Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “brain microenvironment”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 379 records · Page 21Linked to original sources
PubMed1989

Evoked effects of cholesterol binding on integral proteins and lipid fluidity of dog brain synaptosomal plasma membranes.

Binding of cholesterol into dog brain synaptosomal plasma membranes (SPM) within the limits of concentration used (0.5-5 microM) follows an exponential curve described by the general formula y = a.ebx. This curve, which represents the total binding (specific and nonspecific), acquires sigmoid character in the presence of 100 microM cholesterol glucoside, with a Hill coefficient of h = 2.98 +/- 0.18. The specific activity of the Na+/K+-transporting ATPase and Ca2+-transporting ATPase rose after a 2-h preincubation of SPM with cholesterol (up to 5 microM) or its glucoside (up to 50 microM) to at least 50% above their original values. Fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) increased with cholesterol glucoside (50 microM) incorporation. Cholesterol (5 microM) had no effect on the DPH fluorescence polarization. Arrhenius plots of Na+/K+-transporting ATPase activity exhibited a break point at 23.2 +/- 1.1 degrees C in control SPM, which was elevated to 29.5 +/- 1.4 degrees C in SPM treated with cholesterol glucoside (50 microM) and abolished in SPM treated with cholesterol (5 microM). The allosteric properties of SPM-bound Na+/K+-transporting ATPase inhibited by F- and Ca2+-transporting ATPase inhibited by Na+ (as reflected by changes in the Hill coefficient) were modulated by cholesterol. It could be stated that cholesterol glucoside (50 microM) produced an increased packing of the bulk lipids, while cholesterol (5 microM) increased the fluidity of the lipid microenvironment of both Na+/K+-transporting ATPase and Ca2+-transporting ATPase.

Animals↗
PubMed1988

Nuclear magnetic resonance in the investigation of cerebral tumors and cerebral edema: a clue to the cellular alterations that may affect the distribution of water.

The understanding of tumor-associated cerebral edema involves an elucidation of the mechanisms involved in the altered distribution of water in the vicinity of cells. Changes in cellular macromolecules such as intracellular proteins, extracellular matrix components, and cell-membrane proteins may alter the water interactions in and around cells. The technique of pulsed nuclear magnetic resonance (NMR) gives a measure of the relaxation properties of protons in water molecules in such systems. The T1 and T2 relaxation times are increased in cerebral tumors and peritumoral tissue compared with normal brain. The in vitro study of cerebral tumors requires a tumor model that possesses the properties of the actual tumor under study. The C6 astrocytoma cell line has many of the properties of glioblastoma multiforme. An NMR study of C6 astrocytoma cells grown in monolayer, as spheroids of varying sizes and when implanted into rat hosts, has been undertaken. Results show that T1 and T2 relaxation times are not a static feature of the tumor cells but may reflect changing microenvironments that result from the contribution of a number of interacting factors present in the growing tumor.

Astrocytoma↗
PubMed2025

Parabacteroides goldsteinii mitigates parkinsonism in LRRK2 mutant mice by reducing neuroinflammation through Gut-Brain axis.

