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Accumulation of hyaluronan around different cell population in stage HH 23, shown in photomicrographs of transverse sections of the spinal cord. Fluorescent double labeling with HA (red, in all panels), PCNA (A, green), Lim1,2 (B, green), MNR2 (C, green). The enframed areas are enlarged on A , B and C . Scale bars: 20 m.
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One major component of the extracellular matrix is hyaluronan (HA) which is thought to play a crucial role in the development of different organs including the central nervous system (CNS). HA is bound by specific receptors, CD44 and RHAMM, depending on cell types of CNS. However, data are lacking on the relation of HA to different cell populations...
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Context 1
... fluorescent double labeling, increased HA accumula- tion was detected in the intermediate zone where the numbers of PCNA-immunoreactive proliferating cells were suddenly decreased compared to the ventricular zone ( Fig. 2A). The differentiating neurons of Lim1,2 positivity and early cells with motoneuron fate expressing the MNR2 homeodomain demarcated the HA reach area in stage HH23 (Fig. 2B and ...
Context 2
... HA accumula- tion was detected in the intermediate zone where the numbers of PCNA-immunoreactive proliferating cells were suddenly decreased compared to the ventricular zone ( Fig. 2A). The differentiating neurons of Lim1,2 positivity and early cells with motoneuron fate expressing the MNR2 homeodomain demarcated the HA reach area in stage HH23 (Fig. 2B and ...
Citations
... More importantly, the CACNA1C gene was found to significantly affect limb performance in mice, specifically manifested as limb shortening in CACNA1C mutant mice, which was believed to be related to abnormalities in the Ca 2+ pathway (Atsuta et al., 2019). Huh et al. (2007), Meszar et al. (2008), and Gallina et al. (2016) found that CD44, as a component of hyaluronic acid, was involved in cell migration and spinal cord development, and might play a role in early neuronal development and corneal and retinal development in chicken embryos (Huh et al., 2007;Meszar et al., 2008;Gallina et al., 2016). CD44 were ralated to T cell activity (Naghizadeh et al., 2022), the self-renewal and pluripotency of bone marrow mesenchymal stem cells (Gong et al., 2011;Adhikari et al., 2019), and also played a role in the differentiation of progenitor cells into osteoblasts and chondrocytes (Wang et al., 2018a). ...
... More importantly, the CACNA1C gene was found to significantly affect limb performance in mice, specifically manifested as limb shortening in CACNA1C mutant mice, which was believed to be related to abnormalities in the Ca 2+ pathway (Atsuta et al., 2019). Huh et al. (2007), Meszar et al. (2008), and Gallina et al. (2016) found that CD44, as a component of hyaluronic acid, was involved in cell migration and spinal cord development, and might play a role in early neuronal development and corneal and retinal development in chicken embryos (Huh et al., 2007;Meszar et al., 2008;Gallina et al., 2016). CD44 were ralated to T cell activity (Naghizadeh et al., 2022), the self-renewal and pluripotency of bone marrow mesenchymal stem cells (Gong et al., 2011;Adhikari et al., 2019), and also played a role in the differentiation of progenitor cells into osteoblasts and chondrocytes (Wang et al., 2018a). ...
