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Protein & Cell Jan 2024The seat of human intelligence is the human cerebral cortex, which is responsible for our exceptional cognitive abilities. Identifying principles that lead to the...
The seat of human intelligence is the human cerebral cortex, which is responsible for our exceptional cognitive abilities. Identifying principles that lead to the development of the large-sized human cerebral cortex will shed light on what makes the human brain and species so special. The remarkable increase in the number of human cortical pyramidal neurons and the size of the human cerebral cortex is mainly because human cortical radial glial cells, primary neural stem cells in the cortex, generate cortical pyramidal neurons for more than 130 days, whereas the same process takes only about 7 days in mice. The molecular mechanisms underlying this difference are largely unknown. Here, we found that bone morphogenic protein 7 (BMP7) is expressed by increasing the number of cortical radial glial cells during mammalian evolution (mouse, ferret, monkey, and human). BMP7 expression in cortical radial glial cells promotes neurogenesis, inhibits gliogenesis, and thereby increases the length of the neurogenic period, whereas Sonic Hedgehog (SHH) signaling promotes cortical gliogenesis. We demonstrate that BMP7 signaling and SHH signaling mutually inhibit each other through regulation of GLI3 repressor formation. We propose that BMP7 drives the evolutionary expansion of the mammalian cortex by increasing the length of the neurogenic period.
Topics: Animals; Mice; Humans; Ependymoglial Cells; Hedgehog Proteins; Ferrets; Cerebral Cortex; Neurogenesis; Mammals; Neuroglia; Bone Morphogenetic Protein 7
PubMed: 37300483
DOI: 10.1093/procel/pwad036 -
Frontiers in Cellular Neuroscience 2023Müller cells play an integral role in the development, maintenance, and photopic signal transmission of the retina. While lower vertebrate Müller cells can... (Review)
Review
Müller cells play an integral role in the development, maintenance, and photopic signal transmission of the retina. While lower vertebrate Müller cells can differentiate into various types of retinal neurons to support retinal repair following damage, there is limited neurogenic potential of mammalian Müller cells. Therefore, it is of great interest to harness the neurogenic potential of mammalian Müller cells to achieve self-repair of the retina. While multiple studies have endeavored to induce neuronal differentiation and proliferation of mammalian Müller cells under defined conditions, the efficiency and feasibility of these methods often fall short, rendering them inadequate for the requisites of retinal repair. As the mechanisms and methodologies of Müller cell reprogramming have been extensively explored, a summary of the reprogramming process of unlocking the neurogenic potential of Müller cells can provide insight into Müller cell fate development and facilitate their therapeutic use in retinal repair. In this review, we comprehensively summarize the progress in reprogramming mammalian Müller cells and discuss strategies for optimizing methods and enhancing efficiency based on the mechanisms of fate regulation.
PubMed: 38155865
DOI: 10.3389/fncel.2023.1305896 -
The Kaohsiung Journal of Medical... Sep 2023The blood-retinal barrier (BRB), homeostasis, neuronal integrity, and metabolic processes are all directly influenced by Müller cells, the most important retinal glial...
The blood-retinal barrier (BRB), homeostasis, neuronal integrity, and metabolic processes are all directly influenced by Müller cells, the most important retinal glial cells. We isolated primary Müller cells from Sprague-Dawley (SD) neonatal rats and treated them with glucose at varying doses. CCK-8 was used to quantify cellular viability, and a TUNEL assay was performed to detect cell apoptosis. ELISA, immunofluorescence, and western blotting were used to assess cAMP/PKA/CREB signaling, Kir4.1, AQP4, GFAP, and VEGF levels, respectively. H&E staining was used to examine histopathological alterations in diabetic retinopathy (DR)-affected retinal tissue in rats. As glucose concentration increases, gliosis of Müller cells became apparent, as evidenced by a decline in cell activity, an increase in apoptosis, downregulation of Kir4.1 level, and overexpression of GFAP, AQP4, and VEGF. Treatments with low, intermediate, and high glucose levels led to aberrant activation of cAMP/PKA/CREB signaling. Interestingly, blocking cAMP and PKA reduced high glucose-induced Müller cell damage and gliosis by a significant amount. Further in vivo results suggested that cAMP or PKA inhibition significantly improved edema, bleeding, and retinal disorders. Our findings showed that high glucose exacerbated Müller cell damage and gliosis via a mechanism involving cAMP/PKA/CREB signaling.