INTRODUCTION: Alterations in the gut microbiota accompanied by intestinal inflammation are early features of Parkinson's disease (PD). Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent a common genetic risk factor for PD and inflammatory bowel disease. Parabacteroides goldsteinii has been reported to alleviate intestinal and systemic inflammation. However, whether modulation of the gut microenvironment at early disease stage can attenuate PD progression remains unclear. OBJECTIVE: To investigate the impact of P. goldsteinii colonization prior to the onset of motor dysfunction on PD progression. METHODS: We established a germ-free PD mouse model carrying the LRRK2 G2019S mutation and administered P. goldsteinii orally at the pre-symptomatic stage to evaluate its effects on motor performance and PD-related neuropathology. Spatial and bulk RNA transcriptomic analyses of brain tissue, together with cytokine profiling, were conducted to assess central changes. To investigate gut immunomodulatory mechanisms, we performed intestinal bulk and single-cell RNA sequencing, spectral flow cytometry as well as cellular bioenergetic analyses. RESULTS: Germ-free conditions partially alleviated PD-like phenotypes in LRRK2 G2019S mice. Colonization with P. goldsteinii at 5-months of age, prior to motor symptom onset, further improved locomotor performance, reduced neuronal α-synuclein aggregations, and mitigated microglial activation and dopaminergic neurodegeneration. Neuroprotection was mediated through enhanced noncanonical neuronal IL-12 receptor-dependent neurotrophic support without activating the canonical STAT4 phosphorylation pathway, along with suppression of microglial activation and downregulation of LRRK2 kinase activity. At the intestinal level, P. goldsteinii suppressed TLR4-driven inflammation, expanded anti-inflammatory intraepithelial CD4+CD8αα+ T cells, promoted dendritic cell and macrophage differentiation, upregulated epithelial tight-junction genes, and improved mitochondrial bioenergetics in intestinal cells. CONCLUSION: P. goldsteinii colonization attenuates the progression of LRRK2-associated parkinsonism by restoring intestinal homeostasis and reducing neuroinflammation. These findings underscore the therapeutic potential of modulating the gut-immune-brain axis during the prodromal stage of PD.

Animals↗
PubMed2006

Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization.

Immunological alterations have been demonstrated in peripheral blood and cerebrospinal fluid of patients with schizophrenia, while previous postmortem studies have provided an inconsistent picture as to the role of microglia in the context of schizophrenia. Microglial activation is a sensitive indicator of changes in the CNS microenvironment, such as inflammatory and neurodegenerative processes. The aim of the present postmortem study was to examine HLA class II (HLA-DR) expression on microglia in brain regions which are particularly relevant for schizophrenia, with regard to hemispheric lateralization. Dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), hippocampus and mediodorsal thalamus (MD) were studied in 16 cases with schizophrenia and 16 control subjects. Immunostaining was found in all brain regions and was not restricted to macrophage-like ameboid cells, but also appeared in ramified cells. Region-specific HLA-DR-positive cell density was not significantly different between cases with schizophrenia and controls. However, ameboid microglial cells were lateralized towards the right hemisphere in healthy subjects but not in the schizophrenia group (P=0.01). Postmortem interval correlated with ramified cell numbers in ACC/DLPFC (P=0.01/0.04) and ameboid cell density in hippocampus (P=0.03). Age, gender, duration of disease, medication dosage, storage delay and whole brain volume had no effect. Single case analysis revealed highly elevated microglial cell numbers in ACC and MD of two schizophrenic patients who had committed suicide during acute psychosis. In conclusion, the present data suggest the absence of microgliosis but decreased cerebral lateralization of ameboid microglia in schizophrenia.

Adult↗
PubMed1991

Arachidonic acid and diacylglycerol act synergistically to activate protein kinase C in vitro and in vivo.

Using a well-defined model membrane bilayer system, incorporation of both lipid second messengers, 1,2-diacylglycerol and arachidonic acid, at submaximal activating concentrations, resulted in a synergistic activation of protein kinase C in a Ca2+/phosphatidylserine-dependent manner as measured by monitoring phosphorylation of phosphoprotein substrates. The arachidonic acid appears to modulate membrane properties both at the hydrocarbon core and the membrane surface increasing the availability of the diacylglycerol which can bind to and subsequently activate the enzyme. Co-application of these two lipid activators to the Hermissenda photoreceptor reduced K+ channel conductance in a synergistic manner via a PKC-dependent pathway. Thus, these in vivo and in vitro studies suggest that the membrane bilayer properties of these PKC lipid activators interact to specifically regulate the cellular lipid microenvironment resulting in PKC activation.

Animals↗
PubMed1999

Identification in human brain tumors of DNA sequences specific for SV40 large T antigen.