The bird beak is mainly functioned as feeding and attacking, and its shape has extremely important significance for survival and reproduction. In chickens, since beak shape could lead to some disadvantages including pecking and waste of feed, it is important to understand the inheritance of chicken beak shape. In the present study, we firstly established 4 indicators to describe the chicken beak shapes, including upper beak length (UL), lower beak length (LL), distance between upper and lower beak tips (DB) and upper beak curvature (BC). And then, we measured the 4 beak shape indicators as well as some production traits including body weight (BW), shank length (SL), egg weight (EW), eggshell strength (ES) of a layer breed, Rhode Island Red (RIR), in order to estimate genetic parameters of chicken beak shape. The heritabilities of UL and LL were 0.41 and 0.37, and the heritabilities of DB and BC were 0.22 and 0.21, indicating that beak shape was a highly or mediumly heritable. There were significant positive genetic and phenotypic correlations among UL, LL, and DB. And UL was positively correlated with body weight (BW18) and shank length (SL18) at 18 weeks of age in genetics, and DB was positively correlated with BC in terms of genetics and phenotype. We also found that layers of chicken cages played a role on beak shape, which could be attributed to the difference of lightness in different cage layers. By a genome-wide association study (GWAS) for the chicken UL, we identified 9 significant candidate genes associated with UL in RIR. For the variants with low minor allele frequencies (MAF <0.01) and outside of high linkage disequilibrium (LD) regions, we also conducted rare variant association studies (RVA) and GWAS to find the association between genotype and phenotype. We also analyzed transcriptomic data from multiple tissues of chicken embryos and revealed that all of the 9 genes were highly expressed in beak of chicken embryos, indicating their potential function for beak development. Our results provided the genetic foundation of chicken beak shape, which could help chicken breeding on beak related traits.
... HMW HA is known to reduce inflammation in a variety of tissues, while fragments of different sizes either promote or inhibit inflammatory processes [6,8]. HMW HA also reduces proliferation of multiple neural cell types [9][10][11][12][13], and both HMW HA and HA fragments can regulate cell differentiation in the CNS [12][13][14][15]. Additionally, HA signaling can change based on its association with other ECM components as well as covalent modifications. ...
... HMW HA is known to reduce inflammation in a variety of tissues, while fragments of different sizes either promote or inhibit inflammatory processes [6,8]. HMW HA also reduces proliferation of multiple neural cell types [9][10][11][12][13], and both HMW HA and HA fragments can regulate cell differentiation in the CNS [12][13][14][15]. Additionally, HA signaling can change based on its association with other ECM components as well as covalent modifications. ...
... After neurulation, the lowest concentration of HA is found in the ventricular zone where neural stem cells (NSCs) are undergoing self-renewal [13]. HA receptors including CD44 and RHAMM are also expressed in the ventricular zone, and RNA analyses of the developing CNS indicate that cell-ECM interactions through these and other ECM receptors may be crucial for the proliferative capacity of NSCs [40][41][42]. ...
Hyaluronic acid (HA) plays a vital role in the extracellular matrix of neural tissues. Originally thought to hydrate tissues and provide mechanical support, it is now clear that HA is also a complex signaling molecule that can regulate cell processes in the developing and adult nervous systems. Signaling properties are determined by molecular weight, bound proteins, and signal transduction through specific receptors. HA signaling regulates processes such as proliferation, differentiation, migration, and process extension in a variety of cell types including neural stem cells, neurons, astrocytes, microglia, and oligodendrocyte progenitors. The synthesis and catabolism of HA and the expression of HA receptors are altered in disease and influence neuroinflammation and disease pathogenesis. This review discusses the roles of HA, its synthesis and breakdown, as well as receptor expression in neurodevelopment, nervous system function and disease.
... It has become clear that molecules of the extracellular matrix (ECM) play an important role in neural development, proliferation, migration, axonal guidance, synapse formation and remodeling (Barros et al. 2011;Bruckner et al. 2008;Celio et al. 1998;Dityatev and Fellin 2008;Dzyubenko et al. 2016;Faissner et al. 2010;Fawcett 2015;Kwok et al. 2011;Reinhard et al. 2015;Wiese and Faissner 2015). The major components of the ECM are (1) hyaluronan (HA), (2) chondroitin sulfate proteoglycans (CSPG) or lecticans including aggrecan, brevican, neurocan, versican (3) glycoproteins e.g., tenascin-R (TN-R), and link proteins (Carulli et al. 2006;Delpech et al. 1989;Dityatev and Schachner 2003;Eggli et al. 1992;Gong et al. 1994;Hartig et al. 1992;Margolis et al. 1975;Matesz et al. 2005;Meszar et al. 2008; Morawski et al. 2012;Szigeti et al. 2006;Yasuhara et al. 1994;Zimmermann and Dours-Zimmermann 2008). In the olfactory bulb only the role of TN-R was examined. ...