Topics: Rats; Animals; Diabetic Retinopathy; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A; Gliosis; Glucose; Diabetes Mellitus
PubMed: 37338034
DOI: 10.1002/kjm2.12722 -
ELife Nov 2023In the lesioned zebrafish retina, Müller glia produce multipotent retinal progenitors that generate all retinal neurons, replacing lost cell types. To study the...
In the lesioned zebrafish retina, Müller glia produce multipotent retinal progenitors that generate all retinal neurons, replacing lost cell types. To study the molecular mechanisms linking Müller glia reactivity to progenitor production and neuronal differentiation, we used single-cell RNA sequencing of Müller glia, progenitors and regenerated progeny from uninjured and light-lesioned retinae. We discover an injury-induced Müller glia differentiation trajectory that leads into a cell population with a hybrid identity expressing marker genes of Müller glia and progenitors. A glial self-renewal and a neurogenic trajectory depart from the hybrid cell population. We further observe that neurogenic progenitors progressively differentiate to generate retinal ganglion cells first and bipolar cells last, similar to the events observed during retinal development. Our work provides a comprehensive description of Müller glia and progenitor transcriptional changes and fate decisions in the regenerating retina, which are key to tailor cell differentiation and replacement therapies for retinal dystrophies in humans.
Topics: Animals; Humans; Zebrafish; Gene Regulatory Networks; Retina; Nerve Regeneration; Neuroglia; Sequence Analysis, RNA; Cell Proliferation
PubMed: 37988404
DOI: 10.7554/eLife.86507 -
Cells Jan 2024Glaucoma is a group of ocular diseases that cause irreversible blindness. It is characterized by multifactorial degeneration of the optic nerve axons and retinal... (Review)
Review
Glaucoma is a group of ocular diseases that cause irreversible blindness. It is characterized by multifactorial degeneration of the optic nerve axons and retinal ganglion cells (RGCs), resulting in the loss of vision. Major components of glaucoma pathogenesis include glia-driven neuroinflammation and impairment of mitochondrial dynamics and bioenergetics, leading to retinal neurodegeneration. In this review article, we summarize current evidence for the emerging role of apolipoprotein A-I binding protein (AIBP) as an important anti-inflammatory and neuroprotective factor in the retina. Due to its association with toll-like receptor 4 (TLR4), extracellular AIBP selectively removes excess cholesterol from the plasma membrane of inflammatory and activated cells. This results in the reduced expression of TLR4-associated, cholesterol-rich lipid rafts and the inhibition of downstream inflammatory signaling. Intracellular AIBP is localized to mitochondria and modulates mitophagy through the ubiquitination of mitofusins 1 and 2. Importantly, elevated intraocular pressure induces AIBP deficiency in mouse models and in human glaucomatous retina. AIBP deficiency leads to the activation of TLR4 in Müller glia, triggering mitochondrial dysfunction in both RGCs and Müller glia, and compromising visual function in a mouse model. Conversely, restoring AIBP expression in the retina reduces neuroinflammation, prevents RGCs death, and protects visual function. These results provide new insight into the mechanism of AIBP function in the retina and suggest a therapeutic potential for restoring retinal AIBP expression in the treatment of glaucoma.
Topics: Mice; Animals; Humans; Toll-Like Receptor 4; Neuroinflammatory Diseases; Glaucoma; Retina; Cholesterol
PubMed: 38275823
DOI: 10.3390/cells13020198 -
Frontiers in Molecular Neuroscience 2023The electroretinogram (ERG) measures the electrical activity of retinal neurons and glial cells in response to a light stimulus. Amongst other techniques, clinicians... (Review)
Review
The electroretinogram (ERG) measures the electrical activity of retinal neurons and glial cells in response to a light stimulus. Amongst other techniques, clinicians utilize the ERG to diagnose various eye diseases, including inherited conditions such as cone-rod dystrophy, rod-cone dystrophy, retinitis pigmentosa and Usher syndrome, and to assess overall retinal health. An ERG measures the scotopic and photopic systems separately and mainly consists of an a-wave and a b-wave. The other major components of the dark-adapted ERG response include the oscillatory potentials, c-wave, and d-wave. The dark-adapted a-wave is the initial corneal negative wave that arises from the outer segments of the rod and cone photoreceptors hyperpolarizing in response to a light stimulus. This is followed by the slower, positive, and prolonged b-wave, whose origins remain elusive. Despite a large body of work, there remains controversy around the mechanisms involved in the generation of the b-wave. Several hypotheses attribute the origins of the b-wave to bipolar or Müller glial cells or a dual contribution from both cell types. This review will discuss the current hypothesis for the cellular origins of the dark-adapted ERG, with a focus on the b-wave.
