Marginal Cells Research Articles

Tagged actin mRNA dysregulation in IGF2BP1−/− mice

Gene expression is tightly regulated by RNA-binding proteins (RBPs) to facilitate cell survival, differentiation, and migration. Previous reports have shown the importance of the Insulin-like Growth Factor II mRNA-Binding Protein (IGF2BP1/IMP1/ZBP1) in regulating RNA fate, including localization, transport, and translation. Here, we generated and characterized a knockout mouse to study RBP regulation. We report that IGF2BP1 is essential for proper brain development and neonatal survival. Specifically, these mice display disorganization in the developing neocortex, and further investigation revealed a loss of cortical marginal cell density at E17.5. We also investigated migratory cell populations in the IGF2BP1[Formula: see text] mice, using BrdU labeling, and detected fewer mitotically active cells in the cortical plate. Since RNA localization is important for cellular migration and directionality, we investigated the regulation of β-actin messenger RNA (mRNA), a well-characterized target with established roles in cell motility and development. To aid in our understanding of RBP and target mRNA regulation, we generated mice with endogenously labeled β-actin mRNA (IGF2BP1[Formula: see text]; β-actin-MS2[Formula: see text]). Using endogenously labeled β-actin transcripts, we report IGF2BP1[Formula: see text] neurons have increased transcription rates and total β-actin protein content. In addition, we found decreased transport and anchoring in knockout neurons. Overall, we present an important model for understanding RBP regulation of target mRNA.

Hormone pathway comparison in non-idiopathic and idiopathic progressive subglottic stenosis.

Our previous study on the idiopathic progressive subglottic stenosis (IPSS) highlighted a possible hormonal mechanism, with over-expression of estrogen receptors alpha (ER-α) and progesterone receptors (PR). We tested whether such over-expression take place in non-idiopathic subglottic stenosis (NISS) as well. 37 specimens of iatrogenic NISS were analyzed (20 females; mean age, 59 ± 12years; range 41-85). Immunoreactivity of ER-α and PR was calculated as the product of intensity (1 = weak, 2 = moderate, 3 = strong) and positive cells percentage (1 to 4, for < 10%, 10-50%, 50-80%, and > 80%). This score was calculated on the stenotic tissue (ST), and stenosis margins (SM). The expression of PR was significantly higher in ST of IPSS compared with female and male NISS patients (8.7 ± 3.1 vs. 4.9 ± 3.2, p < 0.001 for IPSS vs. female and 8.7 ± 3.1 vs. 2.1 ± 2.7, p < 0.01 for IPSS vs. male NISS patients). Contrarily, ER-α showed gender differences, as both IPSS and female NISS patients had similar, yet higher ER-α expression compared with male NISS patients (7.0 ± 4.2 vs. 6.5 ± 2.5, p = NS for IPSS vs. female and 7.0 ± 4.2 vs. 3.4 ± 2.0, p < 0.02 for IPSS vs. male NISS patients). There was no difference in fibroblast receptor expression between ST and SM. However, ER-α and PR expression was significantly lower in marginal mucous glands when compared with ST. The IPSS pathogenesis appears to be driven by hormonal mechanisms, in particular, by over-expression of PR. Marginal cells display a reduced hormone receptor density. This finding could be interpreted as a compensatory mechanism. These findings could open up for targeted IPSS treatment.

Pyrenopeziza orientalipetiolaris sp. nov. in Japan and morphological and genetic comparison with its relevant species P. petiolaris in Europe.

Some Asian fungi are morphologically very similar to European species but belong to different species. A fungus that resembles Pyrenopeziza petiolaris, which commonly occurs on the petioles of Acer pseudoplatanus in Europe, was found on the petioles of Acer spp. and other tree leaves in Japan. The apothecia of this fungus were smaller than those of P. petiolaris, suggesting that it is a different species. To examine this possibility, specimens of this fungus were collected from various hosts in Japan. A detailed morphological examination elucidated that this fungus differed from P. petiolaris in smaller apothecia, marginal cells of the ectal excipulum, and conidia. The ITS sequence difference between this fungus and P. petiolaris was 3.3-4.3%, and they formed distinct clades in the phylogenetic analysis, supporting that they are different species. Consequently, a new species, P. orientalipetiolaris is described. Since an undescribed phialophora-state was observed in the cultures of P. petiolaris for the first time, the morphology under culture is also reported in detail.

