary fetal mouse VM tissue. Cells were transplanted into the striatum of 6-OHDA lesioned mice pre-treated with L-DOPA. Drug-induced rotations, a number of motor tests and drug-induced abnormal involuntary movements (AIMs) were assessed. Functional improvements were demonstrated post-transplantation in some behavioral tests, with no difference in graft volume or the number of TH immuno-positive cells in the grafts of the two transplant groups. L-DOPA-induced AIMs and amphetamine-induced AIMs were observed in both transplant groups, with no differences in rate or severity between the two groups. Collectively, in this mouse-to-mouse allograft system, we report no significant differences in the functional ability between the gold standard primary VM derived and pluripotent stem cell-derived DAergic transplants.
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http://dx.doi.org/10.3389/fnins.2020.00312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154167PMC
April 2020

Hypertension, Antihypertensive Use and the Delayed-Onset of Huntington's Disease.

Authors:
Jessica J Steventon Anne E Rosser Emma Hart Kevin Murphy

Mov Disord 2020 06 4;35(6):937-946. Epub 2020 Feb 4.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Physics and Astronomy, Maindy Road, Cardiff University, Cardiff, Wales, UK.

Background: Hypertension is a modifiable cardiovascular risk factor implicated in neurodegeneration and dementia risk. In Huntington's disease, a monogenic neurodegenerative disease, autonomic and vascular abnormalities have been reported. This study's objective was to examine the relationship between hypertension and disease severity and progression in Huntington's disease.

Methods: Using longitudinal data from the largest worldwide observational study of Huntington's disease (n = 14,534), we assessed the relationship between hypertension, disease severity, and rate of clinical progression in Huntington's disease mutation carriers. Propensity score matching was used to statistically match normotensive and hypertensive participants for age, sex, body mass index, ethnicity, and CAG length.

Results: Huntington's disease patients had a lower prevalence of hypertension compared with age-matched gene-negative controls. Huntington's disease patients with hypertension had worse cognitive function, a higher depression score, and more marked motor progression over time compared with Huntington's disease patients without hypertension. However, hypertensive patients taking antihypertensive medication had less motor, cognitive, and functional impairment than Huntington's disease patients with untreated hypertension and a later age of clinical onset compared with untreated hypertensive patients and normotensive individuals with Huntington's disease.

Conclusions: We report the novel finding that hypertension and antihypertensive medication use are associated with altered disease severity, progression, and clinical onset in patients with Huntington's disease. These findings have implications for the management of hypertension in Huntington's disease and suggest that prospective studies of the symptomatic or disease-modifying potential of antihypertensives in neurodegenerative diseases are warranted. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317197PMC
June 2020

Insensitivity to loss predicts apathy in huntington's disease.

Authors:
Duncan J McLauchlan Thomas Lancaster David Craufurd David E J Linden Anne E Rosser

Mov Disord 2019 09 30;34(9):1381-1391. Epub 2019 Jul 30.

Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Background: Apathy is a deficit in goal-directed behavior that significantly affects quality of life and function. It is common in Huntington's disease and other disorders affecting corticostriatal pathways. Deficits in processing of reward, altered effort, and executive dysfunction are associated with apathy in other disorders, but the cognitive processes leading to apathy in Huntington's disease remain largely unknown. A previously reported deficit in learning from losses in Huntington's disease raises the possibility of a hitherto unrecognized mechanism leading to apathy. This study's objective was to delineate the cognitive processes associated with apathy in HD.

Methods: We tested 51 Huntington's disease participants and 26 controls on a battery of novel and established measures to assess the contribution to apathy in Huntington's disease of executive function, reward value, reward-effort calculations, instrumental learning, and response to reward and loss.

Results: Huntington's disase participants had deficits in instrumental learning with impaired response to loss, but no evidence to suggest altered reward-related behavior or effort. We also saw an executive dysfunction contribution to apathy in Huntington's disease.

Discussion: We report the novel finding that apathy in Huntington's disease is associated with blunted responses to losses and impaired instrumental learning. This association is consistent with the known early degeneration of the indirect pathway and amygdala involvement in apathy in Huntington's disease, but is previously unreported in any disorder. In keeping with the comparative preservation of the ventral striatum and orbitofrontal cortex in Huntington's disease, reward valuation and reward-effort calculations did not contribute to apathy. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27787DOI Listing
September 2019

Outcome of cell suspension allografts in a patient with Huntington's disease.