Simian virus 40 (SV40) sequences have recently been identified in a variety of human neoplasms, including mesothelioma, osteosarcoma, and brain tumors, but significant discrepancies exist regarding the frequency at which this occurs. The SV40 genome is 70% homologous to JC and BK, two related polyomaviruses that are highly prevalent in humans and which may cause in immune-compromised patients progressive multifocal leukoencephalopathy (PML) and cystitis, respectively. We have established a specific and sensitive method to identify SV40 sequence in DNA extracted from histological sections, using PCR followed by Southern hybridization to probes specific to the large T region. We found SV40 large T antigen sequences in all brain tumor types investigated. High frequencies were found in low-grade astrocytomas, anaplastic astrocytomas and secondary glioblastomas derived thereof (13/22, 59%) while somewhat lower frequencies were found in gemistocytic astrocytomas (9/28, 32%) and oligodendrogliomas (3/12, 25%). Primary glioblastomas, giant cell glioblastomas, and gliosarcomas, which clinically develop de novo, contained SV40 sequences in 11-25% of cases. Presence of viral DNA was also observed in pediatric brain tumors, including ependymomas (9/16, 56%), choroid plexus papillomas (6/16, 38%), and medulloblastomas (5/17, 29%). In 8 tumor biopsies with SV40 sequences, the adjacent normal brain tissue was also analyzed but was devoid of viral DNA in all but one case. BK and JC virus sequences were rarely detected, the overall frequencies being 3% and 2%, respectively. It remains to be shown whether the presence of SV40 contributes significantly to malignant transformation or whether certain human neoplasms provide a microenvironment that favors viral replication in humans with latent SV40 infection.

Adolescent↗
PubMed2001

Dopamine-mediated volume transmission in midbrain is regulated by distinct extracellular geometry and uptake.

Somatodendritic release of dopamine (DA) in midbrain is, at least in part, nonsynaptic; moreover, midbrain DA receptors are predominantly extrasynaptic. Thus somatodendritic DA mediates volume transmission, with an efficacy regulated by the diffusion and uptake characteristics of the local extracellular microenvironment. Here, we quantitatively evaluated diffusion and uptake in substantia nigra pars compacta (SNc) and reticulata (SNr), ventral tegmental area (VTA), and cerebral cortex in guinea pig brain slices. The geometric parameters that govern diffusion, extracellular volume fraction (alpha) and tortuosity (lambda), together with linear uptake (k'), were determined for tetramethylammonium (TMA(+)), and for DA, using point-source diffusion combined with ion-selective and carbon-fiber microelectrodes. TMA(+)-diffusion measurements revealed a large alpha of 30% in SNc, SNr, and VTA, which was significantly higher than the 22% in cortex. Values for lambda and k' for TMA(+) were similar among regions. Point-source DA-diffusion curves fitted theory well with linear uptake, with significantly higher values of k' for DA in SNc and VTA (0.08--0.09 s(-1)) than in SNr (0.006 s(-1)), where DA processes are sparser. Inhibition of DA uptake by GBR-12909 caused a greater decrease in k' in SNc than in VTA. In addition, DA uptake was slightly decreased by the norepinephrine transport inhibitor, desipramine in both regions, although this was statistically significant only in VTA. We used these data to model the radius of influence of DA in midbrain. Simulated release from a 20-vesicle point source produced DA concentrations sufficient for receptor activation up to 20 microm away with a DA half-life at this distance of several hundred milliseconds. Most importantly, this model showed that diffusion rather than uptake was the most important determinant of DA time course in midbrain, which contrasts strikingly with the striatum where uptake dominates. The issues considered here, while specific for DA in midbrain, illustrate fundamental biophysical properties relevant for all extracellular communication.

Animals↗
PubMed2006

Adoptive transfer of type 1 CTL mediates effective anti-central nervous system tumor response: critical roles of IFN-inducible protein-10.