Amanita calida sp. nov., una nueva especie europea de Amanita sect. Vaginatae

Amanita calida is illustrated and described from collections made in Andalusia and Catalonia, in a Mediterranean environment, associated with Quercus. Macroscopically, this species is characterized by a whitish, beige to grayish cuticle, with a sometimes prominent darker brown umbo, a widely striated margin of the pileus, a very elongated stipe in proportion to the diameter of the pileus, whitish or with similar but fainter shades to those of the pileus; and a sacciform, membranous, whitish volva with brownish macules on the outside. Microscopically, it has subglobose, multigutulate basidiospores, spheropedunculate to clavate marginal cells and loosely divergent bilateral lamellar trama. The analyses of the ITS and LSU (nrDNA) genetic markers, support its differentiation from other species of the genus, and that it is an undescribed species.

HIF-1α enhances autophagy to alleviate apoptosis in marginal cells in the stria vascular in neonatal rats under hypoxia

In the cochlea, various factors, such as noise, aging, and inflammation, induce hypoxia, resulting in the up-regulation of hypoxia inducible factor-1α (HIF-1α). The role of HIF-1α in hypoxic marginal cells (MCs) of the stria vascularis is unknown. This study examined HIF-1α-mediated autophagy in MCs of neonatal rats and its mechanism of action. We found that an increase in HIF-1α expression was associated with autophagy and apoptosis. Treatment with PX478, a specific inhibitor of HIF-1α, decreased the HIF-1α level, and the degree of autophagy decreased in hypoxic and apoptotic MCs. By contrast, treatment with DMOG, an activator of HIF-1α, increased autophagy and decreased apoptosis. Both PX478 and DMOG had no effect on the apoptotic rate after treatment with 3-methyladenine, an inhibitor of autophagy, indicating that HIF-1α promoted autophagy to protect MCs from hypoxia-induced apoptosis. Lastly, we silenced Bnip3(Bcl-2/adenovirus E1B 19-kDa interacting protein) in MCs to identify the mechanism of action. Our results show that the HIF-1α-BNIP3 pathway mediates the anti-apoptotic effects through an increase in autophagy.

AAV8BP2 and AAV8 transduce the mammalian cochlear lateral wall and endolymphatic sac with high efficiency

Inner ear gene therapy using adeno-associated viruses (AAVs) has been successfully applied to several mouse models of hereditary hearing loss to improve their auditory function. While most inner ear gene therapy studies have focused on the mechanosensory hair cells and supporting cells in the organ of Corti, the cochlear lateral wall and the endolymphatic sac have not garnered much attention. The cochlear lateral wall and the endolymphatic sac play critical roles in inner ear ionic and fluid homeostasis. Mutations in genes expressed in the cochlear lateral wall and the endolymphatic sac are present in a large percentage of patients with hereditary hearing loss. In this study, we examine the transduction patterns and efficiencies of conventional (AAV2 and AAV8) and synthetic (AAV2.7m8, AAV8BP2, and Anc80L65) AAVs in the mouse inner ear. We found that AAV8BP2 and AAV8 are capable of transducing the marginal cells and intermediate cells in the stria vascularis. These two AAVs can also transduce the epithelial cells of the endolymphatic sac. Our data suggest that AAV8BP2 and AAV8 are highly useful viral vectors for gene therapy studies targeting the cochlear lateral wall and the endolymphatic sac.

The Potential Clinical Application of Induced Tolerogenic Macrophages.

The Potential Clinical Application of Induced Tolerogenic Macrophages.