Extracellular matrix (ECM) became an important player over the last few decades when studying the plasticity and regeneration of the central nervous system. In spite of the established role of ECM in these processes throughout the central nervous system (CNS), only few papers were published on the ECM of the olfactory system, which shows a lifelong plasticity, synaptic remodeling and postnatal neurogenesis. In the present study, we have described the localization and organization of major ECM molecules, the hyaluronan, the lecticans, tenascin-R and HAPLN1 link protein in the olfactory bulb (OB) of the rat. We detected all of these molecules in the OB showing differences in the molecular composition, staining intensity, and organization of ECM between the layers and in some cases within a single layer. One of the striking features of ECM staining pattern in the OB was that the reactions are shown dominantly in the neuropil, the PNNs were found rarely and they exhibited thin or diffuse appearance Similar organization was shown in human and mice samples. As the PNN limits the neural plasticity, its rare appearance may be related to the high degree of plasticity in the OB.
... Neural and glial cells synthesise HA in culture and as an ECM CNS component (Fowke et al. 2017, Hagenfeld et al. 2010, Lin et al. 2007, Meszar et al. 2008. Depolarization of the neural plasma membrane by HA represents a novel signal transduction pathway (Hagenfeld et al. 2010) complementing CD44 mediated signal transduction. ...
Compared to the other classes of glycosaminoglycans (GAGs), that is, chondroitin/dermatan sulfate, heparin/heparan sulfate and hyaluronan, keratan sulfate (KS), have the least known of its interactive properties. In the human body, the cornea and the brain are the two most abundant tissue sources of KS. Embryonic KS is synthesized as a linear poly‐N‐acetyllactosamine chain of d‐galactose‐GlcNAc repeat disaccharides which become progressively sulfated with development, sulfation of GlcNAc is more predominant than galactose. KS contains multi‐sulfated high‐charge density, monosulfated and non‐sulfated poly‐N‐acetyllactosamine regions and thus is a heterogeneous molecule in terms of chain length and charge distribution. A recent proteomics study on corneal KS demonstrated its interactivity with members of the Slit‐Robbo and Ephrin‐Ephrin receptor families and proteins which regulate Rho GTPase signaling and actin polymerization/depolymerization in neural development and differentiation. KS decorates a number of peripheral nervous system/CNS proteoglycan (PG) core proteins. The astrocyte KS‐PG abakan defines functional margins of the brain and is up‐regulated following trauma. The chondroitin sulfate/KS PG aggrecan forms perineuronal nets which are dynamic neuroprotective structures with anti‐oxidant properties and roles in neural differentiation, development and synaptic plasticity. Brain phosphacan a chondroitin sulfate, KS, HNK‐1 PG have roles in neural development and repair. The intracellular microtubule and synaptic vesicle KS‐PGs MAP1B and SV2 have roles in metabolite transport, storage, and export of neurotransmitters and cytoskeletal assembly. MAP1B has binding sites for tubulin and actin through which it promotes cytoskeletal development in growth cones and is highly expressed during neurite extension. The interactive capability of KS with neuroregulatory ligands indicate varied roles for KS‐PGs in development and regenerative neural processes.
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... During development of the chick, HA is concentrated in the intermediate zone which gives rise to the white matter 58 . HA is crucial in maintaining neural progenitor cells in an undifferentiated state 59 . ...