Authors:
Alexander Maxan Sarah Mason Martine Saint-Pierre Emma Smith Aileen Ho Timothy Harrower Colin Watts Yen Tai Nicola Pavese Julie C Savage Marie-Ève Tremblay Peter Gould Anne E Rosser Stephen B Dunnett Paola Piccini Roger A Barker Francesca Cicchetti

Ann Neurol 2018 12 25;84(6):950-956. Epub 2018 Oct 25.

Centre de Recherche du CHU de Québec (CHUQ), Axe Neurosciences, Québec, QC, Canada.

For patients with incurable neurodegenerative disorders such as Huntington's (HD) and Parkinson's disease, cell transplantation has been explored as a potential treatment option. Here, we present the first clinicopathological study of a patient with HD in receipt of cell-suspension striatal allografts who took part in the NEST-UK multicenter clinical transplantation trial. Using various immunohistochemical techniques, we found a discrepancy in the survival of grafted projection neurons with respect to grafted interneurons as well as major ongoing inflammatory and immune responses to the grafted tissue with evidence of mutant huntingtin aggregates within the transplant area. Our results indicate that grafts can survive more than a decade post-transplantation, but show compromised survival with inflammation and mutant protein being observed within the transplant site. Ann Neurol 2018;84:950-956.
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http://dx.doi.org/10.1002/ana.25354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587549PMC
December 2018

Oxygen producing microscale spheres affect cell survival in conditions of oxygen-glucose deprivation in a cell specific manner: implications for cell transplantation.

Authors:
Heike Newland Dimitri Eigel Anne E Rosser Carsten Werner Ben Newland

Biomater Sci 2018 Sep;6(10):2571-2577

Leibniz Institute of Polymer Research Dresden (IPF), Hohe Strasse 6, 01069 Dresden, Germany.

This study outlines the synthesis of microscale oxygen producing spheres, which, when used in conjunction with catalase, can raise the dissolved oxygen content of cell culture media for 16-20 hours. In conditions of oxygen and glucose deprivation, designed to mimic the graft environment in vivo, the spheres rescue SH-SY5Y cells and meschymal stem cells, showing that oxygen producing biomaterials may hold potential to improve the survival of cells post-transplantation.
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http://dx.doi.org/10.1039/c8bm00490kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157640PMC
September 2018

Rethinking Functional Outcome Measures: The Development of a Novel Upper Limb Token Transfer Test to Assess Basal Ganglia Dysfunction.

Authors:
Susanne P Clinch Monica Busse Mariah J Lelos Anne E Rosser

Front Neurosci 2018 30;12:366. Epub 2018 May 30.

School of Biosciences, Cardiff University, Cardiff, United Kingdom.

The basal ganglia are implicated in a wide range of motor, cognitive and behavioral activities required for normal function. This region is predominantly affected in Huntington's disease (HD), meaning that functional ability progressively worsens. However, functional outcome measures for HD, particularly those for the upper limb, are limited meaning there is an imperative for well-defined, quantitative measures. Here we describe the development and evaluation of the Moneybox test (MBT). This novel, functional upper limb assessment was developed in accordance with translational neuroscience and physiological principles for people with a broad disease manifestation, such as HD. Participants with HD ( = 64) and healthy controls ( = 21) performed the MBT, which required subjects to transfer tokens into a container in order of size (Baseline Transfer), value (Complex Transfer) with and without reciting the alphabet (Dual Transfer). Disease specific measures of motor, cognition, behavior, and function were collected. HD patients were grouped into disease stage, from which, discriminative and convergent validity was assessed using Analysis of Variance and Pearson's correlation respectively. Manifest HD participants were slower than pre-manifest and control participants, and achieved significantly lower MBT total scores. Performance in the Complex Transfer and Dual Transfer tasks were significantly different between pre-manifest and stage 1 HD. All MBT performance variables significantly correlated with routinely used measures of motor, cognition, behavior, and function. The MBT provides a valid, sensitive, and affordable functional outcome measure. Unlike current assessments, MBT performance significantly distinguished the subtle differences between the earliest disease stages of HD, which are the populations typically targeted in clinical trials.
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http://dx.doi.org/10.3389/fnins.2018.00366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988893PMC
May 2018

Dissection and Preparation of Human Primary Fetal Ganglionic Eminence Tissue for Research and Clinical Applications.

Authors:
Victoria H Roberton Anne E Rosser Anne-Marie McGorrian Sophie V Precious

Methods Mol Biol 2018 ;1780:573-583

Brain Repair Group, Cardiff University, Cardiff, UK.