The development of effective immunotherapeutic strategies for central nervous system (CNS) tumors requires a firm understanding of factors regulating the trafficking of tumor antigen-specific CTLs into CNS tumor lesions. Using C57BL/6 mice bearing intracranial (i.c.) ovalbumin-transfected melanoma (M05), we evaluated the efficacy and tumor homing of i.v. transferred type 1 or 2 CTLs (Tc1 or Tc2, respectively) prepared from ovalbumin-specific T-cell receptor-transgenic OT-1 mice. We also tested our hypothesis that intratumoral (i.t.) delivery of dendritic cells that had been transduced with IFN-alpha cDNA (DC-IFN-alpha) would enhance the tumor-homing and antitumor effectiveness of adoptively transferred Tc1 via induction of an IFN-gamma-inducible protein 10 (IP-10). In vitro, DC-IFN-alpha induced IP-10 production by M05 and enhanced the cytolytic activity of Tc1. In vivo, i.v. transferred Tc1 trafficked efficiently into i.c. M05 and mediated antitumor responses more effectively than Tc2, and their effect was IP-10 dependent. I.t. injections of DC-IFN-alpha remarkably enhanced the tumor homing, therapeutic efficacy, and in situ IFN-gamma production of i.v. delivered Tc1, resulting in the long-term survival and persistence of systemic ovalbumin-specific immunity. These data suggest that Tc1-based adoptive transfer therapy may represent an effective modality for CNS tumors, particularly when combined with strategies that promote a type 1 polarized tumor microenvironment.

Animals↗
PubMed2006

New approaches to primary brain tumor treatment.

Primary brain tumors represent over 100 different tumor types with widely divergent biologies and clinical outcomes, but these neoplasms frequently pose similar challenges to neuro-oncologists. Malignant gliomas are the most common type of primary intrinsic brain tumor in adults and remain extremely lethal. Current standard-of-care therapies for these cancers include surgery, radiation and palliative cytotoxics, which have significant side-effects and limited efficacy. Advances in our understanding of the molecular underpinnings of cancer have led to targeted molecular therapies that may permit improvement in therapeutic efficacy and reduced toxicity; these therapies, however, still face many challenges. Signal transduction pathways that are inappropriately regulated in brain cancers include growth factors and their receptors (e.g. epidermal growth factor receptor, vascular endothelial growth factor receptor and platelet-derived growth factor receptor), which regulate cellular interactions with the microenvironment and intracellular oncogenic pathways. Low-molecular-weight inhibitors have been developed to target many kinases and may have advantages in terms of delivery. Monoclonal antibodies may have greater specificity, but face delivery restrictions. Preferential tumor delivery of chemotherapies, conjugated toxins and radioisotopes has been achieved through convection-enhanced delivery, intratumoral implants and intra-arterial infusion. Despite these advances, few molecularly targeted therapies have demonstrated significant antineoplastic activity for a broad range of patients, possibly due to tumor and patient heterogeneity. Improved functional neuropathology and imaging may permit identification of patient subgroups for which clinical responses may be enriched. It is probable, however, that targeted therapies will be most effective in combination either with one another or with cytotoxic therapies. In this study, we review the current state of new therapies for malignant gliomas.

Angiogenesis Inhibitors↗
PubMed1992

Age-related changes in [3H] ouabain binding to synaptic plasma membranes isolated from mouse brains.

Age-related changes in ouabain binding to synaptic plasma membranes isolated from cerebral cortices of C57BL/6 mice were investigated to examine whether the density of Na+, K(+)-ATPase decreases with advancing age. Specific binding of [3H]ouabain did not change until around 20 months of age, but a 22% decrease in binding was found in the late senescent stage (29 months). Scatchard analysis of the binding revealed that the maximum number of binding sites (Bmax) was lower in aged mice, while the binding affinity (Kd) for ouabain receptor remained unchanged with aging. These results indicate that the density of Na+,K(+)-ATPase enzyme sites in the plasma membranes of brain synapses decreases in aged mice. Since the activity of Na+,K(+)-ATPase has been found to start declining at a much earlier stage [Tanaka, Y. & Ando, S. (1990) Brain Res. 506, 46-52; Ando, S. & Tanaka, Y. (1990) Gerontology 36, 10-14] than that at which the decrease of Bmax is manifested, at least two mechanisms may underlie the age-related decrease of the enzyme activity. We speculate that the lipid microenvironment which regulates the enzyme activity starts to change at the early stage of senescence, followed by the decrease in the enzyme content in the later stage, that is, both changes cooperatively diminish the Na+,K(+)-ATPase activity in senescence.

Aging↗
PubMed2026

Spatial transcriptomics of primary and metastatic ALK-rearranged NSCLC reveals site-specific adaptations.

