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The role of thymosin-β4 in kidney disease.

17 October 2018

Therapies that modulate inflammation and fibrosis have the potential to reduce the morbidity and mortality associated with chronic kidney disease (CKD). A promising avenue may be manipulating thymosin-β4, a naturally occurring peptide, which is the major G-actin sequestering protein in mammalian cells and a regulator of inflammation and fibrosis. Thymosin-β4 is already being tested in clinical trials for heart disease and wound healing. This editorial outlines the evidence that thymosin-β4 may also have therapeutic benefit in CKD.

Fanning the flames to regenerate the heart

17 October 2018

Damage to the adult mammalian heart is irreversible, and lost cells are not replaced through regeneration. In neonatal mice, prior to P7, heart tissue can be regenerated after injury; however, the factors that facilitate cardiac regeneration in the neonatal heart are not known. In this issue of the JCI, Aurora and colleagues evaluated the immune response following myocardial infarction in P1 mice compared with that in P14 mice, which have lost their regenerative capacity, and identified a population of macrophages as mediators of cardiac repair. Further understanding of the immune modulators that promote the regenerative properties of this macrophage subset could potentially be exploited to recapitulate regenerative function in the adult heart.

The epicardium signals the way towards heart regeneration

17 October 2018

© 2014. From historical studies of developing chick hearts to recent advances in regenerative injury models, the epicardium has arisen as a key player in heart genesis and repair. The epicardium provides paracrine signals to nurture growth of the developing heart from mid-gestation, and epicardium-derived cells act as progenitors of numerous cardiac cell types. Interference with either process is terminal for heart development and embryogenesis. In adulthood, the dormant epicardium reinstates an embryonic gene programme in response to injury. Furthermore, injury-induced epicardial signalling is essential for heart regeneration in zebrafish. Given these critical roles in development, injury response and heart regeneration, the application of epicardial signals following adult heart injury could offer therapeutic strategies for the treatment of ischaemic heart disease and heart failure.

Early exclusion of hand1-deficient cells from distinct regions of the left ventricular myocardium in chimeric mouse embryos.

17 October 2018

The basic helix-loop-helix transcription factor gene Hand1 has been implicated in development of the heart. However, the early lethality of Hand1-null mutant mouse embryos has precluded a precise understanding of its function. In this study, we have generated Hand1 homozygous mutant ES cells and performed in vitro differentiation experiments and chimeric analysis to study the role of Hand1 function during cardiac development. Hand1-null ES cells were able to differentiate into beating cardiomyocytes in vitro that expressed cardiac myosin and several cardiac-specific transcripts including Nkx2-5, alpha-cardiac actin, and the myofilament genes myosin light chain 2a and 2v. In chimeras derived from Hand1-null ES cells and ROSA26 embryos, mutant cells were underrepresented in the left caudal region of the linear heart tube at E8.0. By E9.5, after cardiac looping, mutant cells were underrepresented in the anterior region of the outer curvature of the left ventricular myocardium, but did contribute to other parts of the left ventricle and to other cardiac chambers. These results imply that Hand1 is not essential for differentiation of ventricular cardiomyocytes. Hand1-null cells were also underrepresented in several other regions of later embryos, including the rhombencephalic neural tube that was associated with a deficiency of mutant cells in the neural crest cell-derived cardiac outflow tract and first branchial arch. In summary, Hand1 has cell-autonomous functions during cardiac morphogenesis in both mesodermal and neural crest derivatives.

The human subventricular zone in neuropsychiatric disease

17 October 2018

Blocked angiogenesis in Galectin-3 null mice does not alter cellular and behavioral recovery after middle cerebral artery occlusion stroke.

17 October 2018

Angiogenesis is thought to decrease stroke size and improve behavioral outcomes and therefore several clinical trials are seeking to augment it. Galectin-3 (Gal-3) expression increases after middle cerebral artery occlusion (MCAO) and has been proposed to limit damage 3days after stroke. We carried out mild MCAO that damages the striatum but spares the cerebral cortex and SVZ. Gal-3 gene deletion prevented vascular endothelial growth factor (VEGF) upregulation after MCAO. This inhibited post-MCAO increases in endothelial proliferation and angiogenesis in the striatum allowing us to uniquely address the function of angiogenesis in this model of stroke. Apoptosis and infarct size were unchanged in Gal-3(-/-) mice 7 and 14 days after MCAO, suggesting that angiogenesis does not affect lesion size. Microglial and astrocyte activation/proliferation after MCAO was similar in wild type and Gal-3(-/-) mice. In addition, openfield activity, motor hemiparesis, proprioception, reflex, tremors and grooming behaviors were essentially identical between WT and Gal-3(-/-) mice at 1, 3, 7, 10 and 14 days after MCAO, suggesting that penumbral angiogenesis has limited impact on behavioral recovery. In addition to angiogenesis, increased adult subventricular zone (SVZ) neurogenesis is thought to provide neuroprotection after stroke in animal models. SVZ neurogenesis and migration to lesion were overall unaffected by the loss of Gal-3, suggesting no compensation for the lack of angiogenesis in Gal-3(-/-) mice. Because angiogenesis and neurogenesis are usually coordinately regulated, identifying their individual effects on stroke has hitherto been difficult. These results show that Gal-3 is necessary for angiogenesis in stroke in a VEGF-dependant manner, but suggest that angiogenesis may be dispensable for post-stroke endogenous repair, therefore drawing into question the clinical utility of augmenting angiogenesis.

Loss of galectin-3 decreases the number of immune cells in the subventricular zone and restores proliferation in a viral model of multiple sclerosis.

