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PubMed2006

Development of the pancreas and pancreatic cancer.

The pancreas is specified during embryonic development from the gut endoderm. Among the signaling pathways required for the proper development of the organ are the notch and hedgehog signaling pathways. Both of these pathways are reactivated in pancreatic cancers, and sustained hedgehog signaling is required for the viability of most pancreatic cancer cell lines. Further, mouse models of the disease show activation of these pathways, and expression of pancreas progenitor markers. These findings indicate that developmentally regulated gene expression programs are important in the pathogenesis of pancreatic cancer.

Adenocarcinoma↗
PubMed2026

Multidimensional Proteomics Reveals the Pro-apoptotic Mechanism of Platycodin D: Targeting RFC4 to Regulate the Notch Signaling Axis in Non-Small Cell Lung Cancer.

Platycodin D (PD), a major bioactive saponin isolated from the traditional Chinese medicine Platycodon grandiflorus, has shown promising therapeutic potential against non-small cell lung cancer (NSCLC). However, the functional mechanisms of PD in NSCLC progression remains unclear. This study aimed to explore the pharmacological mechanism of PD against NSCLC. Thermal proteome profiling approach, molecular docking, cellular thermal shift assay and peptide-centric local stability assay were employed to identify the potential binding target of PD. Subsequent Western Blot and immunoprecipitation-Western Blot experiments were conducted to investigate the downstream signaling pathways of the target. Furthermore, proteomic and ubiquitinomic profiling of PD-treated cells were performed to investigate its functions on global. replication factor C subunit 4 (RFC4) was identified as a potential binding target of PD by thermal proteome profiling and their binding sites were further exposed by peptide-centric local stability assay. PD-RFC4 complex promotes the degradation of Notch1 and Notch3 by reducing nuclear entry of their domains. Compared with control treatment, the differentially expressed proteins induced by PD were found to be primarily involved in ferroptosis, ubiquitination, platinum drug resistance, and ribosome-related processes. The ubiquitin proteome analysis revealed that proteins associated with the Notch pathway underwent ubiquitin modifications. PD binds to RFC4 and inhibits its activity, leading to downregulation of the Notch signaling pathway, ultimately triggering cancer cell apoptosis. PD is a natural product with potential therapeutic value for NSCLC.

Saponins↗
PubMed2005

Subdividing the embryo: a role for Notch signaling during germ layer patterning in Xenopus laevis.

The development of all vertebrate embryos requires the establishment of a three-dimensional coordinate system in order to pattern embryonic structures and create the complex shape of the adult organism. During the process of gastrulation, the three primary germ layers are created under the guidance of numerous signaling pathways, allowing cells to communicate during development. Cell-cell communication, mediated by receptors of the Notch family, has been shown to be involved in mediating diverse cellular behaviors during development and has been implicated in the regulation of cell fate decisions in both vertebrate and invertebrate organisms. In order to investigate a role for Notch signaling during boundary formation between the mesoderm and endoderm during gastrulation, we manipulated Notch signaling in gastrula stage embryos and examined gene expression in resultant tissues and organs. Our findings demonstrate a much broader role for Notch signaling during germ layer determination than previously reported in a vertebrate organism. Activation of the Notch pathway, specifically in gastrula stage embryos, results in a dramatic decrease in the expression of genes necessary to create many different types of mesodermal tissues while causing a dramatic expansion of endodermal tissue markers. Conversely, temporally controlled suppression of this pathway results in a loss of endodermal cell types and an expansion of molecular markers of mesoderm. Thus, our data are consistent with and significantly extend the implications of prior observations suggesting roles for Notch signaling during germ layer formation and establish an evolutionarily conserved role for Notch signaling in mediating mesoderm-endoderm boundaries during early vertebrate development.

Animals↗
PubMed2001

Characterization and developmental expression of the amphioxus homolog of Notch (AmphiNotch): evolutionary conservation of multiple expression domains in amphioxus and vertebrates.