Anatomical Examinations of Selected Wood Species of Nigerian Genera in Anacardiaceae Family

Nigerian Anacarddiacea family was investigated in this study on the account of their inherent structures with a view to bringing to the fore those features that could facilitate identification towards proper utilization based on wood quality. Mature wood species of Lannea grandis, Lannea welwitchii, Mangifera indica, Nothospondis staudtia, Pseudospondias microcarpa, Sclerocarya burrea, Sorindeia trimeris, Spondias mangifera, Spondias mombin and Trichoscypha acuminate were got from the Forestry Research Institute of Nigeria herbaratum, in Ibadan. Wood samples from the wood species were sectioned into cross sectional, tangential and radial sections of about 20μm thick using a Reichert sliding microtome. Photomicrographs were taken using a digital camera mounted on a Reichert light microscope at 40 ×. The results showed that vessels were large in all the wood species except in Lannea species, Sclerocarya burrea, Nothospondis staudtia and Trichoscypha acuminata. Body ray cells were procumbent with one row of upright and/or square marginal cells in all the wood species, but could be up to four rows in Sorindeia trimeris. Generally, septate fibres, silica,crystals and gum were observed in almost all the wood species, yet, fibre pits in Mangifera indica, Nothospondis staudtia, Pseudospondias microcarpa, Sclerocarya burrea, Spondias mombin, and L. grandis were not as bordered as they were in L. acida, L. welwitchii, Sorindeia trimeris, Spondias mangifera, and Trichoscypha acuminata. S..mombin and S. mangifera can be separated on this account. It also appears that rays were storied only in Sorindeia trimeris and L. grandis. In the aspect of wood utilization, some were expected to possess fine texture, lustrous patterns and also regions of failures as a result of high rays.&#x0D; &#x0D; Received: 11 April 2022 / Accepted: 30 June 2022 / Published: 5 July 2022

MiR-106a facilitates the sensorineural hearing loss induced by oxidative stress by targeting connexin-43

ABSTRACT Sensorineural hearing loss (SNHL) is a common clinical side effect resulted from the overusing of aminoglycoside antibacterial drugs, such as gentamicin. Oxidative stress is recently evidenced to be an important inducer for SNHL, which is reported to be associated with the knockdown of connexin-43. MiR-106a is recently found as a regulator of connexin-43. The present study aims to investigate whether miR-106a is a vital mediator in the development of SNHL. Firstly, upregulated miR-106a was observed in the peripheral blood sample of SNHL patients. Glucose oxidase (GO) was utilized to induce oxidative injury in isolated rat cochlear marginal cells (MCs), followed by introducing the miR-106a inhibitor. We found that the declined proliferation ability, increased apoptosis, and activated oxidative stress in GO-stimulated MCs were dramatically abolished by the miR-106a inhibitor, accompanied by the upregulation of connexin-43. The targeting correlation between miR-106a and connexin-43 was predicted and confirmed by the dual luciferase gene reporter assay. Furthermore, the regulatory effect of miR-106a inhibitor against the proliferation, apoptosis, and oxidative stress in GO-treated MCs were dramatically abolished by the knockdown of connexin-43. Gentamicin was utilized to establish the SNHL model in rats, followed by the treatments of antagomir-106a and antagomir-106a combined with carbenoxolone, an inhibitor of connexin-43. The alleviated pathological state, reduced apoptosis, and ameliorated oxidative stress in cochlea tissues were observed in antagomir-106a treated SNHL rats, which were dramatically reversed by the co-administration of carbenoxolone. Collectively, miR-106a facilitated the SNHL induced by oxidative stress via targeting connexin-43.

Cell growth dynamics in two types of apical meristems in fern gametophytes.