PubMed: 37465364
DOI: 10.3389/fnmol.2023.1153934 -
Plant Physiology Feb 2024Plants must rapidly and dynamically adapt to changes in their environment. Upon sensing environmental signals, plants convert them into cellular signals, which elicit... (Review)
Review
Plants must rapidly and dynamically adapt to changes in their environment. Upon sensing environmental signals, plants convert them into cellular signals, which elicit physiological or developmental changes that allow them to respond to various abiotic and biotic cues. Because plants can be simultaneously exposed to multiple environmental cues, signal integration between plant cells, tissues, and organs is necessary to induce specific responses. Recently, CLAVATA3/EMBRYO SURROUNDING REGION-related (CLE) peptides and their cognate CLAVATA-type receptors received increased attention for their roles in plant-environment interactions. CLE peptides are mobile signaling molecules, many of which are induced by a variety of biotic and abiotic stimuli. Secreted CLE peptides are perceived by receptor complexes on the surface of their target cells, which often include the leucine-rich repeat receptor-like kinase CLAVATA1. Receptor activation then results in cell-type and/or environment-specific responses. This review summarizes our current understanding of the diverse roles of environment-regulated CLE peptides in modulating plant responses to environmental cues. We highlight how CLE signals regulate plant physiology by fine-tuning plant-microbe interactions, nutrient homeostasis, and carbon allocation. Finally, we describe the role of CLAVATA receptors in the perception of environment-induced CLE signals and discuss how diverse CLE-CLAVATA signaling modules may integrate environmental signals with plant physiology and development.
Topics: Gene-Environment Interaction; Signal Transduction; Biological Transport; Carbon; Peptides
PubMed: 37930810
DOI: 10.1093/plphys/kiad591 -
Scientific Reports Sep 2023In Lyme borreliosis, the skin constitutes a major interface for the host, the bacteria and the tick. Skin immunity is provided by specialized immune cells but also by...
In Lyme borreliosis, the skin constitutes a major interface for the host, the bacteria and the tick. Skin immunity is provided by specialized immune cells but also by the resident cells: the keratinocytes and the fibroblasts. Discoveries on the role of the microbiome in the modulation of skin inflammation and immunity have reinforced the potential importance of the skin in vector-borne diseases. In this study, we analyzed in vitro the interaction of human primary keratinocytes and fibroblasts with Borrelia burgdorferi sensu stricto N40 in presence or absence of bacterial commensal supernatants. We aimed to highlight the role of resident skin cells and skin microbiome on the inflammation induced by B. burgdorferi s.s.. The secretomes of Staphylococcus epidermidis, Corynebacterium striatum and Cutibacterium acnes showed an overall increase in the expression of IL-8, CXCL1, MCP-1 and SOD-2 by fibroblasts, and of IL-8, CXCL1, MCP-1 and hBD-2 in the undifferentiated keratinocytes. Commensal bacteria showed a repressive effect on the expression of IL-8, CXCL1 and MCP-1 by differentiated keratinocytes. Besides the inflammatory effect observed in the presence of Borrelia on all cell types, the cutaneous microbiome appears to promote a rapid innate response of resident skin cells during the onset of Borrelia infection.
Topics: Animals; Humans; Borrelia burgdorferi; Interleukin-8; Secretome; Lyme Disease; Inflammation; Immunity, Innate; Ixodes
PubMed: 37773515
DOI: 10.1038/s41598-023-43566-0 -
Neurology(R) Neuroimmunology &... Sep 2023Mechanisms of visual impairment in aquaporin 4 antibody (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein...
BACKGROUND AND OBJECTIVES
Mechanisms of visual impairment in aquaporin 4 antibody (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disorder (MOGAD) are incompletely understood. The respective impact of optic nerve demyelination and primary and secondary retinal neurodegeneration are yet to be investigated in animal models.