Notch encodes a transmembrane protein that functions in intercellular signaling. Although there is one Notch gene in Drosophila, vertebrates have three or more with overlapping patterns of embryonic expression. We cloned the entire 7575-bp coding region of an amphioxus Notch gene (AmphiNotch), encoding 2524 amino acids, and obtained the exon/intron organization from a genomic cosmid clone. Southern blot and PCR data indicate that AmphiNotch is the only Notch gene in amphioxus. AmphiNotch, like Drosophila Notch and vertebrate Notch1 and Notch2, has 36 EGF repeats, 3 Notch/lin-12 repeats, a transmembrane region, and 6 ankyrin repeats. Phylogenetic analysis places it at the base of all the vertebrate genes, suggesting it is similar to the ancestral gene from which the vertebrate Notch family genes evolved. AmphiNotch is expressed in all three embryonic germ layers in spatiotemporal patterns strikingly similar to those of all the vertebrate homologs combined. In the developing nerve cord, AmphiNotch is first expressed in the posteriormost part of the neural plate, then it becomes more broadly expressed and later is localized dorsally in the anteriormost part of the nerve cord corresponding to the diencephalon. In late embryos and larvae, AmphiNotch is also expressed in parts of the pharyngeal endoderm, in the anterior gut diverticulum, and, like AmphiPax2/5/8, in the rudiment of Hatschek's kidney. A comparison with Notch1 and Pax5 and Pax8 expression in the embryonic mouse kidney helps support homology of the amphioxus and vertebrate kidneys. AmphiNotch is also an early marker for presumptive mesoderm, transcripts first being detectable at the gastrula stage in a ring of mesendoderm just inside the blastopore and subsequently in the posterior mesoderm, notochord, and somites. As in sea urchins and vertebrates, these domains of AmphiNotch expression overlap with those of several Wnt genes and brachyury. These relationships suggest that amphioxus shares with other deuterostomes a common mechanism for patterning along the anterior/posterior axis involving a posterior signaling center in which the Notch and Wnt pathways and brachyury interact.

Amino Acid Sequence↗
PubMed1994

Modulation of wingless signaling by Notch in Drosophila.

Extensive genetic and molecular analyses indicate that Notch acts as a transmembrane receptor in an evolutionarily conserved cell interaction mechanism that appears to control a common step in the progression of an uncommitted cell towards the differentiated state. In Drosophila, Notch mutations were shown to affect the development of a broad spectrum of tissues, including the wing. We found that mutations in the segment polarity gene wingless are capable of acting as dominant enhancers of notchoid, a recessive Notch allele affecting the wing. The Wingless protein is homologous to the mammalian proto-oncoprotein Wnt-1 and is thought to act as the signal in a cell interaction mechanism that specifies differentiation of the embryonic epidermis as well as imaginal structures such as the wing. Although some components of the Wingless signal transduction pathway have been identified, the receptor for Wingless remains elusive. This genetic link between the Wingless and Notch pathways has been further examined by determining the relative expression patterns and subcellular localization of Notch and Wingless in mutant and wild-type backgrounds. We find that Notch is necessary for the implementation of the Wingless signal in specifying normal wing development. We discuss the possibility that Notch is directly involved in the reception of Wingless in the light of current models for the developmental action of Notch.

Animals↗
PubMed2001

Zebrafish deadly seven functions in neurogenesis.

In a genetic screen, we isolated a mutation that perturbed motor axon outgrowth, neurogenesis, and somitogenesis. Complementation tests revealed that this mutation is an allele of deadly seven (des). By creating genetic mosaics, we demonstrate that the motor axon defect is non-cell autonomous. In addition, we show that the pattern of migration for some neural crest cell populations is aberrant and crest-derived dorsal root ganglion neurons are misplaced. Furthermore, our analysis reveals that des mutant embryos exhibit a neurogenic phenotype. We find an increase in the number of primary motoneurons and in the number of three hindbrain reticulospinal neurons: Mauthner cells, RoL2 cells, and MiD3cm cells. We also find that the number of Rohon-Beard sensory neurons is decreased whereas neural crest-derived dorsal root ganglion neurons are increased in number supporting a previous hypothesis that Rohon-Beard neurons and neural crest form an equivalence group during development. Mutations in genes involved in Notch-Delta signaling result in defects in somitogenesis and neurogenesis. We found that overexpressing an activated form of Notch decreased the number of Mauthner cells in des mutants indicating that des functions via the Notch-Delta signaling pathway to control the production of specific cell types within the central and peripheral nervous systems.

