Aiqing Chen

Transplantation of magnetically labeled mesenchymal stem cells in a model of perinatal brain injury

Periventricular white matter injury (PVWMI) in preterm infants is a leading cause of cerebral palsy. Mesenchymal stem cell (MSC) transplantation in experimental models of adult demyelinating conditions is reported to reduce neurological deficits so we investigated their potential for treating developmental PVWMI. Neonatal rat MSCs, when cultured and labeled in vitro with fluorescent, micrometer-sized paramagnetic iron oxide particles (MPIO), retained their differentiation potential. Rats received bilateral intracerebral injections of ibotenic acid at postnatal day 5 causing PVWMI-like lesions with localized hypomyelination and sensorimotor deficits. MPIO-labeled MSCs were transplanted near the lesion in the right hemisphere 1 day postlesioning. Animals receiving cell transplants showed significantly increased antimyelin immunoreactivity in the corpus callosum, and improved reaching and retrieval skills, compared to animals receiving conditioned medium only. In separate experiments, in vivo MRI demonstrated that MPIO-labeled cells migrated away from the injection site toward lesioned areas in both hemispheres, confirmed by microscopy postmortem, but double-labeling studies found little evidence of differentiation into neural phenotypes. MSC transplantation led to significantly more forebrain cell proliferation, assayed by bromodeoxyuridine incorporation, than in controls. MSC transplants may have been neuroprotective and indirectly contributed to brain repair.

Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia

White matter hyperintensities are associated with post-stroke cognitive dysfunction, but the underlying mechanisms are unclear. Chen et al. provide evidence from human and experimental studies that clasmatodendrosis – a marker of irreversible astrocyte damage – and gliovascular abnormalities are increased in the frontal white matter of subjects who succumb to vascular dementia.

Multiplex analyte assays to characterize different dementias: brain inflammatory cytokines in poststroke and other dementias

Both the inflammatory potential and cognitive function decline during aging. The association between the repertoire of inflammatory biomarkers and cognitive decline is unclear. Inflammatory cytokines have been reported to be increased, decreased, or unchanged in the cerebrospinal fluid and sera of subjects with dementia. We assessed 112 postmortem brains from subjects diagnosed with poststroke dementia (PSD), vascular dementia, mixed dementia, and Alzheimers disease (AD), comparing those to poststroke nondemented (PSND) subjects and age-matched controls. We analyzed 5 brain regions including the gray and white matter from the frontal and temporal lobes for a panel of cytokine and/or chemokine analytes using multiplex-array assays. Of the 37 analytes, 14 were under or near the detection limits, 7 were close to the lowest detection level, and 16 cytokines were within the linear range of the assay. We observed widely variable concentrations of C-reactive protein (CRP) and serum amyloid A at the high end (1–150 ng/mg protein), whereas several of the interleukins (IL, interferon-gamma and tumor necrosis factor) at the low end (1–10 pg/mg). There were also regional variations; most notable being high concentrations of some cytokines (e.g., CRP and angiogenesis panel) in the frontal white matter. Overall, we found decreased concentrations of several cytokines, including IL-1 beta (p = 0.000), IL-6 (p = 0.000), IL-7 (p = 0.000), IL-8 (p = 0.000), IL-16 (p = 0.001), interferon-inducible protein–10 (0.044), serum amyloid A (p = 0.011), and a trend in IL-1 alpha (p = 0.084) across all dementia groups compared to nondemented controls. IL-6 and IL-8 were significantly lower in dementia subjects than in nondemented subjects in every region. In particular, lower levels of IL-6 and IL-8 were notable in the PSD compared to PSND subjects. Because these 2 stroke groups had comparable degree of vascular pathology, the lower production of IL-6 and IL-8 in PSD reaffirms a possible specific involvement of immunosenescence in dementia pathogenesis. In contrast, CRP was not altered between dementia and nondementia subjects or between PSD and PSND. Our study provides evidence not only for the feasibility of tracking cytokines in postmortem brain tissue but also suggests differentially impaired inflammatory mechanisms underlying dementia including AD. There was a diminished inflammatory response, possibly reflecting immunosenescence and cerebral atrophy, in all dementias. Strategies to enhance anti-inflammatory cytokines and boost the immune system of the brain may be beneficial for preventing cognitive dysfunction, especially after stroke.