INTRODUCTION: Genetic alterations and the tumor microenvironment (TME) influence treatment response in anaplastic lymphoma kinase-rearranged non-small cell lung cancer (ALK+ NSCLC). This study maps site-specific TME adaptations and exploratory risk-associated signatures in lymph node metastases (LNT) to investigate metastatic evolution. METHOD: We applied spatial transcriptomics to profile tumor (PanCK+) and stromal (PanCK-) compartments in a pilot cohort of 16 cases: primary lung tumors (LT, n = 3), LNT (n = 10), and brain metastases (BT, n = 3), with three site-matched non-tumor controls. LNT-derived prognostic signatures were evaluated using The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA LUAD) cohorts. RESULTS: Distinct, site-specific TME features were observed. LNT stroma was enriched in fibroblasts and macrophages, while tumor segments showed increased neutrophils. BT exhibited a macrophage-associated immunosuppressive TME. Tumor cells evolved divergently: LT retained pulmonary identity and showed trend towards translation-associated programs, LNT cells shifted toward senescence and epigenetic remodeling, and BT cells showed activation of Class A/1 (Rhodopsin-like) receptor, GPCR and drug metabolism pathways. In LNT, exploratory risk-associated differences were observed. Low-risk cases (n = 6) showed adaptive immune signatures, whereas high-risk cases (n = 4) showed enrichment for stromal MET signaling and stress-response pathways. Because treatment exposure differed markedly between the risk groups, these observations should be interpreted as hypothesis-generating. TCGA LUAD analysis suggested the broader biological relevance of immune-associated markers, but reflected general LUAD rather than ALK+ specific biology. Discordant associations for GCLC and TIMP1 underscored the importance of spatial context. CONCLUSION: Site-specific microenvironments may influence tumor adaptation across metastatic niches in ALK+ NSCLC. The exploratory risk-associated findings require validation in larger, uniformly treated cohorts.

Humans↗
PubMed2002

Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis.

BACKGROUND: Multiple sclerosis is an inflammatory disease of the central nervous system that destroys myelin, oligodendrocytes, and axons. Since most of the lesions of multiple sclerosis are not remyelinated, enhancement of remyelination is a possible therapeutic strategy that could perhaps be achieved with the transplantation of oligodendrocyte-producing cells into the lesions. We investigated the frequency distribution and configuration of oligodendrocytes in chronic lesions of multiple sclerosis to determine whether these factors limit remyelination. METHODS: Forty-eight chronic lesions obtained at autopsy from 10 patients with multiple sclerosis were examined immunocytochemically for oligodendrocytes and oligodendrocyte progenitor cells. Using confocal microscopy, we examined the three-dimensional relations between axons and the processes of premyelinating oligodendrocytes. RESULTS: Thirty-four of the 48 chronic lesions of multiple sclerosis contained oligodendrocytes with multiple extended processes that associated with demyelinated axons but failed to myelinate them. These axons were dystrophic and contained multiple swellings. In some regions, the densities of premyelinating oligodendrocytes (25 per square millimeter of tissue) were similar to those in the developing rodent brain (23 per square millimeter). In the patients with disease of long duration (more than 20 years), there were fewer lesions with premyelinating oligodendrocytes (P<0.001). CONCLUSIONS: Premyelinating oligodendrocytes are present in chronic lesions of multiple sclerosis, so remyelination is not limited by an absence of oligodendrocyte progenitors or their failure to generate oligodendrocytes. Our findings suggest that in the chronic lesions of multiple sclerosis, the axons are not receptive for remyelination. Understanding the cellular interactions between premyelinating oligodendrocytes, axons, and the microenvironment of lesions of multiple sclerosis may lead to effective strategies for enhancing remyelination.

Adult↗
PubMed2024

Integrated bioinformatics analysis and experimental validation reveal the relationship between ALOX5AP and the prognosis and immune microenvironment in glioma.