Perineuronal nets (PNNs) are the key regulators of neuronal plasticity and regeneration in the mature central nervous system (CNS). They are a unique and highly organised extracellular matrix (ECM) structure, found around sub-population of neurons, composed mainly of chondroitin sulfate proteoglycan (CSPG). Chondroitin sulfate (CS) is a linear polysaccharide belonging to glycosaminoglycans (GAGs) family. The sulphation pattern defines different types of CS, which interact with different signalling proteins including those regulating axonal outgrowth and guidance such as semaphorin 3A (Sema3A). Sema3A is a secreted chemorepulsive protein found accumulated in the PNNs through its interaction with CS. This process is believed to potentiate Sema3A signalling through plexin A1 (PlxnA1) and Neuropilin 1 (Nrp1) and regulate plasticity and regeneration. The aim of the thesis project is to characterise the interface of Sema3A- CS interaction.For this purpose, Sema3A is expressed in eukaryote cells and purified. Interestingly, two major forms were obtained: a full length Sema3A (90 kDa) which remains attached to the cell surface GAGs and a truncated form without the C-ter part (65 kDa) which is released to the culture medium. With the use of surface plasmon resonance (SPR), we observed that full length Sema3A binds selectively to CS-E (4,6-disulfated chondroitin) and heparan sulfate with a high affinity (KD in the sub pM range), while the truncated Sema3A does not bind to any GAG. Four putative GAG binding sequences were identified in the C-ter of Sema3A and mutated using site directed mutagenesis. SPR analysis then revealed that two out of these four sites are required for the binding to CS-E. The importance of these GAG-binding sequences in inhibition of neurites outgrowth of dorsal root ganglion neurons in culture was also reported, indicating thus the importance of GAG-binding in Sema3A signalling. In parallel, the minimal required sequence of Sema3A-binding of CS-E was determined as being a tetrasaccharide. The Sema3A-CS interface was thus characterized. Furthermore, quartz crystal microbalance with dissipation monitoring analysis suggested that Sema3A could crosslink GAG chains. This suggests Sema3A could be involved in stabilising the PNN network and induces mechanical changes on neuronal surface.The detail characterization of Sema3A-CS interaction may enable the design of new strategies aiming at enhancing plasticity and regeneration for neurodegenerative diseases or spinal cord injury.
... Although the majority of these molecules appear as a diffuse network in the neuropil, the condensed forms may also present as they surround the neuronal cell body, dendrites and axon initial segment as the perineuronal net (PNN), or form the axonal coat around the presynaptic bouton, or associated with the node of Ranvier as nodal ECM (Celio et al., 1998;Carulli et al., 2006;Bruckner et al., 2008;Bekku et al., 2009;Bekku and Oohashi, 2010;Dityatev, 2010;Frischknecht and Seidenbecher, 2012;Lendvai et al., 2012;Blosa et al., 2013). The ECM shows an area-dependent distribution pattern, and its molecular and structural heterogeneity is correlated with the morphological and functional properties of the neurons (Matesz et al., 2005;Szigeti et al., 2006;Meszar et al., 2008;Morawski et al., 2009;Gati et al., 2010;Lendvai et al., 2012;Morawski et al., 2012;Jager et al., 2013;Gaal et al., 2014;Gaati et al., 2014;Racz et al., 2014Racz et al., , 2015bKecskes et al., 2015). The ECM molecules are involved in the synaptic transmission as they are the fourth components of synaptic machinery besides the presynaptic and postsynaptic neurons as well as the astroglia cell (Dityatev and Schachner, 2006;Faissner et al., 2010;Dityatev and Rusakov, 2011;Chelini et al., 2018). ...
Previously we described similarities and differences in the organization and molecular composition of an aggrecan based extracellular matrix (ECM) in three precerebellar nuclei, the inferior olive, the prepositus hypoglossi nucleus and the red nucleus of the rat associated with their specific cytoarchitecture, connection and function in the vestibular system. The aim of present study is to map the ECM pattern in a mesencephalic precerebellar nucleus, the pararubral area, which has a unique function among the precerebellar nuclei with its retinal connection and involvement in the circadian rhythm regulation. Using histochemistry and immunohistochemistry we have described for the first time the presence of major ECM components, the hyaluronan, aggrecan, versican, neurocan, brevican, tenascin-R (TN-R), and the HAPLN1 link protein in the pararubral area. The most common form of the aggrecan based ECM was the diffuse network in the neuropil, but each type of the condensed forms was also recognizable. Characteristic perineuronal nets (PNNs) were only recognizable with Wisteria floribunda agglutinin (WFA) and aggrecan staining around some of the medium-sized neurons, whereas the small cells were rarely surrounded by a weakly stained PNNs. The moderate expression of key molecules of PNN, the hyaluronan (HA) and HAPLN1 suggests that the lesser stability of ECM assembly around the pararubral neurons may allow quicker response to the modified neuronal activity and contributes to the high level of plasticity in the vestibular system.