Here, we describe detailed dissection and enzymatic dissociation protocols for the ganglionic eminences from the developing human brain to generate viable quasi-single cell suspensions for subsequent use in transplantation or cell culture. These reliable and reproducible protocols can provide tissue for use in the study of the developing human brain, as well as for the preparation of donor cells for transplantation in Huntington's disease (HD). For use in the clinic as a therapy for HD, the translation of these protocols from the research laboratory to the GMP suite is described, including modification to reagents used and appropriate monitoring and tissue release criteria.
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http://dx.doi.org/10.1007/978-1-4939-7825-0_26DOI Listing
February 2019

Kv7 channels are upregulated during striatal neuron development and promote maturation of human iPSC-derived neurons.

Authors:
Vsevolod Telezhkin Marco Straccia Polina Yarova Monica Pardo Sun Yung Ngoc-Nga Vinh Jane M Hancock Gerardo Garcia-Diaz Barriga David A Brown Anne E Rosser Jonathan T Brown Josep M Canals Andrew D Randall Nicholas D Allen Paul J Kemp

Pflugers Arch 2018 09 24;470(9):1359-1376. Epub 2018 May 24.

School of Biosciences, Cardiff University, The Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, UK.

Kv7 channels determine the resting membrane potential of neurons and regulate their excitability. Even though dysfunction of Kv7 channels has been linked to several debilitating childhood neuronal disorders, the ontogeny of the constituent genes, which encode Kv7 channels (KNCQ), and expression of their subunits have been largely unexplored. Here, we show that developmentally regulated expression of specific KCNQ mRNA and Kv7 channel subunits in mouse and human striatum is crucial to the functional maturation of mouse striatal neurons and human-induced pluripotent stem cell-derived neurons. This demonstrates their pivotal role in normal development and maturation, the knowledge of which can now be harnessed to synchronise and accelerate neuronal differentiation of stem cell-derived neurons, enhancing their utility for disease modelling and drug discovery.
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http://dx.doi.org/10.1007/s00424-018-2155-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096767PMC
September 2018

The Effect of Tissue Preparation and Donor Age on Striatal Graft Morphology in the Mouse.

Authors:
David J Harrison Victoria H Roberton Ngoc-Nga Vinh Simon P Brooks Stephen B Dunnett Anne E Rosser

Cell Transplant 2018 02;27(2):230-244

1 Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom.

Huntington's disease (HD) is a progressive neurodegenerative disease in which striatal medium spiny neurons (MSNs) are lost. Neuronal replacement therapies aim to replace MSNs through striatal transplantation of donor MSN progenitors, which successfully improve HD-like deficits in rat HD models and have provided functional improvement in patients. Transplants in mouse models of HD are more variable and have lower cell survival than equivalent rat grafts, yet mice constitute the majority of transgenic HD models. Improving the quality and consistency of mouse transplants would open up access to this wider range of rodent models and facilitate research to increase understanding of graft mechanisms, which is essential to progress transplantation as a therapy for HD. Here we determined how donor age, cell preparation, and donor/host strain choice influenced the quality of primary embryonic grafts in quinolinic acid lesion mouse models of HD. Both a within-strain (W-S) and a between-strain (B-S) donor/host paradigm were used to compare transplants of donor tissues derived from mice at embryonic day E12 and E14 prepared either as dissociated suspensions or as minimally manipulated tissue pieces (TP). Good graft survival was observed, although graft volume and cellular composition were highly variable. The effect of cell preparation on grafts differed significantly depending on donor age, with E14 cell suspensions yielding larger grafts compared to TP. Conversely, TP were more effective when derived from E12 donor tissue. A W-S model produced larger grafts with greater MSN content, and while high levels of activated microglia were observed across all groups, a greater number was found in B-S transplants. In summary, we show that the effect of tissue preparation on graft morphology is contingent on the age of donor tissue used. The presence of microglial activation in all groups highlights the host immune response as an important consideration in mouse transplantation.
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http://dx.doi.org/10.1177/0963689717744788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898691PMC
February 2018

Exploring computerised cognitive training as a therapeutic intervention for people with Huntington's disease (CogTrainHD): protocol for a randomised feasibility study.

Authors:
Emma Yhnell Hannah Furby Rachel S Breen Lucy C Brookes-Howell Cheney J G Drew Rebecca Playle Gareth Watson Claudia Metzler-Baddeley Anne E Rosser Monica E Busse

Pilot Feasibility Stud 2018 6;4:45. Epub 2018 Feb 6.

3Centre for Trials Research (CTR), Cardiff University, 4th and 7th Floors, Neuadd Meironnydd, Heath Park, Cardiff, CF14 4YS Wales UK.

Background: Cognitive impairments, especially deficits of executive function, have been well documented as a core and early feature in Huntington's disease (HD). Cognitive impairments represent considerable burden and can be devastating for people and families affected by HD. Computerised cognitive training interventions that focus on improving executive function present a possible non-pharmacological treatment option. We propose to determine the feasibility, acceptability, and appropriate outcome measures for use in a randomised controlled feasibility study.