Alleles↗
PubMed2001

Nicastrin binds to membrane-tethered Notch.

The presenilins and nicastrin, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the beta-amyloid precursor protein (betaAPP) and Notch in their transmembrane domains. The former process (termed gamma-secretase cleavage) generates amyloid beta-peptide (Abeta), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length betaAPP and the substrates of gamma-secretase (C99- and C83-betaAPP fragments), and modulates the activity of gamma-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate gamma-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and betaAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and betaAPP pathways do not significantly compete with each other.

Alzheimer Disease↗
PubMed2003

Patterning the sea urchin embryo: gene regulatory networks, signaling pathways, and cellular interactions.

We discuss steps in the specification of major tissue territories of the sea urchin embryo that occur between fertilization and hatching blastula stage and the cellular interactions required to coordinate morphogenetic processes that begin after hatching. We review evidence that has led to new ideas about how this embryo is initially patterned: (1) Specification of most of the tissue territories is not direct, but proceeds gradually by progressive subdivision of broad, maternally specified domains that depend on opposing gradients in the ratios of animalizing transcription factors (ATFs) and vegetalizing (beta-catenin) transcription factors; (2) the range of maternal nuclear beta-catenin extends further than previously proposed, that is, into the animal hemisphere, where it programs many cells to adopt early aboral ectoderm characteristics; (3) cells at the extreme animal pole constitute a unique ectoderm region, lacking nuclear beta-catenin; (4) the pluripotential mesendoderm is created by the combined outputs of ATFs and nuclear beta-catenin, which initially overlap in the macromeres, and by an undefined early micromere signal; (5) later micromere signals, which activate Notch and Wnt pathways, subdivide mesendoderm into secondary mesenchyme and endoderm; and (6) oral ectoderm specification requires reprogramming early aboral ectoderm at about the hatching blastula stage. Morphogenetic processes that follow initial fate specification depend critically on continued interactions among cells in different territories. As illustrations, we discuss the regulation of (1) the ectoderm/endoderm boundary, (2) mesenchyme positioning and skeletal growth, (3) ciliated band formation, and (4) several suppressive interactions operating late in embryogenesis to limit the fates of multipotent cells.

Animals↗
PubMed2002

Regulation of lipocalin-type prostaglandin D synthase gene expression by Hes-1 through E-box and interleukin-1 beta via two NF-kappa B elements in rat leptomeningeal cells.

The promoter function of the rat lipocalin-type prostaglandin D synthase (L-PGDS) gene was characterized in primary cultures of leptomeningeal cells prepared from the neonatal rat brain. Luciferase reporter assays with deletion and site-directed mutation of the promoter region (-1250 to +77) showed that an AP-2 element at -109 was required for activation and an E-box at +57, for repression. Binding of nuclear factors to each of these cis-elements was demonstrated by an electrophoretic mobility shift assay. Several components of the Notch-Hes signaling pathway, Jagged, Notch1, Notch3, and Hes-1, were expressed in the leptomeningeal cells. Human Hes-1 co-expressed in the leptomeningeal cells bound to the E-box of the rat L-PGDS gene, and repressed the promoter activity of the rat L-PGDS gene in a dose-dependent manner. The L-PGDS gene expression was up-regulated slowly by interleukin-1 beta to the maximum level at 24 h. The reporter assay with deletion and mutation revealed that two NF-kappa B elements at -1106 and -291 were essential for this up-regulation. Binding of two NF-kappa B subunits, p65 and c-Rel, to these two NF-kappa B elements occurred after the interleukin-1 beta treatment. Therefore, the L-PGDS gene is the first gene identified as the target for the Notch-Hes signal through the E-box among a variety of genes involved in the prostanoid biosynthesis, classified to the lipocalin family, and expressed in the leptomeninges. Moreover, the L-PGDS gene is a unique gene that is activated slowly by the NF-kappa B system.

Animals↗
PubMed2003

Prepattern genes and signaling molecules regulate stripe expression to specify Drosophila flight muscle attachment sites.