... It is particularly abundant in the fetal brain and surrounding immature neurons during differentiation in the spinal cord, indicative of its vital role in CNS development. [62][63][64] Second, the hydrogel formulation can be well controlled and defined with better reproducibility than Matrigel. 24,65 Third, our Me-HA hydrogels can combine with other hydrogel systems (i.e. ...
Human induced pluripotent stem cell-derived neural progenitor cells (hiPSC-NPCs) are considered as a promising cell source for transplantation and have been used for organoid fabrication to recapitulate central nervous system (CNS) diseases in vitro. The establishment of three-dimensional (3D) in vitro model with hiPSC-NPCs and control of their differentiation is significantly critical for understanding biological processes and CNS disease and regeneration. Here we implemented 3D methacrylated hyaluronic acid (Me-HA) hydrogels with encapsulation of hiPSC-NPCs as in vitro culture models and further investigated the role of the hydrogel rigidity on the cell behavior of hiPSC-NPCs. We first encapsulated single dispersive hiPSC-NPCs within both soft and stiff Me-HA hydrogel and found that hiPSC-NPCs gradually self-assembled and aggregated to form 3D spheroids. Then, the hiPSC-NPCs were laden into Me-HA hydrogels in the form of spheroids to evaluate their spontaneous differentiation in response to hydrogel rigidity. The soft Me-HA hydrogel-encapsulated hiPSC-NPCs displayed robust neurite outgrowth and showed high levels of spontaneous neural differentiation. We further encapsulated Down Syndrome (DS) patient-specific hiPSC-derived NPCs (DS-NPCs) spheroids within our hydrogels. DS-NPCs remained excellent cell viability in both soft and stiff Me-HA hydrogels. Similarly, soft hydrogels promoted neural differentiation of DS-NPCs by significantly upregulating neural maturation markers. This study demonstrates that soft matrix promotes neural differentiation of hiPSC-NPCs and HA-based hydrogels with hiPSC-NPCs or DS-NPCs are effective 3D models for CNS disease study.
... Additionally, the high molecular weight of HA adds an essential structural and organizational element into the ECM of native tissues (Kreger and Voytik-Harbin, 2009;Toole, 2004). It is instrumental in cell migration (Baier et al., 2007;Turley et al., 2002), nerve regeneration (Faroni et al., 2015;Ikeda et al., 2003;Seidlits et al., 2010), neuronal (Baier et al., 2007;Banerjee and Toole, 1991;Margolis et al., 1975;Mészár et al., 2008;Rauch et al., 2005) and glial development (Back et al., 2005;Liu et al., 2004), and wound healing (Aya and Stern, 2014). Hyaluronic acid has only minor crossspecies variation and excellent biocompatibility (Dana et al., 2004;Leach et al., 2003). ...
This paper discusses "bioink", bioprintable materials used in three dimensional (3D) bioprinting processes, where cells and other biologics are deposited in a spatially controlled pattern to fabricate living tissues and organs. It presents the first comprehensive review of existing bioink types including hydrogels, cell aggregates, microcarriers and decellularized matrix components used in extrusion-, droplet- and laser-based bioprinting processes. A detailed comparison of these bioink materials is conducted in terms of supporting bioprinting modalities and bioprintability, cell viability and proliferation, biomimicry, resolution, affordability, scalability, practicality, mechanical and structural integrity, bioprinting and post-bioprinting maturation times, tissue fusion and formation post-implantation, degradation characteristics, commercial availability, immune-compatibility, and application areas. The paper then discusses current limitations of bioink materials and presents the future prospects to the reader.