BACKGROUND: Treatment of gliomas, the most prevalent primary malignant neoplasm of the central nervous system, is challenging. Arachidonate 5-lipoxygenase activating protein (ALOX5AP) is crucial for converting arachidonic acid into leukotrienes and is associated with poor prognosis in multiple cancers. Nevertheless, its relationship with the prognosis and the immune microenvironment of gliomas remains incompletely understood. METHODS: The differential expression of ALOX5AP was evaluated based on public Databases. Kaplan-Meier, multivariate Cox proportional hazards regression analysis, time-dependent receiver operating characteristic, and nomogram were used to estimate the prognostic value of ALOX5AP. The relationship between ALOX5AP and immune infiltration was calculated using ESTIMATE and CIBERSORT algorithms. Relationships between ALOX5AP and human leukocyte antigen molecules, immune checkpoints, tumor mutation burden, TIDE score, and immunophenoscore were calculated to evaluate glioma immunotherapy response. Single gene GSEA and co-expression network-based GO and KEGG enrichment analysis were performed to explore the potential function of ALOX5AP. ALOX5AP expression was verified using multiplex immunofluorescence staining and its prognostic effects were confirmed using a glioma tissue microarray. RESULT: ALOX5AP was highly expressed in gliomas, and the expression level was related to World Health Organization&#xa0;(WHO) grade, age, sex, IDH mutation status, 1p19q co-deletion status, MGMTp methylation status, and poor prognosis. Single-cell RNA sequencing showed that ALOX5AP was expressed in macrophages, monocytes, and T cells but not in tumor cells. ALOX5AP expression positively correlated with M2 macrophage infiltration and poor immunotherapy response. Immunofluorescence staining demonstrated that ALOX5AP was upregulated in WHO higher-grade gliomas, localizing to M2 macrophages. Glioma tissue microarray confirmed the adverse effect of ALOX5AP in the prognosis of glioma. CONCLUSION: ALOX5AP is highly expressed in M2 macrophages and may act as a potential biomarker for predicting prognosis and immunotherapy response in patients with glioma.

Humans↗
PubMed1995

RB-reconstituted human retinoblastoma cells form RB-positive intraocular and intracerebral but not subcutaneous tumors in SCID mice.

WERI-Rb27 human retinoblastoma cells were reconstituted with an intact RB gene by retrovirus-mediated gene transfer, in order to study the phenotypic effects of the protein in vitro and in vivo. Extensive morphological changes were observed, dominated by the formation of multinucleated giant cells. Six weeks after retroviral infection, the giant cells began to die and small cells emerged, resembling the parental non-reconstituted line. They expressed RB and continued to grow, although they showed an increased sensitivity to serum starvation. The original RB-negative cells grew progressively after subcutaneous inoculation into SCID mice, whereas the reconstituted cells failed to grow. RB-positive cells grew progressively in the corpus vitreum of the eye and in the brain, however. The RB-reconstituted cells grew more slowly and were less invasive than the parental cells and cells infected with a firefly luciferase (LUX) gene carrying retrovirus, used as controls. RB-reconstituted cells re-explanted from the intraocular and intracranial tumors continued to express full-length RB protein. RBeye2, an RB-positive cell line established from an eye tumor, was still unable to grow subcutaneously. The reduced tumorigenicity of the RB-reconstituted cells in the subcutaneous space may be due to the influence of locally acting growth-controlling signals or the absence of microenvironment-specific trophic factors. Alternatively, it may reflect the action of residual immune effectors in the SCID mice. If this is the case, these would have to be more effective at the subcutaneous site than in the eye or brain.

Animals↗
PubMedDate not supplied

[Comparative study of membrane-bound acetylcholinesterase in guinea pig and rabbit brains].

As a result of kinetic studies on acetylcholinesterase inhibition by allosteric effector d-tubocurarine it was shown that interaction between modifier and catalytic sites of rabbit and guinea pig acetylcholinesterase are different for these two species. Judging by the inhibition curves and sensitivity of d-tubocurarine theses differences involve enzyme microenvironment in the membrane. Addition to 7,15-10-6 M d-tubocurarune to solubilized preparation led to a significant fall in the value of Hill coefficient for enzyme-substrate interaction. This may be indicative of the changes in the conformational state of the enzyme after its dissociation from the membrane, i. e. of the membrane structure role in the formation of the structural and functional enzyme properties.