In Drosophila, muscles attach to epidermal tendon cells specified by the gene stripe (sr). Flight muscle attachment sites are prefigured on the wing imaginal disc by sr expression in discrete domains. We describe the mechanisms underlying the specification of these domains of sr expression. We show that the concerted activities of the wingless (wg), decapentaplegic (dpp) and Notch (N) signaling pathways, and the prepattern genes pannier (pnr) and u-shaped (ush) establish domains of sr expression. N is required for initiation of sr expression. pnr is a positive regulator of sr, and is inhibited by ush in this function. The Wg signal differentially influences the formation of different sr domains. These results identify the multiple regulatory elements involved in the positioning of Drosophila flight muscle attachment sites.

Alleles↗
PubMed2005

tantalus, a potential link between Notch signalling and chromatin-remodelling complexes.

The tantalus (tan) gene encodes a protein that interacts specifically with the Polycomb/trithorax group protein Additional sex combs (ASX). Both loss-of-function and gain-of-function mutations in tan cause tissue-specific defects in the eyes, wing veins and bristles of adult flies. As these defects are also typical for components of the Notch (N) signalling pathway, we wished to determine if TAN interacts with this pathway. Through careful examination of ectopic tan phenotypes, we find that TAN specifically disrupts all three major processes associated with the N signalling pathway (boundary formation, lateral inhibition, and lineage decisions). Furthermore, ectopic tan expression abolishes expression of two N target genes, wingless (wg) and cut, at the dorsal-ventral boundary of the wing. An interaction between tan and N was also observed using a genetic assay that previously detected interactions between tan and Asx. The previously observed ability of TAN to move between the cytoplasm and nucleus, and to associate with DNA, provides a potential mechanism for TAN to respond to N signalling.

Animals↗
PubMed2000

Restricted patterning of vestigial expression in Drosophila wing imaginal discs requires synergistic activation by both Mad and the drifter POU domain transcription factor.

The Drosophila Vestigial protein has been shown to play an essential role in the regulation of cell proliferation and differentiation within the developing wing imaginal disc. Cell-specific expression of vg is controlled by two separate transcriptional enhancers. The boundary enhancer controls expression in cells near the dorsoventral (DV) boundary and is regulated by the Notch signal transduction pathway, while the quadrant enhancer responds to the Decapentaplegic and Wingless morphogen gradients emanating from cells near the anteroposterior (AP) and DV boundaries, respectively. MAD-dependent activation of the vestigial quadrant enhancer results in broad expression throughout the wing pouch but is excluded from cells near the DV boundary. This has previously been thought to be due to direct repression by a signal from the DV boundary; however, we show that this exclusion of quadrant enhancer-dependent expression from the DV boundary is due to the absence of an additional essential activator in those cells. The Drosophila POU domain transcriptional regulator, Drifter, is expressed in all cells within the wing pouch expressing a vgQ-lacZ transgene and is also excluded from the DV boundary. Viable drifter hypomorphic mutations cause defects in cell proliferation and wing vein patterning correlated with decreased quadrant enhancer-dependent expression. Drifter misexpression at the DV boundary using the GAL4/UAS system causes ectopic outgrowths at the distal wing tip due to induction of aberrant Vestigial expression, while a dominant-negative Drifter isoform represses expression of vgQ-lacZ and causes severe notching of the adult wing. In addition, we have identified an essential evolutionarily conserved sequence element bound by the Drifter protein with high affinity and located adjacent to the MAD binding site within the quadrant enhancer. Our results demonstrate that Drifter functions along with MAD as a direct activator of Vestigial expression in the wing pouch.

Animals↗
PubMed1999

scalloped functions in a regulatory loop with vestigial and wingless to pattern the Drosophila wing.