17 October 2018

Multiple sclerosis (MS) frequently starts near the lateral ventricles, which are lined by subventricular zone (SVZ) progenitor cells that can migrate to lesions and contribute to repair. Because MS-induced inflammation may decrease SVZ proliferation and thus limit repair, we studied the role of galectin-3 (Gal-3), a proinflammatory protein. Gal-3 expression was increased in periventricular regions of human MS in post-mortem brain samples and was also upregulated in periventricular regions in a murine MS model, Theiler's murine encephalomyelitis virus (TMEV) infection. Whereas TMEV increased SVZ chemokine (CCL2, CCL5, CCL, and CXCL10) expression in wild type (WT) mice, this was inhibited in Gal-3(-/-) mice. Though numerous CD45+ immune cells entered the SVZ of WT mice after TMEV infection, their numbers were significantly diminished in Gal-3(-/-) mice. TMEV also reduced neuroblast and proliferative SVZ cell numbers in WT mice but this was restored in Gal-3(-/-) mice and was correlated with increased numbers of doublecortin+ neuroblasts in the corpus callosum. In summary, our data showed that loss of Gal-3 blocked chemokine increases after TMEV, reduced immune cell migration into the SVZ, reestablished SVZ proliferation and increased the number of progenitors in the corpus callosum. These results suggest Gal-3 plays a central role in modulating the SVZ neurogenic niche's response to this model of MS.

Regional differences in human ependymal and subventricular zone cytoarchitecture are unchanged in neuropsychiatric disease

17 October 2018

Much work has focused on the possible contribution of adult hippocampal neurogenesis to neuropsychiatric diseases. The hippocampal subgranular zone and the other stem cell-containing neurogenic niche, the subventricular zone (SVZ), share several cytological features and are regulated by some of the same molecular mechanisms. However, very little is known about the SVZ in neuropsychiatric disorders. This is important since it surrounds the lateral ventricles and in schizophrenia ventricular enlargement frequently follows forebrain nuclei shrinkage. Also, adult neurogenesis has been implicated in pharmacotherapy for affective disorders and many of the molecules associated with neuropsychiatric disorders affect SVZ biology. To assess the neurogenic niche, we examined material from 60 humans (Stanley Collection) and characterized the cytoarchitecture of the SVZ and ependymal layer in age-, sex-and post mortem interval-matched controls, and patients diagnosed with schizophrenia, bipolar illness, and depression (n = 15 each). There is a paucity of post mortem brains available for study in these diseases, so to maximize the number of possible parameters examined here, we quantified individual sections rather than a large series. Previous work showed that multiple sclerosis is associated with increased width of the hypocellular gap, a cell-sparse region that typifies the human SVZ. Statistically there were no differences between disease groups and controls in the width of the hypocellular gap or in the density of cells in the hypocellular gap. Because ventricular enlargement in schizophrenia may disrupt ependymal cells, we quantified them, but observed no difference between diagnostic groups and controls. There are significant differences in the prevalence of neuropsychiatric illness between the sexes. Therefore, we looked for male versus female differences, but did not observe any in the parameters quantified. We next turned to a finer spatial resolution and asked if there were differences amongst the disease groups in dorsal ventral subdivisions of the SVZ. Similar to when we treated the SVZ as a whole, we did not find such differences. However, compared to the dorsal SVZ, the ventral SVZ had a wider hypocellular gap and more ependymal cells in all four groups. In contrast, cell density was similar in dorsal ventral subregions of the SVZ hypocellular gap. These results show that though there are regional differences in the SVZ in humans, neuropsychiatric disorders do not seem to alter several fundamental histological features of this adult neurogenic zone. © 2012 S. Karger AG, Basel.

Lineage analysis in the vertebrate central nervous system

17 October 2018

© 1997 by Oxford University Press. All rights reserved. This chapter focuses on lineage analysis in the vertebrate nervous system. It begins with the definition of lineal analysis followed by a discussion of methods of lineage analysis. It then presents examples of lineage analysis conducted in the vertebrate central nervous system (CNS). Lineage analysis of the retina has shown that retinal progenitors are multipotent, most likely through the final cell division; the pattern of cell divisions can be symmetric or asymmetric with respect to the mitotic behavior of daughter cells; and postmitotic retinal cells migrate radially with relatively little tangential migration.

Subventricular zone cytoarchitecture changes in Autism

17 October 2018

Autism is thought to be a neurodevelopmental disorder with symptoms developing during neonatal neurogenesis in the subventricular zone (SVZ). Autism associated genes alter SVZ proliferation and cytoarchitecture, yet the response of the human SVZ in autism is unknown. Epilepsy drives neurogenesis in rodents, but it is unclear how epilepsy interacts with autism in SVZ responses. The striatal and septal SVZ derive from separate lineages in rodents and generate different interneuron types. Yet it is unclear if autism unevenly regulates the striatal and septal SVZ. The human SVZ was immunohistochemically examined post-mortem from individuals with autism (n = 11) and controls (n = 11). Autism showed a lower cell density in the septal, but not striatal, SVZ hypocellular gap only in the absence of epilepsy. There was a decline in septal hypocellular gap cells with age in autism, but no correlation with age in controls. In contrast, PCNA+ cell numbers increased only in autism with epilepsy both in the hypocellular gap and in the ependymal layer on the septal but not striatal side. Ependymal cells also became GFAP immunoreactive in autism irrespective of epilepsy co-morbidity; however, this only occurred on the striatal side. In examining these questions we also discovered a subset of ependymal, astrocyte ribbon and RMS cells which express PCNA and Ki67, PLP, and α-tubulin. These results are the first example of a neuropsychiatric disease differentially affecting the septal and striatal SVZ. Altered cell density in the hypocellular gap and proliferation marker expression suggest individuals with autism may follow a different growth-trajectory. © 2013 Wiley Periodicals, Inc.