... HAPLN1 (Ha¨rtig et al., 1992;Celio et al., 1998;Carulli et al., 2006;Bru¨ckner et al., 2008;Zimmermann and Dours-Zimmermann, 2008;Kwok et al., 2011;Morawski et al., 2012). According to the recent observations, the molecular and structural heterogeneity of the ECM in various regions of the CNS is correlated with the morphological, neurochemical and functional properties of neurons Szigeti et al., 2006;Meszar et al., 2008;Gati et al., 2010Gati et al., , 2014Lendvai et al., 2012;Morawski et al., 2012;Ja¨ger et al., 2013;Gaal et al., 2014Gaal et al., , 2015bRacz et al., 2014;Kecskes et al., 2015). ECM molecules are involved in various events of the CNS during both development and in adulthood. ...
Previous studies in our laboratory showed that the organization and heterogeneous molecular composition of extracellular matrix is associated with the variable cytoarchitecture, connections and specific functions of the vestibular nuclei and two related areas of the vestibular neural circuits, the inferior olive and prepositus hypoglossi nucleus. The aim of the present study is to reveal the organization and distribution of various molecular components of extracellular matrix in the red nucleus, a midbrain premotor center. Morphologically and functionally the red nucleus is comprised of the magno- and parvocellular parts, with overlapping neuronal population. By using histochemical and immunohistochemical methods, the extracellular matrix appeared as perineuronal net, axonal coat, perisynaptic matrix or diffuse network in the neuropil. In both parts of the red nucleus we have observed positive hyaluronan, tenascin-R, link protein, and lectican (aggrecan, brevican, versican, neurocan) reactions. Perineuronal nets were detected with each of the reactions and the aggrecan showed the most intense staining in the pericellular area. The two parts were clearly distinguished on the basis of neurocan and HAPLN1 expression as they have lower intensity in the perineuronal nets of large cells and in the neuropil of the magnocellular part. Additionally, in contrast to this pattern, the aggrecan was heavily labeled in the magnocellular region sharply delineating from the faintly stained parvocellular area. The most characteristic finding was that the appearance of perineuronal nets was related with the neuronal size independently from its position within the two subdivisions of red nucleus. In line with these statements none of the extracellular matrix molecules were restricted exclusively to the magno- or parvocellular division. The chemical heterogeneity of the perineuronal nets may support the recently accepted view that the red nucleus comprises more different population of neurons than previously reported.
... For instance, during development of the chick spinal cord, HA expression is observed around ventricular zones, which are hypothesized to be an NSC ''niche'', and around differentiating neurons, including motor neurons. 42 Although HA content continues to decrease with age, 11,43,44 HA-NSC interactions remain vital for proper function and repair of the CNS throughout adulthood. Many of the interactions and biological effects of HA are mediated by CD44, which is highly expressed by NSCs. ...
While in the past hyaluronic acid (HA) was considered a passive component with a primarily structural role in tissues, research over the past few decades has revealed its diverse and complex biological functions, resulting in a major ideological shift. HA is abundant during normal central nervous system (CNS) development and, although down-regulated, remains ubiquitous in adult extracellular matrix (ECM). Significant changes in HA content are associated with pathological conditions, including stroke, traumatic injury and multiple sclerosis, and these changes likely disrupt repair by endogenous neural stem cells (NSCs). In this review, we describe recent findings in HA biology relevant to NSCs-focusing on the potential of HA-NSC interactions to mediate CNS regeneration. Currently, HA biomaterials are being developed to counteract matrix changes associated with CNS injury and disease, thereby promoting NSC survival and directing differentiation. In parallel, HA-based biomaterials engineered to mimic the native CNS microenvironment are being used to investigate the relationship between NSCs and their HA-rich surroundings within a controlled experimental space. As our understanding of HA-NSC interactions improves, so will the therapeutic potential of HA-based biomaterials. Efforts to better understand the relationship between HA bioactivities and biomaterial design parameters are already underway. Although significant progress has been made improving techniques for controlled fabrication of HA-based hydrogels with precisely defined features, there is still much work to be done. Ideally, future designs will incorporate multiple types of microenvironmental cues-orthogonally tuned in time and space-to direct differentiation of NSCs into various specialized lineages within a single biomaterial platform.