The development of the Drosophila wing involves progressive patterning events. In the second larval instar, cells of the wing disc are allotted wing or notum fates by a wingless-mediated process and dorsal or ventral fates by the action of apterous and wingless. Notch-mediated signalling is required for the expression of the genes vestigial and scalloped in the presumptive wing blade. Later, wingless, Notch and cut are involved in cell fate specification along the wing margin. The function of scalloped in this process is not well understood and is the focus of this study. We show that patterning downstream of Notch and wingless pathways is altered in scalloped mutants. Reduction in scalloped expression results in a loss of expression of wing blade- and margin-specific markers. Misexpression of scalloped in the presumptive wing causes misexpression of scalloped, vestigial and wingless reporter genes. However, high levels of scalloped expression have a negative influence on wingless, vestigial and its own expression. Our results demonstrate that scalloped functions in a level-dependent manner in the presumptive wing blade in a loop that involves vestigial and itself. We suggest that wing development requires the regulated expression of scalloped together with vestigial-the "wing formation" effects of Vestigial in other imaginal discs are probably due to its interaction with the scalloped gene product normally expressed in these discs.

Animals↗
PubMed2001

Spatial regulation of DELTA expression mediates NOTCH signalling for segmentation of Drosophila legs.

The Notch (N) signalling pathway is recruited for segregation of cell fates in a number of Drosophila tissue types. We show here that N dependent segmentation of Drosophila legs is regulated by a dynamic pattern of expression of its ligand, DELTA (DL). During third larval instar and early stages of pupation, high levels of DL expression is seen in stripes of cells in the leg imaginal discs which later form the proximal borders of leg joints. These domains also displayed heightened Dl enhancer activity. During subsequent stages of pupation, following segmentation of the leg primordium, DL expression becomes uniform throughout these segments barring the joints. We further show that regulatory Dl mutations or mis-expression of DL abolish leg segmentation. Domains of N signalling for segmentation of legs of flies are thus set up by a stringent spatial regulation of expression of its ligand at the segment border. Further, a comparable role of DL in antennal development reveals a common paradigm of DL-N signalling for segmentation of appendages in flies.

Animals↗
PubMed1998

The lunatic fringe gene is a target of the molecular clock linked to somite segmentation in avian embryos.

The most obvious segments of the vertebrate embryo are the trunk mesodermal somites which give rise to the segmented vertebral column and the skeletal muscles of the body. Mechanistic insights into vertebrate somitogenesis have recently been gained from observations of rhythmic expression of the avian hairy-related gene (c-hairy1) in chick presomitic mesoderm (PSM), suggesting the existence of a molecular clock linked to somite segmentation ([1]; reviewed in [2]). Here, we show that lunatic Fringe (IFng), a vertebrate homolog of the Drosophila Fringe gene, is also expressed rhythmically in PSM. The PSM expression of IFng was observed as coordinated pulses of mRNA resembling the expression of c-hairy1. We show that c-hairy1 and IFng expression in the PSM are coincident, indicating that both genes are responding to the same segmentation clock. The genes were found to differ in their regulation, however; in contrast to c-hairy1, IFng mRNA oscillations required continued protein synthesis, suggesting that IFng could be acting downstream of c-hairy1 in the clock mechanism. In Drosophila, Fringe has been shown to play a role in modulating Notch-Delta signalling [3,4], a pathway which in vertebrates has been implicated in defining somite boundaries [5-9]. These observations place the segmentation clock upstream of the Notch-Delta pathway during vertebrate somitogenesis.

Animals↗
PubMed1999

Frizzled regulation of Notch signalling polarizes cell fate in the Drosophila eye.

The Drosophila eye, a paradigm for epithelial organization, is highly polarized with mirror-image symmetry about the equator. The R3 and R4 photoreceptors in each ommatidium are vital in this polarity; they adopt asymmetrical positions in adult ommatidia and are the site of action for several essential genes. Two such genes are frizzled (fz) and dishevelled (dsh), the products of which are components of a signalling pathway required in R3, and which are thought to be activated by a diffusible signal. Here we show that the transmembrane receptor Notch is required downstream of dsh in R3/R4 for them to adopt distinct fates. By using an enhancer for the Notch target gene Enhancer of split mdelta, we show that Notch becomes activated specifically in R4. We propose that Fz/Dsh promotes activity of the Notch ligand Delta and inhibits Notch receptor activity in R3, creating a difference in Notch signalling capacity between R3 and R4. Subsequent feedback in the Notch pathway ensures that this difference becomes amplified. This interplay between Fz/Dsh and Notch indicates that polarity is established through local comparisons between two cells and explains how a signal from one position (for example, the equator in the eye) could be interpreted by all ommatidia in the field.