SUMMARYIn contrast to seed plants, the gametophytes of seed‐free plants develop pluripotent meristems, which promote and sustain their independent growth and development. To date, the cellular basis of meristem development in gametophytes of seed‐free ferns remains largely unknown. In this study, we used Woodsia obtusa, the blunt‐lobe cliff fern, to quantitatively determine cell growth dynamics in two different types of apical meristems – the apical initial centered meristem and the multicellular apical meristem in gametophytes. Through confocal time‐lapse live imaging and computational image analysis and quantification, we determined unique patterns of cell division and growth that sustain or terminate apical initials, dictate the transition from apical initials to multicellular apical meristems, and drive proliferation of apical meristems in ferns. Quantitative results showed that small cells correlated to active cell division in fern gametophytes. The marginal cells of multicellular apical meristems in fern gametophytes undergo division in both anticlinal and periclinal orientations, not only increasing cell numbers but also playing a dominant role in increasing cell layers during gametophyte development. All these findings provide insights into the function and regulation of meristems in gametophytes of seed‐free vascular plants, suggesting both conserved and diversified mechanisms underlying meristem cell proliferation across land plants.

Retina regeneration: lessons from vertebrates.

Unlike mammals, vertebrates such as fishes and frogs exhibit remarkable tissue regeneration including the central nervous system. Retina being part of the central nervous system has attracted the interest of several research groups to explore its regenerative ability in different vertebrate models including mice. Fishes and frogs completely restore the size, shape and tissue structure of an injured retina. Several studies have unraveled molecular mechanisms underlying retina regeneration. In teleosts, soon after injury, the Müller glial cells of the retina reprogram to form a proliferating population of Müller glia-derived progenitor cells capable of differentiating into various neural cell types and Müller glia. In amphibians, the transdifferentiation of retinal pigment epithelium and differentiation of ciliary marginal zone cells contribute to retina regeneration. In chicks and mice, supplementation with external growth factors or genetic modifications cause a partial regenerative response in the damaged retina. The initiation of retina regeneration is achieved through sequential orchestration of gene expression through controlled modulations in the genetic and epigenetic landscape of the progenitor cells. Several developmental biology pathways are turned on during the Müller glia reprogramming, retinal pigment epithelium transdifferentiation and ciliary marginal zone differentiation. Further, several tumorigenic pathways and gene expression events also contribute to the complete regeneration cascade of events. In this review, we address the various retinal injury paradigms and subsequent gene expression events governed in different vertebrate species. Further, we compared how vertebrates such as teleost fishes and amphibians can achieve excellent regenerative responses in the retina compared with their mammalian counterparts.

An anatomical comparison of epidermal cells in wild-type and homeotic mutant flowers of Clarkia tembloriensis Vasek (Onagraceae) 1

Flowers consist of four whorls of organs (sepals, petals, stamens, and carpels), each expressing unique characteristics. In floral homeotic mutants, organs develop abnormally, and floral organs of one whorl express characteristics of another whorl. Much of our current understanding of the development of floral organs has been based on studies of floral homeotic mutants. In the homeotic mutant crinkle-petal (cp) of Clarkia tembloriensis, previous investigations demonstrated that the cp petal is a hybrid organ combining characteristics of sepals and petals. This investigation extends those studies with a comparative anatomical study of trichomes, guard cells, and marginal epidermal cells in wild-type (WT) sepals, WT petals, and cp petals. The aim was to determine if cp petals exhibit a hybrid epidermal anatomy of WT sepals and WT petals. Floral buds 1 day pre-anthesis and flowers 1 day post-anthesis were collected and prepared for light microscopy or scanning electron microscopy. Trichomes and guard cell pairs were described and counted, and marginal cells were observed and described. This anatomical study of trichomes, guard cells, and marginal cells demonstrated that cp petals of C. tembloriensis combine characteristics of both WT sepals and WT petals. These results provide further support for the hybrid nature of cp petals in Clarkia tembloriensis.

Cochlear Marginal Cell Pyroptosis Is Induced by Cisplatin via NLRP3 Inflammasome Activation.