Lysine deacetylase inhibition promotes relaxation of arterial tone and C‐terminal acetylation of HSPB6 (Hsp20) in vascular smooth muscle cells

There is increasing interest in establishing the roles that lysine acetylation of non nuclear proteins may exert in modulating cell function. Lysine deacetylase 8 (KDAC8), for example, has been suggested to interact with α‐actin and control the differentiation of smooth muscle cells. However, a direct role of smooth muscle non nuclear protein acetylation in regulating tone is unresolved. We sought to define the actions of two separate KDAC inhibitors on arterial tone and identify filament‐interacting protein targets of acetylation and association with KDAC8. Compound 2 (a specific KDAC8 inhibitor) or Trichostatin A (TSA, a broad‐spectrum KDAC inhibitor) inhibited rat arterial contractions induced by phenylephrine (PE) or high potassium solution. In contrast to the predominantly nuclear localization of KDAC1 and KDAC2, KDAC8 was positioned in extranuclear areas of native vascular smooth muscle cells. Several filament‐associated proteins identified as putative acetylation targets colocalized with KDAC8 by immunoprecipitation (IP): cortactin, α‐actin, tropomyosin, HSPB1 (Hsp27) and HSPB6 (Hsp20). Use of anti‐acetylated lysine antibodies showed that KDAC inhibition increased acetylation of each protein. A custom‐made antibody targeting the C‐terminal acetylated lysine of human HSPB6 identified this as a novel target of acetylation that was increased by KDAC inhibition. HSPB6 phosphorylation, a known vasodilatory modification, was concomitantly increased. Interrogation of publicly available mass spectrometry data identified 50 other proteins with an acetylated C‐terminal lysine. These novel data, in alliance with other recent studies, alert us to the importance of elucidating the mechanistic links between changes in myofilament‐associated protein acetylation, in conjunction with other posttranslational modifications, and the regulation of arterial tone.

A comparison of behavioural and histological outcomes of periventricular injection of ibotenic acid in neonatal rats at postnatal days 5 and 7.

Periventricular white matter injury (PVWMI) in premature babies is a major cause of cerebral palsy. Excitotoxic ibotenic acid (IBA) causes PVWMI-like lesions when injected into the white matter of neonatal rodents, however, whether it causes sensorimotor behavioural deficits that could also model cerebral palsy has not been tested. We compared IBA injection at postnatal day 7 (P7) when rodent development is equivalent to the stage of human corticospinal maturation vulnerable to PVWMI and P5 when rodent oligodendrocyte precursor cells are more vulnerable to excitotoxicity. IBA or saline were injected bilaterally into white matter between the external angle of the lateral ventricle and the forelimb sensorimotor cortex. By P14, IBA injection at P5 caused localised hypomyelination and cyst formation in this region, although cortical grey matter remained intact. Treatment at P7 produced less hypomyelination, but more widespread loss of neurofilament immunoreactivity. From P28 onwards, corticospinal function was assessed by testing reaching and retrieval of food rewards. All rats improved with age, but there was a consistent and significant difference between IBA treated rats (P5 and P7) and controls. Histological examination following testing revealed no difference in forebrain cross-sectional area but that the lateral ventricles were significantly larger in IBA treated animals than controls, especially at P7. P5 treatment caused a significantly reduced density of anti-myelin immunoreactivity in the corpus callosum compared to the anterior commissure that was not consistently seen following P7 treatment. We conclude that IBA induced lesions provide a satisfactory model of PVWMI, particularly when made at P5.

Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases

Brain clusterin is known to be associated with the amyloid‐β deposits in Alzheimers disease (AD). We assessed the distribution of clusterin immunoreactivity in cerebrovascular disorders, particularly focusing on white matter changes in small vessel diseases.

The effects of environmental enrichment on white matter pathology in a mouse model of chronic cerebral hypoperfusion

White matter (WM) disintegration is common in the older population and is associated with vascular cognitive impairment (VCI). This study explored the effects of environmental enrichment (EE) on pathological sequelae in a mouse model of chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS). Male C57BL/6 J mice underwent BCAS or sham surgery. One-week after surgery, mice were exposed to three different degrees of EE; either standard housing conditions (std), limited 3 h exposure to EE per day (3 h) or full-time exposure to EE (full) for 12 weeks. At 13 weeks after surgery, cognitive testing was performed using a three-dimensional 9-arm radial maze. At 16 weeks after surgery, nesting ability was assessed in each mouse immediately before euthanasia. Brains retrieved after perfusion fixation were examined for WM pathology. BCAS caused WM changes, as demonstrated by corpus callosum atrophy and greater WM disintegrity. BCAS also caused impaired nesting ability and cognitive function. These pathological changes and working memory deficits were attenuated, more so by limited rather than full-time exposure to EE regime. Our results suggest that limited exposure to EE delays the onset of WM degeneration. Therefore, the implementation of even limited EE may be beneficial for patients diagnosed with VCI.

Could autologous cord blood stem cell transplantation treat cerebral palsy

The young human brain is highly plastic and thus early brain lesions can lead to aberrant development of connectivity and mapping of functions. This is why initially in cerebral palsy only subtle changes in spontaneous movements are seen after the time of lesion, followed by a progressive evolution of a movement disorder over many months and years. Thus we propose that interventions to treat cerebral palsy should be initiated as soon as possible in order to restore the nervous system to the correct developmental trajectory. One such treatment might be autologous stem cell transplantation either intracerebrally or intravenously. All babies come with an accessible supply of stem cells, the umbilical cord, which can supply cells that could theoretically replace missing neural cell types, or act indirectly by supplying trophic support or modulating inflammatory responses to hypoxia/ischaemia. However, for such radical treatment to be proposed, it is necessary to be able to detect and accurately predict the outcomes of brain injury from a very early age. This article reviews our current understanding of perinatal injuries that lead to cerebral palsy, how well modern imaging might predict outcomes, what stem cells are yielded from umbilical cord blood and experimental models of brain repair using stem cells.

Severe White Matter Astrocytopathy in CADASIL: White Matter Astrocytopathy in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by strategic white matter (WM) hyperintensities on MRI. Pathological features include WM degeneration, arteriolosclerosis, lacunar infarcts, and the deposition of granular osmiophilic material. Based on the hypothesis that the gliovascular unit is compromised, we assessed the nature of astrocyte damage in the deep WM of CADASIL subjects.

White matter clasmatodendrosis and gliovascular abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Dementia Research Group, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Level 1, Learning & Research, Southmead Hospital, Bristol, BS10 5NB, UK; Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK; 3 Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, OX3 9DU, UK; Department of Neuropathology, Institute of Pathology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary & Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London, SE5 8AF, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, Midlothian, EH4 2XU UK; Department of Clinical Neuropathology, First floor, Academic Neuroscience Building, Kings College Hospital, Denmark Hill, London, SE5 9RS, UK; Institute of Cancer & Genetics, Cardiff University School of Medicine, Institute of Medical Genetics Building, Heath Park, Cardiff, CF14 4XN, UK; Institute of Brain, Behaviour and Mental Health, Clinical and Cognitive Neuroscience Research group, University of Manchester, A304 Clinical Sciences Building, Salford Royal Hospital, Stott Lane, Salford M6 8HD; 9 Institute of Infection & Immunity, Cardiff University School of Medicine, Henry Wellcome Building ,Heath Park, Cardiff CF14 4N, UK; School of Social and Community Medicine, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.