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Results for “Phenotypic modulation”

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PubMed2003

Smooth muscle alpha-actin gene requires two E-boxes for proper expression in vivo and is a target of class I basic helix-loop-helix proteins.

Changes in the differentiated state of smooth muscle cells (SMCs) play a key role in vascular diseases, yet the mechanisms controlling SMC differentiation are still largely undefined. We addressed the role of basic helix-loop-helix (bHLH) proteins in SMC differentiation by first determining the role of two E-box (CAnnTG) motifs, binding sites for bHLH proteins, in the transcriptional regulation of the SMC differentiation marker gene, smooth muscle alpha-actin (SM alpha-actin), in vivo. Mutation of one or both E-boxes significantly reduced the expression of a -2560- to 2784-bp SM alpha-actin promoter/LacZ reporter gene in vivo in transgenic mice. We then determined the potential role of class I bHLH proteins, E12, E47, HEB, and E2-2, in SM alpha-actin regulation. In cotransfection experiments, E12, HEB, and E2-2 activated the SM alpha-actin promoter. Activation by HEB and E2-2 was synergistic with serum response factor. Additionally, the dominant-negative/inhibitory HLH proteins, Id2, Id3, and Twist, inhibited both the E12 and serum response factor-induced activations of the SM alpha-actin promoter. Finally, we demonstrated that E2A proteins (E12/E47) specifically bound the E-box-containing region of the SM alpha-actin promoter in vivo in the context of intact chromatin in SMCs. Taken together, these results provide the first evidence of E-box-dependent regulation of a SMC differentiation marker gene in vivo in transgenic mice. Moreover, they demonstrate a potential role for class I bHLH factors and their inhibitors, Id and Twist, in SM alpha-actin regulation and suggest that these factors may play an important role in control of SMC differentiation and phenotypic modulation.

3T3 Cells↗

PubMed2005

Molecular determinants of vascular smooth muscle cell diversity.

Although the primary role of vascular smooth muscle cells (SMCs) is contraction, they exhibit extensive phenotypic diversity and plasticity during normal development, during repair of vascular injury, and in disease states. Results of recent studies indicate that there are unique as well as common transcriptional regulatory mechanisms that control expression of various SMC marker genes in distinct SMC subtypes, and that these mechanisms are complex and dynamic even at the single cell level. This article will review recent progress in our understanding of the transcriptional regulatory mechanisms involved in controlling expression of SMC marker genes with a particular focus on examination of processes that contribute to the phenotypic diversity of SMCs. In addition, because of considerable controversy in the literature regarding the relationship between phenotypically modulated SMCs and myofibroblasts, we will briefly consider both similarities and differences in regulation of gene expression between these cell types.

Animals↗

PubMed2006

Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification.

Vascular calcification is associated with cardiovascular morbidity and mortality. Hyperphosphatemia is an important contributor to vascular calcification. Our previous studies demonstrated that elevated phosphate induces calcification of smooth muscle cells (SMC) in vitro. Inhibition of phosphate transport by phosphonoformic acid blocked phosphate-induced calcification, implicating sodium-dependent phosphate cotransporters in this process. In the present study, we have investigated the role of the type III sodium-dependent phosphate cotransporter, Pit-1, in SMC calcification in vitro. Human SMC stably expressing Pit-1 small interfering double-stranded RNA (SMC-iRNA) were established using a retroviral system. SMC-iRNA had decreased Pit-1 mRNA and protein levels and sodium-dependent phosphate transport activity compared with the control transduced cells (SMC-CT) (2.9 versus 9.78 nmol/mg protein per 30 minutes, respectively). Furthermore, phosphate-induced SMC calcification was significantly inhibited in SMC-iRNA compared with SMC-CT at all time points examined. Overexpression of Pit-1 restored phosphate uptake and phosphate-induced calcification in Pit-1 deficient cells. Mechanistically, although Pit-1-mediated SMC calcification was not associated with apoptosis or cell-derived vesicles, inhibition of phosphate uptake in Pit-1 knockdown cells blocked the induction of the osteogenic markers Cbfa-1 and osteopontin. Our results indicate that phosphate uptake through Pit-1 is essential for SMC calcification and phenotypic modulation in response to elevated phosphate.

Aorta↗

PubMed1998

Cyclic GMP-dependent protein kinase inhibits osteopontin and thrombospondin production in rat aortic smooth muscle cells.