Better understanding the mechanism of cisplatin-induced ototoxicity is of great significance for clinical prevention and treatment of cisplatin-related hearing loss. However, the mechanism of cisplatin-induced inflammatory response in cochlear stria vascularis and the mechanism of marginal cell (MC) damage have not been fully clarified. In this study, a stable model of cisplatin-induced MC damage was established in vitro, and the results of PCR and Western blotting showed increased expressions of NLRP3, Caspase-1, IL-1β, and GSDMD in MCs. Incomplete cell membranes including many small pores appearing on the membrane were also observed under transmission electron microscopy and scanning electron microscopy. In addition, downregulation of NLRP3 by small interfering RNA can alleviate cisplatin-induced MC pyroptosis, and reducing the expression level of TXNIP possesses the inhibition effect on NLRP3 inflammasome activation and its mediated pyroptosis. Taken together, our results suggest that NLRP3 inflammasome activation may mediate cisplatin-induced MC pyroptosis in cochlear stria vascularis, and TXNIP is a possible upstream regulator, which may be a promising therapeutic target for alleviating cisplatin-induced hearing loss.

Hyaluronan Synthase 1: A Novel Candidate Gene Associated With Late-Onset Non-syndromic Hereditary Hearing Loss

ObjectivesHyaluronan synthase 1 (HAS1) is a membrane-bound protein that is abundant in the epidermis and dermis, and it is important for skin function. However, its association with hearing loss has not yet been studied. Herein, we sought to evaluate the potential contribution of HAS1: c.1082G>A to genetic hearing loss.MethodsWe used whole-exome sequencing to analyze blood DNA samples of six patients of a family with autosomal dominant familial late-onset progressive hearing loss, which was revealed to be related to a variant of the HAS1 gene. Confirmatory Sanger sequencing was performed with samples from 10 members. A missense variant was detected in HAS1 (c.1082 G>A, p.Cys361Tyr). In silico analyses predicted this variant to result in the functional loss of HAS1. Immunostaining was conducted using wild-type mouse samples to verify HAS1 expression.ResultsHas1 was detected in an otocyst at E10.5. In the pup, Has1 expression was localized in the stria vascularis (SV), hair cells, supporting cells of the organ of Corti, and some spiral ganglion neurons. SV marginal cells markedly expressed Has1 in the adult stage. The hearing threshold in the Has1-depleted condition was investigated by accessing the International Mouse Phenotyping Consortium’s Auditory Brainstem Response (ABR) data. ABR of Has1 knock-out mice showed threshold elevations at 6, 12, and 18 kHz in young male adults.ConclusionHAS1 may have a close relationship with auditory function and genetic hearing loss. Further investigation is needed to reveal the precise role of HAS1 in the auditory system. HAS1 is a candidate gene for future hereditary hearing loss genetic testing.

Na/K-ATPase Gene Expression in the Human Cochlea: A Study Using mRNA in situ Hybridization and Super-Resolution Structured Illumination Microscopy.

BackgroundThe pervasive Na/K-ATPase pump is highly expressed in the human cochlea and is involved in the generation of the endocochlear potential as well as auditory nerve signaling and relay. Its distribution, molecular organization and gene regulation are essential to establish to better understand inner ear function and disease. Here, we analyzed the expression and distribution of the ATP1A1, ATP1B1, and ATP1A3 gene transcripts encoding the Na/K-ATPase α1, α3, and β1 isoforms in different domains of the human cochlea using RNA in situ hybridization.Materials and MethodsArchival paraformaldehyde-fixed sections derived from surgically obtained human cochleae were used to label single mRNA gene transcripts using the highly sensitive multiplex RNAscope® technique. Localization of gene transcripts was performed by super-resolution structured illumination microscopy (SR-SIM) using fluorescent-tagged probes. GJB6 encoding of the protein connexin30 served as an additional control.ResultsSingle mRNA gene transcripts were seen as brightly stained puncta. Positive and negative controls verified the specificity of the labeling. ATP1A1 and ATP1B1 gene transcripts were demonstrated in the organ of Corti, including the hair and supporting cells. In the stria vascularis, these transcripts were solely expressed in the marginal cells. A large number of ATP1B1 gene transcripts were found in the spiral ganglion cell soma, outer sulcus, root cells, and type II fibrocytes. The ATP1B1 and ATP1A3 gene transcripts were rarely detected in axons.DiscussionSurgically obtained inner ear tissue can be used to identify single mRNA gene transcripts using high-resolution fluorescence microscopy after prompt formaldehyde fixation and chelate decalcification. A large number of Na/K-ATPase gene transcripts were localized in selected areas of the cochlear wall epithelium, fibrocyte networks, and spiral ganglion, confirming the enzyme’s essential role for human cochlear function.