Methods/design: Participants will be randomised into either a computerised cognitive training group or a control group. Those randomised to the training group will be asked to complete a cognitive training intervention based on the HappyNeuron Pro software tasks of executive function, for a minimum of 30 min, three times a week for the 12-week study duration. Participants in the control group will not receive computerised cognitive training but will receive a similar degree of social interaction via equivalent study and home visits. We will explore quantitative outcome measures, including measures of cognitive performance, motor function, questionnaires and semi-structured interviews, as well as magnetic resonance imaging (MRI) measures in a subset of participants. Feasibility will be determined through assessment of recruitment, retention, adherence and acceptability of the intervention.

Discussion: The results of this study will provide crucial guidance and information regarding the feasibility of conducting a randomised controlled study into computerised cognitive training in HD. This study is crucial for the development of larger definitive randomised controlled trials which are powered to determine efficacy and for the development of future cognitive training programmes for people affected by HD.

Trial Registration: The study is registered on clinicaltrials.gov and has the unique identifier NCT02990676.
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http://dx.doi.org/10.1186/s40814-018-0237-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801672PMC
February 2018

Pluripotent stem cell-derived neurons for transplantation in Huntington's disease.

Authors:
Meng Li Anne E Rosser

Prog Brain Res 2017 2;230:263-281. Epub 2017 May 2.

Cardiff University Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff, United Kingdom; Cardiff University School of Biosciences, Cardiff, United Kingdom. Electronic address:

Pluripotent stem cells present a potentially unlimited source of cells for regenerative medicine, providing that they can be efficiently and accurately differentiated to the target cell type. The principle target cell for Huntington's disease is the striatal medium spiny neuron. In this chapter, we review strategies for directing medium spiny neuron differentiation, based on known developmental principles, and we discuss the remaining hurdles on the road to engineering such cells for therapeutic application in Huntington's disease.
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http://dx.doi.org/10.1016/bs.pbr.2017.02.009DOI Listing
May 2018

Reprogramming the diseased brain.

Authors:
Stephen B Dunnett Anne E Rosser

Nat Biotechnol 2017 05;35(5):426-428

The Brain Repair Group, Cardiff University School of Biosciences, Cardiff, Wales, UK.

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http://dx.doi.org/10.1038/nbt.3869DOI Listing
May 2017

Is there a place for human fetal-derived stem cells for cell replacement therapy in Huntington's disease?

Authors:
Sophie V Precious Rike Zietlow Stephen B Dunnett Claire M Kelly Anne E Rosser

Neurochem Int 2017 Jun 27;106:114-121. Epub 2017 Jan 27.

Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK; Wales Brain Repair and Intracranial Neurotherapeutics Unit (B.R.A.I.N), School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. Electronic address:

Huntington's disease (HD) is a neurodegenerative disease that offers an excellent paradigm for cell replacement therapy because of the associated relatively focal cell loss in the striatum. The predominant cells lost in this condition are striatal medium spiny neurons (MSNs). Transplantation of developing MSNs taken from the fetal brain has provided proof of concept that donor MSNs can survive, integrate and bring about a degree of functional recovery in both pre-clinical studies and in a limited number of clinical trials. The scarcity of human fetal tissue, and the logistics of coordinating collection and dissection of tissue with neurosurgical procedures makes the use of fetal tissue for this purpose both complex and limiting. Alternative donor cell sources which are expandable in culture prior to transplantation are currently being sought. Two potential donor cell sources which have received most attention recently are embryonic stem (ES) cells and adult induced pluripotent stem (iPS) cells, both of which can be directed to MSN-like fates, although achieving a genuine MSN fate has proven to be difficult. All potential donor sources have challenges in terms of their clinical application for regenerative medicine, and thus it is important to continue exploring a wide variety of expandable cells. In this review we discuss two less well-reported potential donor cell sources; embryonic germ (EG) cells and fetal neural precursors (FNPs), both are which are fetal-derived and have some properties that could make them useful for regenerative medicine applications.
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http://dx.doi.org/10.1016/j.neuint.2017.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582194PMC
June 2017

Can manipulation of differentiation conditions eliminate proliferative cells from a population of ES cell-derived forebrain cells?

Authors:
Sophie V Precious Claire M Kelly Nicholas D Allen Anne E Rosser

Neurogenesis (Austin) 2016 11;3(1):e1127311. Epub 2016 Jan 11.

Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK; Departments of Neurology and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.