METHODS
Active MOG experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6Jrj mice, and monoclonal MOG-IgG (8-18C5, murine), recombinant AQP4-IgG (rAb-53, human), or isotype-matched control IgG (Iso-IgG, human) was administered 10 days postimmunization. Mobility impairment was scored daily. Visual acuity by optomotor reflex and ganglion cell complex thickness (GCC, 3 innermost retinal layers) by optical coherence tomography (OCT) were longitudinally assessed. Histopathology of optic nerve and retina was investigated during presymptomatic, acute, and chronic disease phases for immune cells, demyelination, complement deposition, natural killer (NK) cell, AQP4, and astrocyte involvement, retinal ganglion cells (RGCs), and Müller cell activation. Groups were compared by nonparametric tests with a value <0.05 indicating statistical significance.
RESULTS
Visual acuity decreased from baseline to chronic phase in MOG-IgG (mean ± standard error of the mean: 0.54 ± 0.01 to 0.46 ± 0.02 cycles/degree, < 0.05) and AQP4-IgG EAE (0.54 ± 0.01 to 0.43 ± 0.02, cycles/degree, < 0.05). Immune cell infiltration of optic nerves started in presymptomatic AQP4-IgG, but not in MOG-IgG EAE (5.85 ± 2.26 vs 0.13 ± 0.10 macrophages/region of interest [ROI] and 1.88 ± 0.63 vs 0.15 ± 0.06 T cells/ROI, both < 0.05). Few NK cells, no complement deposition, and stable glial fibrillary acid protein and AQP4 fluorescence intensity characterized all EAE optic nerves. Lower GCC thickness (Spearman correlation coefficient = -0.44, < 0.05) and RGC counts ( = -0.47, < 0.05) correlated with higher mobility impairment. RGCs decreased from presymptomatic to chronic disease phase in MOG-IgG (1,705 ± 51 vs 1,412 ± 45, < 0.05) and AQP4-IgG EAE (1,758 ± 14 vs 1,526 ± 48, < 0.01). Müller cell activation was not observed in either model.
DISCUSSION
In a multimodal longitudinal characterization of visual outcome in animal models of MOGAD and NMOSD, differential retinal injury and optic nerve involvement were not conclusively clarified. Yet optic nerve inflammation was earlier in AQP4-IgG-associated pathophysiology. Retinal atrophy determined by GCC thickness (OCT) and RGC counts correlating with mobility impairment in the chronic phase of MOG-IgG and AQP4-IgG EAE may serve as a generalizable marker of neurodegeneration.
Topics: Humans; Animals; Mice; Mice, Inbred C57BL; Neuromyelitis Optica; Optic Nerve; Autoantibodies; Immunoglobulin G; Antibodies, Monoclonal; Encephalomyelitis, Autoimmune, Experimental
PubMed: 37429715
DOI: 10.1212/NXI.0000000000200141 -
APMIS : Acta Pathologica,... Apr 2024Antibiotic susceptibility testing (AST) by agar diffusion has been repeatedly standardized and, in most cases, gives results which predict clinical success when... (Review)
Review
Antibiotic susceptibility testing (AST) by agar diffusion has been repeatedly standardized and, in most cases, gives results which predict clinical success when antibiotic treatment is based on such results. The formation of the inhibition zone is due to a transition from planktonic to biofilm mode of growth. The kinetics of the interaction of antibiotics with bacteria is similar during AST by agar diffusion and during administration of antibiotics to the patients. However, the Mueller-Hinton agar (MHA) recommended for AST agar diffusion test is fundamentally different from the composition of the interstitial fluid in the human body where the infections take place and human cells do not thrive in MH media. Use of RPMI 1640 medium designed for growth of eucaryotic cells for AST of Pseudomonas aeruginosa against azithromycin results in lower minimal inhibitory concentration, compared to results obtained by MHA. The reason is that the RPMI 1640 medium increases uptake and reduces efflux of azithromycin compared to MHA. During treatment of cystic fibrosis patients with azithromycin, mutational resistance occur which is not detected by AST with MHA. Whether this is the case with other antibiotics and bacteria is not known but it is of clinical importance to be studied.
PubMed: 38565324
DOI: 10.1111/apm.13405