The multiciliated cells in Rathke's cleft express CYP26A1 and respond to retinoic acid in the pituitary.

The adenohypophysis consists of the anterior and intermediate lobes (AL and IL). The marginal cell layer (MCL), including the ventral region of the IL and the dorsal region of the AL lining the Rathke's cleft, acts as the primary stem/progenitor cell niches in adult adenohypophysis. The cells of the MCL on the IL side consisted of cluster of differentiation 9 (CD9)-positive stem/progenitor cells with or without motile cilia. However, any additional cellular properties of multiciliated CD9-positive cells are not known. The present study aimed to identify the character of the multiciliated cells in stem cell niche of the pituitary gland. We observed the fine structure of the multiciliated cells in the MCL of male Wistar rats at an early stage after birth and in adulthood (P60) using scanning electron microscopy. Since the previous study showed that the MCL cells of adult rats synthesize retinoic acid (RA), the present study determined whether the multiciliated cells are involved in RA regulation by the expression of retinal aldehyde dehydrogenase 1 (RALDH1) and CYP26A1, an enzyme synthesizing and degrading RA, respectively. Results showed that 96% of multiciliated cells in adult male rats expressed CYP26A1, while 60% expressed RALDH1. Furthermore, the isolated CD9-positive cells from the IL side MCL responded to RA and activated the degradation system of RA by increasing Cyp26a1 expression. These findings indicated that multiciliated cells are involved in RA metabolism in the MCL. Our observations provide novel insights regarding the stem cell niche of the adult pituitary.

Transcription Profile and Pathway Analysis of the Endocannabinoid Receptor Inverse Agonist AM630 in the Core and Infiltrative Boundary of Human Glioblastoma Cells.

Background: We have previously reported that the endocannabinoid receptor inverse agonist AM630 is a potent inhibitor of isocitrade dehydrogenase-1 wild-type glioblastoma (GBM) core tumour cell proliferation. To uncover the mechanism behind the anti-tumour effects we have performed a transcriptional analysis of AM630 activity both in the tumour core cells (U87) and the invasive margin cells (GIN-8), the latter representing a better proxy of post-surgical residual disease. Results: The core and invasive margin cells exhibited markedly different gene expression profiles and only the core cells had high expression of a potential AM630 target, the CB1 receptor. Both cell types had moderate expression of the HTR2B serotonin receptor, a reported AM630 target. We found that the AM630 driven transcriptional response was substantially higher in the central cells than in the invasive margin cells, with the former driving the up regulation of immune response and the down regulation of cell cycle and metastatic pathways and correlating with transcriptional responses driven by established anti-neoplastics as well as serotonin receptor antagonists. Conclusion: Our results highlight the different gene sets involved in the core and invasive margin cell lines derived from GBM and an associated marked difference in responsiveness to AM630. Our findings identify AM630 as an anti-neoplastic drug in the context of the core cells, showing a high correlation with the activity of known antiproliferative drugs. However, we reveal a key set of similarities between the two cell lines that may inform therapeutic intervention.