There is preliminary evidence that implantation of primary fetal striatal cells provides functional benefit in patients with Huntington's disease, a neurodegenerative condition resulting in loss of medium-sized spiny neurons (MSN) of the striatum. Scarcity of primary fetal tissue means it is important to identify a renewable source of cells from which to derive donor MSNs. Embryonic stem (ES) cells, which predominantly default to telencephalic-like precursors in chemically defined medium (CDM), offer a potentially inexhaustible supply of cells capable of generating the desired neurons. Using an ES cell line, with the forebrain marker FoxG1 tagged to the LacZ reporter, we assessed effects of known developmental factors on the yield of forebrain-like precursor cells in CDM suspension culture. Addition of FGF2, but not DKK1, increased the proportion of FoxG1-expressing cells at day 8 of neural induction. Oct4 was expressed at day 8, but was undetectable by day 16. Differentiation of day 16 precursors generated GABA-expressing neurons, with few DARPP32 positive MSNs. Transplantation of day 8 precursor cells into quinolinic acid-lesioned striata resulted in generation of teratomas. However, transplantation of day 16 precursors yielded grafts expressing neuronal markers including NeuN, calbindin and parvalbumin, but no DARPP32 6 weeks post-transplantation. Manipulation of fate of ES cells requires optimization of both concentration and timing of addition of factors to culture systems to generate the desired phenotypes. Furthermore, we highlight the value of increasing the precursor phase of ES cell suspension culture when directing differentiation toward forebrain fate, so as to dramatically reduce the risk of teratoma formation.
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http://dx.doi.org/10.1080/23262133.2015.1127311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973593PMC
September 2016

Longitudinal in vivo MRI in a Huntington's disease mouse model: Global atrophy in the absence of white matter microstructural damage.

Authors:
Jessica J Steventon Rebecca C Trueman Da Ma Emma Yhnell Zubeyde Bayram-Weston Marc Modat Jorge Cardoso Sebastian Ourselin Mark Lythgoe Andrew Stewart Anne E Rosser Derek K Jones

Sci Rep 2016 09 1;6:32423. Epub 2016 Sep 1.

Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Park Place, Cardiff, CF10 3AT, UK.

Huntington's disease (HD) is a genetically-determined neurodegenerative disease. Characterising neuropathology in mouse models of HD is commonly restricted to cross-sectional ex vivo analyses, beset by tissue fixation issues. In vivo longitudinal magnetic resonance imaging (MRI) allows for disease progression to be probed non-invasively. In the HdhQ150 mouse model of HD, in vivo MRI was employed at two time points, before and after the onset of motor signs, to assess brain macrostructure and white matter microstructure. Ex vivo MRI, immunohistochemistry, transmission electron microscopy and behavioural testing were also conducted. Global brain atrophy was found in HdhQ150 mice at both time points, with no neuropathological progression across time and a selective sparing of the cerebellum. In contrast, no white matter abnormalities were detected from the MRI images or electron microscopy images alike. The relationship between motor function and MR-based structural measurements was different for the HdhQ150 and wild-type mice, although there was no relationship between motor deficits and histopathology. Widespread neuropathology prior to symptom onset is consistent with patient studies, whereas the absence of white matter abnormalities conflicts with patient data. The myriad reasons for this inconsistency require further attention to improve the translatability from mouse models of disease.
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http://dx.doi.org/10.1038/srep32423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007531PMC
September 2016

Human t-DARPP is induced during striatal development.

Authors:
Marco Straccia Jordi Carrere Anne E Rosser Josep M Canals

Neuroscience 2016 10 28;333:320-30. Epub 2016 Jul 28.

Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Networked Biomedical Research Centre for NeuroDegenerative Disorders (CIBERNED), Spain; Research and Development Unit, Cell Therapy Program, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain. Electronic address:

Human Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32kDa (DARPP-32, also known as PPP1R1B) gene codes for different transcripts that are mainly translated into two DARPP-32 protein isoforms, full length (fl)-DARPP-32 and truncated (t)-DARPP. The t-DARPP lacks the first 36 residues at the N-terminal, which alters its function. In the central nervous system, fl-DARPP-32 is highly expressed in GABAergic striatal medium spiny neurons (MSNs), where it integrates dopaminergic and glutamatergic input signaling. However, no information about human DARPP-32 isoform expression during MSNs maturation is available. In this study, our aim is to determine the expression of the two DARPP-32 isoforms in human fetal and adult striatal samples. We show that DARPP-32 isoform expression is differentially regulated during human striatal development, with the t-DARPP isoform being virtually absent from whole ganglionic eminence (WGE) and highly induced in the adult striatum (in both caudate and putamen). We next compared the four most common anti-DARPP-32 antibodies used in human specimens, to study their recognition of the two isoforms in fetal and adult human striatal samples by western blot and immunohistochemistry. The four antibodies specifically identify the fl-DARPP-32 in both fetal and adult samples, while t-DARPP form was only detected in adult striatal samples. In addition, the lack of t-DARPP recognition in human adult striatum by the antibody generated against the full-length domain produces in turn different efficacy by immunohistochemical analysis. In conclusion, our results show that expression of human DARPP-32 protein isoforms depends on the striatal neurodevelopmental stage with t-DARPP being specific for the human adult striatum.
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http://dx.doi.org/10.1016/j.neuroscience.2016.07.022DOI Listing
October 2016