Acetylcholinesterase↗
PubMed1992

c-kit receptor and ligand expression in postnatal development of the mouse cerebellum suggests a function for c-kit in inhibitory interneurons.

The c-kit receptor and its cognate ligand, KL, are encoded at the white spotting locus (W) and the steel locus (Sl) of the mouse, respectively. Sl and W mutations affect the same cellular targets in melanogenesis, gametogenesis and hematopoiesis during embryonic development and in adult life. c-kit is expressed in cellular targets of W and Sl mutations, whereas KL is expressed in the microenvironment of these targets. c-kit and KL, however, are also expressed in tissues and cell types that are not targets of W and Sl mutations, including the brain. The cerebellum contains a small number of neural cell types whose developmental origins, pathways of migration, and synaptic contacts are known. We have investigated the patterns of expression of the c-kit and KL RNA and protein products in postnatal cerebellar development of the mouse. In the adult cerebellum, c-kit RNA and protein expression was evident in basket, stellate, and Golgi neurons. Most strikingly, the c-kit protein is expressed in the basket cell axons that form "basket" and "pinceau" structures entwining the Purkinje cell soma and the initial segment of the Purkinje cell axon. KL RNA expression was found in Purkinje cells, and the KL protein was detected in Purkinje cell bodies and dendrites. Soluble KL protein was also present in c-kit-expressing basket, stellate, and Golgi cells, presumably as a result of internalization of ligand-receptor complexes. During postnatal development, c-kit and KL RNA and protein expression in Golgi and Purkinje neurons, respectively, was evident by day 0 and persisted subsequently. c-kit expression in basket and stellate cells was detected from their time of birth, starting at day 4. These results suggest a role for the c-kit receptor system in postnatal development of the cerebellum.

Aging↗
PubMed1992

Immunoregulatory mechanisms of the eye.

Immune-privileged sites, such as the the internal compartments of the eye, and perhaps the brain, are physiological adaptations that act to modify systemic immune responses such that effector mechanisms that invoke locally destructive inflammation are suppressed. In the case of the eye, the parenchymal cells of the iris and ciliary body create an intraocular microenvironment that alters both the induction and expression of immunity to antigens placed within the eye. The immunosuppressive properties of the intraocular microenvironment are mediated by cytokines, especially transforming growth factor-beta (TGF beta). This cytokine has been demonstrated to endow intraocular antigen-presenting cells with the capacity to induce an atypical or deviant form of immunity to intraocular antigens which is selectively deficient in T cells that mediate delayed hypersensitivity. Moreover, TGF beta, along with other intraocular factors, can impair the intraocular expression of pre-existing cell-mediated immunity by inhibiting antigen-driven activation of primed T cells. The strategies employed by the eye to engender specialized immune responses appropriate to its physiological functions are discussed in terms of other privileged sites such as the brain.

Animals↗
PubMed2006

Evaluation of silicon nanoporous membranes and ECM-based microenvironments on neurosecretory cells.

Understanding the interactions between microfabricated synthetic interfaces and cultured cells expressing a neuronal phenotype are critical for advancing research in the field of neural engineering such as neural recording and stimulation and neural microdevice interactions with the human brain. Here we explore the integration of these two components for therapeutic applications of neural prostheses. Microfabricated silicon nanoporous membranes were investigated for their effects on survival, proliferation, and differentiation of the well-known PC12 clonal line. Specifically, cell morphology, examined through fluorescence staining, were comparable in many respects on both silicon membrane and widely-used polystyrene culture surfaces. The attachment and differentiation of PC12 cells cultured on collagen and laminin-modified membranes and standard tissue culture surfaces were similar. Lastly, the differentiation response and tyrosine hydroxylase activity of PC12 cells embedded in a type I collagen matrix on experimental membrane substrates while exposed to NGF were significant and indistinguishable from tissue-culture polystyrene (TC-PS) surfaces. Results from this research suggest that microfabricated silicon nanoporous membranes may be useful, biocompatible permselective structures for neuroprosthetic applications and that collagen may be a useful immobilizing matrix for PC12 cells loaded in implantable macroencapsulation devices designed for the treatment of neurodegenerative disorders.

Animals↗