Immunohistochemical algorithms and gene expression profiling in primary cutaneous B-cell lymphoma

Objectiveto assess whether immunohistochemical (IHC) algorithms used to classify the cell of origin (COO) of nodal Diffuse Large B-cell lymphoma (nDLBCL) in Germinal Center type (GCB) and non-GCB subtypes may be applied to Primary Cutaneous B-cell lymphoma (PCBCL) too, and which of these algorithms performs better on PCBCL. DesignRetrospective case control study. SettingPathology Department of the University Hospital “San Giovanni di Dio e Ruggi d′Aragona” Salerno, Italy. ParticipantsFourteen PCBCL, including Primary Cutaneous follicle centre lymphoma (PCFCL) and primary cutaneous diffuse large B-cell lymphoma, Leg type (PCDLBCL-LT) and 14 nDLBCL were evaluated for 7-year period (January 2011 to December 2017). Primary cutaneous marginal zone cell lymphoma (PCMZL) cases were not included in the present study. InterventionEvaluation of immunohistochemical CD10, BCL6, MUM1/IRF4, BCL2, MYC and Ki-67 expression and classification according to three different algorithms. Gene expression profiling (GEP) was performed on the same series using Lymph2Cx assay (Nanostring). The data obtained were compared and analysed. ResultsAll the IHC algorithms showed 13 GCB and 15 non-GCB. GEP showed 12 GCB, 12 activated B cell–type and 4 unclassified. ConclusionsThe PCBCL were classifiable as GCB and non-GCB like the nDLBCL as IHC algorithms were concordant to GEP and produced the same results.

Brain H+ /CO2 sensing and control by glial cells.

Maintenance of constant brain pH is critically important to support the activity of individual neurons, effective communication within the neuronal circuits, and, thus, efficient processing of information by the brain. This review article focuses on how glial cells detect and respond to changes in brain tissue pH and concentration of CO2 , and then trigger systemic and local adaptive mechanisms that ensure a stable milieu for the operation of brain circuits. We give a detailed account of the cellular and molecular mechanisms underlying sensitivity of glial cells to H+ and CO2 and discuss the role of glial chemosensitivity and signaling in operation of three key mechanisms that work in concert to keep the brain pH constant. We discuss evidence suggesting that astrocytes and marginal glial cells of the brainstem are critically important for central respiratory CO2 chemoreception-a fundamental physiological mechanism that regulates breathing in accord with changes in blood and brain pH and partial pressure of CO2 in order to maintain systemic pH homeostasis. We review evidence suggesting that astrocytes are also responsible for the maintenance of local brain tissue extracellular pH in conditions of variable acid loads associated with changes in the neuronal activity and metabolism, and discuss potential role of these glial cells in mediating the effects of CO2 on cerebral vasculature.

Characterization of Leptin Receptor+ Stromal Cells in Lymph Node.

Lymph node (LN)-resident stromal cells play an essential role in the proper functioning of LNs. The stromal compartment of the LN undergoes significant compensatory changes to produce a milieu amenable for regulation of the immune response. We have identified a distinct population of leptin receptor-expressing (LepR+) stromal cells, located in the vicinity of the high endothelial venules (HEVs) and lymphatics. These LepR+ stromal cells expressed markers for fibroblastic reticular cells (FRCs), but they lacked markers for follicular dendritic cells (FDCs) and marginal reticular cells (MRCs). Leptin signaling deficiency led to heightened inflammatory responses within the LNs of db/db mice, leakiness of HEVs, and lymphatic fragmentation. Leptin signaling through the JAK/STAT pathway supported LN stromal cell survival and promoted the anti-inflammatory properties of these cells. Conditional knockout of the LepR+ stromal cells in LNs resulted in HEV and extracellular matrix (ECM) abnormalities. Treatment of ob/ob mice with an agonist leptin fusion protein restored the microarchitecture of LNs, reduced intra-LN inflammatory responses, and corrected metabolic abnormalities. Future studies are needed to study the importance of LN stomal cell dysfunction to the pathogenesis of inflammatory responses in type 2 diabetes (T2D) in humans.