Respiratory decline is integral to disease progression in Huntington's disease.

Authors:
Una Jones Monica Busse Stephanie Enright Anne E Rosser

Eur Respir J 2016 08 23;48(2):585-8. Epub 2016 Jun 23.

Neurosciences and Mental Health Institute, Cardiff University, Cardiff, UK Cardiff Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK.

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http://dx.doi.org/10.1183/13993003.02215-2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967562PMC
August 2016

Using Actiwatch to monitor circadian rhythm disturbance in Huntington' disease: A cautionary note.

Authors:
Jenny Townhill Alis C Hughes Benny Thomas Monica E Busse Kathy Price Stephen B Dunnett Michael H Hastings Anne E Rosser

J Neurosci Methods 2016 05 14;265:13-8. Epub 2016 Jan 14.

The Cardiff University Brain Repair Group, Life Sciences Building, School of Biosciences, Museum Avenue, Cardiff CF10 3AX, United Kingdom; Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, United Kingdom. Electronic address:

Huntington's disease (HD) is an inherited neurodegenerative disorder that is well recognised as producing progressive deterioration of motor function, including dyskinetic movements, as well as deterioration of cognition and ability to carry out activities of daily living. However, individuals with HD commonly suffer from a wide range of additional symptoms, including weight loss and sleep disturbance, possibly due to disruption of circadian rhythmicity. Disrupted circadian rhythms have been reported in mice models of HD and in humans with HD. One way of assessing an individual's circadian rhythmicity in a community setting is to monitor their sleep/wake cycles, and a convenient method for recording periods of wakefulness and sleep is to use accelerometers to discriminate between varied activity levels (including sleep) during daily life. Here we used Actiwatch(®) Activity monitors alongside ambulatory EEG and sleep diaries to record wake/sleep patterns in people with HD and normal volunteers. We report that periods of wakefulness during the night, as detected by activity monitors, agreed poorly with EEG recordings in HD subjects, and unsurprisingly sleep diary findings showed poor agreement with both EEG recordings and activity monitor derived sleep periods. One explanation for this is the occurrence of 'break through' involuntary movements during sleep in the HD patients, which are incorrectly assessed as wakeful periods by the activity monitor algorithms. Thus, care needs to be taken when using activity monitors to assess circadian activity in individuals with movement disorders.
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http://dx.doi.org/10.1016/j.jneumeth.2016.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863526PMC
May 2016

Direct Comparison of Rat- and Human-Derived Ganglionic Eminence Tissue Grafts on Motor Function.

Authors:
Mariah J Lelos Victoria H Roberton Ngoc-Nga Vinh Carl Harrison Peter Eriksen Eduardo M Torres Susanne P Clinch Anne E Rosser Stephen B Dunnett

Cell Transplant 2016 29;25(4):665-75. Epub 2015 Dec 29.

Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales, UK.

Huntington's disease (HD) is a debilitating, genetically inherited neurodegenerative disorder that results in early loss of medium spiny neurons from the striatum and subsequent degeneration of cortical and other subcortical brain regions. Behavioral changes manifest as a range of motor, cognitive, and neuropsychiatric impairments. It has been established that replacement of the degenerated medium spiny neurons with rat-derived fetal whole ganglionic eminence (rWGE) tissue can alleviate motor and cognitive deficits in preclinical rodent models of HD. However, clinical application of this cell replacement therapy requires the use of human-derived (hWGE), not rWGE, tissue. Despite this, little is currently known about the functional efficacy of hWGE. The aim of this study was to directly compare the ability of the gold standard rWGE grafts, against the clinically relevant hWGE grafts, on a range of behavioral tests of motor function. Lister hooded rats either remained as unoperated controls or received unilateral excitotoxic lesions of the lateral neostriatum. Subsets of lesioned rats then received transplants of either rWGE or hWGE primary fetal tissue into the lateral striatum. All rats were tested postlesion and postgraft on the following tests of motor function: staircase test, apomorphine-induced rotation, cylinder test, adjusting steps test, and vibrissae-evoked touch test. At 21 weeks postgraft, brain tissue was taken for histological analysis. The results revealed comparable improvements in apomorphine-induced rotational bias and the vibrissae test, despite larger graft volumes in the hWGE cohort. hWGE grafts, but not rWGE grafts, stabilized behavioral performance on the adjusting steps test. These results have implications for clinical application of cell replacement therapies, as well as providing a foundation for the development of stem cell-derived cell therapy products.
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http://dx.doi.org/10.3727/096368915X690297DOI Listing
December 2016