Adaptor Proteins, Signal Transducing↗
PubMed2006

NUMB is a break of WNT-Notch signaling cycle.

Notch, FGF and WNT signaling pathways cross-talk during embryogenesis, tissue regeneration and carcinogenesis. Notch-ligand binding to Notch receptors leads to the cleavage of Notch receptors and the following nuclear translocation of Notch intracellular domain (NICD) to induce transcriptional activation of Notch target genes. Notch signaling inhibitors, NUMB and NUMB-like (NUMBL), are docking proteins with PTB domain. We searched for the TCF/LEF-binding site within the promoter region of NUMB and NUMBL genes. Because two TCF/LEF-binding sites were identified within human NUMB promoter based on bioinformatics and human intelligence (Humint), comparative integromics analyses on NUMB orthologs were further performed. Chimpanzee NUBM gene, consisting of 13 exons, was identified within NW_115880.1 genome sequence. XM_510045.1 was not the correct coding sequence for chimpanzee NUMB. Chimpanzee NUMB gene was found to encode a 651-amino-acid protein showing 99.5, 93.9 and 82.6% total-amino-acid identity with human NUMB, mouse Numb and chicken numb, respectively. Human NUMB mRNA was expressed in placenta, ES cells, neural tissues, trachea, testis, uterus, thymus, coronary artery as well as in a variety of tumors, such as cervical cancer, tong tumor, brain tumor, colorectal and breast cancer. Although distal TCF/LEF-binding site within human NUMB promoter was conserved only among primate NUMB orthologs, proximal TCF/LEF-binding site was conserved among primate and rodent NUMB orthologs. NUMB, JAG1, FGF18, FGF20 and SPRY4 are potent targets of the canonical WNT signaling pathway in progenitor cells. NUMB inhibits Notch signaling in progenitor cells to induce differentiation, while JAG1 activates Notch signaling in stem cells to maintain self-renewal potential. Because Notch signaling inhibitor NUMB was identified as the safe apparatus for the WNT - Notch signaling cycle, epigenetic silencing, deletion and loss-of-function mutation of NUMB gene could lead to carcinogenesis through the dysregulation of the WNT - Notch signaling cycle.

Animals↗
PubMed2006

Bone marrow stromal cells induce BMP2/4 production in oxygen-glucose-deprived astrocytes, which promotes an astrocytic phenotype in adult subventricular progenitor cells.

Bone morphogenetic proteins (BMPs) affect cell proliferation and differentiation. Astrocytes in ischemic brain are highly responsive to bone marrow stromal cell (BMSC) treatment. We investigated the effects of BMSCs on astrocytes cultured under oxygen- and glucose-deprived conditions, which in part simulate in vivo stroke conditions, to test the hypothesis that BMSCs alter astrocytic expression of BMPs which may contribute to neurological functional recovery of stroke. Quantitative real-time RT-PCR showed that the expression of BMP2/4 mRNAs decreased within ischemic astrocytes, In contrast, BMP2/4 mRNA was significantly increased after cocultured with BMSCs. Western blotting also confirmed this increase at the protein level in the medium of ischemic astrocytes after coculture with BMSCs. As a source of neural stem and progenitor cells, cultured subventricular zone (SVZ) neurospheres exposed to medium obtained from ischemic astrocytes cocultured with BMSCs were significantly enriched in cells expressing the astrocytic marker glial fibrillary acidic protein (GFAP), but not at the expense of beta-III-tubulin-positive SVZ neuroblasts. The expression of BMP2/4 subsequently increased the phosphorylation of downstream effector Smad1 and the expression of notch signal pathway-induced protein Hes1 in cultured SVZ neurospheres. BMP antagonist Noggin blocked the elevation of phosphorylated Smad1 and the expression of Hes1 as well as reducing the percentage of astrocytic SVZ progenitor cells. Our results indicate that BMSCs increase BMP2/4 expression in ischemic astrocytes. These changes enhance subventricular progenitor cell gliogenesis by activating relevant signaling pathways. BMSC-stimulated signaling of endogenous astrocytes may alter the ischemic environment, promoting remodeling of brain and hence, improve functional recovery after stroke.

Animals↗