Quantitative high-throughput gene expression profiling of human striatal development to screen stem cell-derived medium spiny neurons.

Authors:
Marco Straccia Gerardo Garcia-Diaz Barriga Phil Sanders Georgina Bombau Jordi Carrere Pedro Belio Mairal Ngoc-Nga Vinh Sun Yung Claire M Kelly Clive N Svendsen Paul J Kemp Jamshid Arjomand Ryan C Schoenfeld Jordi Alberch Nicholas D Allen Anne E Rosser Josep M Canals

Mol Ther Methods Clin Dev 2015 16;2:15030. Epub 2015 Sep 16.

Department of Cell Biology, Immunology and Neuroscience, Faculty of Medicine, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), and Networked Biomedical Research Centre for NeuroDegenerative Disorders (CIBERNED), University of Barcelona , Barcelona, Spain.

A systematic characterization of the spatio-temporal gene expression during human neurodevelopment is essential to understand brain function in both physiological and pathological conditions. In recent years, stem cell technology has provided an in vitro tool to recapitulate human development, permitting also the generation of human models for many diseases. The correct differentiation of human pluripotent stem cell (hPSC) into specific cell types should be evaluated by comparison with specific cells/tissue profiles from the equivalent adult in vivo organ. Here, we define by a quantitative high-throughput gene expression analysis the subset of specific genes of the whole ganglionic eminence (WGE) and adult human striatum. Our results demonstrate that not only the number of specific genes is crucial but also their relative expression levels between brain areas. We next used these gene profiles to characterize the differentiation of hPSCs. Our findings demonstrate a temporal progression of gene expression during striatal differentiation of hPSCs from a WGE toward an adult striatum identity. Present results establish a gene expression profile to qualitatively and quantitatively evaluate the telencephalic hPSC-derived progenitors eventually used for transplantation and mature striatal neurons for disease modeling and drug-screening.
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http://dx.doi.org/10.1038/mtm.2015.30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571731PMC
September 2015

In Vivo MRI Evidence that Neuropathology is Attenuated by Cognitive Enrichment in the Yac128 Huntington's Disease Mouse Model.

Authors:
Jessica J Steventon David J Harrison Rebecca C Trueman Anne E Rosser Derek K Jones Simon P Brooks

J Huntingtons Dis 2015 ;4(2):149-60

Brain Repair Group, Life Science Building, 3rd Floor, School of Biosciences, Cardiff University, Museum Avenue, Cardiff, UK.

Background: Environmental enrichment has been shown to improve symptoms and reduce neuropathology in mouse models of Huntington's disease (HD); however results are limited to ex vivo techniques with associated shortcomings. In-vivo magnetic resonance imaging (MRI) can overcome some of the shortcomings and is applied for the first time here to assess the effect of a cognitive intervention in a mouse model of HD.

Objectives: We aimed to investigate whether in-vivo high-field MRI can detect a disease-modifying effect in tissue macrostructure following a cognitive enrichment regime.

Methods: YAC128 transgenic and wild type mice were exposed to cognitive enrichment throughout their lifetime. At 20-months old, mice were scanned with a T2-weighted MRI sequence and a region-of-interest (ROI) approach was used to examine structural changes. Locomotor activity and performance on the rotarod and serial discrimination watermaze task were assessed to measure motor and cognitive function respectively.

Results: Mice exposed to cognitive enrichment were more active and able to stay on a rotating rod longer compared to control mice, with comparable rotarod performance between HD enriched mice and wild-type mice. YAC128 mice demonstrated cognitive impairments which were not improved by cognitive enrichment. In-vivo MRI revealed a reduction in the degree of caudate-putamen atrophy in the enriched HD mice.

Conclusions: We provide in vivo evidence of a beneficial effect of environmental enrichment on neuropathology and motor function in a HD mouse model. This demonstrates the efficacy of MRI in a model of HD and provides the basis for an in-vivo non-destructive outcome measure necessary for longitudinal study designs to understand the effect of enrichment with disease progression.
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http://dx.doi.org/10.3233/JHD-150147DOI Listing
June 2016

Robust MR-based approaches to quantifying white matter structure and structure/function alterations in Huntington's disease.

Authors:
Jessica J Steventon Rebecca C Trueman Anne E Rosser Derek K Jones

J Neurosci Methods 2016 05 31;265:2-12. Epub 2015 Aug 31.

Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Park Place, Cardiff CF10 3AT, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Cathays, Cardiff CF24 4HQ, UK.

Background: Huge advances have been made in understanding and addressing confounds in diffusion MRI data to quantify white matter microstructure. However, there has been a lag in applying these advances in clinical research. Some confounds are more pronounced in HD which impedes data quality and interpretability of patient-control differences. This study presents an optimised analysis pipeline and addresses specific confounds in a HD patient cohort.

Method: 15 HD gene-positive and 13 matched control participants were scanned on a 3T MRI system with two diffusion MRI sequences. An optimised post processing pipeline included motion, eddy current and EPI correction, rotation of the B matrix, free water elimination (FWE) and tractography analysis using an algorithm capable of reconstructing crossing fibres. The corpus callosum was examined using both a region-of-interest and a deterministic tractography approach, using both conventional diffusion tensor imaging (DTI)-based and spherical deconvolution analyses.

Results: Correcting for CSF contamination significantly altered microstructural metrics and the detection of group differences. Reconstructing the corpus callosum using spherical deconvolution produced a more complete reconstruction with greater sensitivity to group differences, compared to DTI-based tractography. Tissue volume fraction (TVF) was reduced in HD participants and was more sensitive to disease burden compared to DTI metrics.

Conclusion: Addressing confounds in diffusion MR data results in more valid, anatomically faithful white matter tract reconstructions with reduced within-group variance. TVF is recommended as a complementary metric, providing insight into the relationship with clinical symptoms in HD not fully captured by conventional DTI metrics.
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http://dx.doi.org/10.1016/j.jneumeth.2015.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863525PMC
May 2016

Neonatal desensitization for the study of regenerative medicine.

Authors:
Victoria H Roberton Anne E Rosser Claire M Kelly

Regen Med 2015 ;10(3):265-74

Brain Repair Group, Sir Martin Evans Building, School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK.

Cell replacement is a therapeutic option for numerous diseases of the CNS. Current research has identified a number of potential human donor cell types, for which preclinical testing through xenotransplantation in animal models is imperative. Immune modulation is necessary to promote donor cell survival for sufficient time to assess safety and efficacy. Neonatal desensitization can promote survival of human donor cells in adult rat hosts with little impact on the health of the host and for substantially longer than conventional methods, and has subsequently been applied in a range of studies with variable outcomes. Reviewing these findings may provide insight into the method and its potential for use in preclinical studies in regenerative medicine.
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http://dx.doi.org/10.2217/rme.14.76DOI Listing
January 2016

Activin A directs striatal projection neuron differentiation of human pluripotent stem cells.

Authors:
Charles Arber Sophie V Precious Serafí Cambray Jessica R Risner-Janiczek Claire Kelly Zoe Noakes Marija Fjodorova Andreas Heuer Mark A Ungless Tristan A Rodríguez Anne E Rosser Stephen B Dunnett Meng Li

Development 2015 Apr;142(7):1375-86

Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK Stem Cell Neurogenesis Group, Neuroscience and Mental Health Research Institute, School of Medicine and School of Bioscience, Cardiff University, Cardiff CF24 4HQ, UK

The efficient generation of striatal neurons from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) is fundamental for realising their promise in disease modelling, pharmaceutical drug screening and cell therapy for Huntington's disease. GABAergic medium-sized spiny neurons (MSNs) are the principal projection neurons of the striatum and specifically degenerate in the early phase of Huntington's disease. Here we report that activin A induces lateral ganglionic eminence (LGE) characteristics in nascent neural progenitors derived from hESCs and hiPSCs in a sonic hedgehog-independent manner. Correct specification of striatal phenotype was further demonstrated by the induction of the striatal transcription factors CTIP2, GSX2 and FOXP2. Crucially, these human LGE progenitors readily differentiate into postmitotic neurons expressing the striatal projection neuron signature marker DARPP32, both in culture and following transplantation in the adult striatum in a rat model of Huntington's disease. Activin-induced neurons also exhibit appropriate striatal-like electrophysiology in vitro. Together, our findings demonstrate a novel route for efficient differentiation of GABAergic striatal MSNs from human pluripotent stem cells.
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http://dx.doi.org/10.1242/dev.117093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378247PMC
April 2015