Vascular lesions resulting from injury are characterized by a thickening of the intima brought about in part through the production of increased amounts of extracellular matrix proteins by the vascular smooth muscle cells (VSMCs). In this study, we tested the hypothesis that cGMP-dependent protein kinase (PKG), an important mediator of NO and cGMP signaling in VSMCs, inhibits the production of two extracellular matrix proteins, osteopontin and thrombospondin, which are involved in the formation of the neointima. VSMCs deficient in PKG were stably transfected with cDNAs encoding either the holoenzyme PKG-Ialpha or the constitutively active catalytic domain of PKG-I in order to directly examine the effects of PKG on osteopontin and thrombospondin production. Cells expressing either of the PKG constructs had dramatically reduced levels of osteopontin and thrombospondin-1 protein compared with control-transfected PKG-deficient cells. PKG transfection also altered the morphology of the VSMCs. These results indicate that PKG may be involved in suppressing extracellular matrix protein expression, which is one important characteristic of synthetic secretory VSMCs. Suppression of these matrix proteins may underlie the effects of NO-cGMP signaling to inhibit VSMC migration and phenotypic modulation.

Animals↗

PubMed1999

Transcriptional activation of the zinc finger transcription factor BTEB2 gene by Egr-1 through mitogen-activated protein kinase pathways in vascular smooth muscle cells.

We have recently demonstrated that a developmentally regulated zinc finger protein, basic transcription regulatory element binding protein 2 (BTEB2), is induced in neointimal smooth muscle in response to vascular injury. In this study, we investigated the molecular mechanisms regulating BTEB2 expression in vascular smooth muscle cells (SMCs) in vitro. BTEB2 mRNA expression is rapidly and persistently induced in SMCs by phorbol 12-myristate 13-acetate (PMA) and basic fibroblast growth factor. We have isolated and characterized the promoter region of the human BTEB2 gene to determine the regulatory network controlling expression of this gene in vascular SMCs. Functional studies on the BTEB2 promoter coupled to a luciferase reporter gene demonstrated activation of the promoter by PMA and basic fibroblast growth factor. Both characterization of DNA-protein complexes in vitro and site-specific mutation analysis of the BTEB2 promoter have defined a 9-bp sequence, 5'-CGCCCGCGC-3', located at -25, as the Egr-1 binding site mediating an induction of the BTEB2 promoter activity by PMA. In addition, we show that this site mediates inducible expression through the mitogen-activated protein kinase pathways. These results indicate that BTEB2 is a target of the early-response gene Egr-1, and mitogen-activated protein kinase pathways directly or indirectly activate BTEB2 expression. Given a rapid induction of Egr-1 on stimulation with growth factors or injury, these findings may represent at least one of the molecular mechanisms underlying phenotypic modulation of smooth muscles after vascular injury.

Animals↗

PubMedDate not supplied

Differentiation-inducing factor-1, a morphogen of dictyostelium, induces G(1) arrest and differentiation of vascular smooth muscle cells.

Differentiation-inducing factor-1 (DIF-1) is a morphogen that induces differentiation of DICTYOSTELIUM: Recently, DIF-1 has been shown to inhibit proliferation and induce differentiation in tumor cells, although the underlying mechanisms remain unknown. In this study, we examined the effects of DIF-1 on the proliferation and differentiation of vascular smooth muscle cells, to explore novel therapeutic strategies for atherosclerosis. DIF-1 nearly completely inhibited DNA synthesis and cell division in mitogen-stimulated cells. DIF-1 inhibited the phosphorylation of the retinoblastoma protein and the activities of cyclin-dependent kinase (Cdk) 4, Cdk6, and Cdk2, which phosphorylate the retinoblastoma protein. DIF-1 strongly suppressed the expression of cyclins D1, D2, and D3, as well as those of cyclins E and A, which normally began after that of the D-type cyclins. The mRNAs for the smooth muscle myosin heavy chains SM1 and SM2 were expressed in quiescent cells in primary culture, and these expression levels decreased after mitogenic stimulation. In the presence of DIF-1, the rate of the reduction was significantly decelerated. Moreover, the addition of DIF-1 to dedifferentiated cells induced the expressions of SM1 and SM2, accompanied by a reduction in the level of SMemb, a nonmuscle-type myosin heavy chain. Therefore, DIF-1 seemed to interrupt a very early stage of G(1) probably by suppressing the expressions of the D-type cyclins. Furthermore, this compound may prevent phenotypic modulation and induce differentiation of vascular smooth muscle cells.

Cell Differentiation↗

PubMed2002

Upregulation of Nox-based NAD(P)H oxidases in restenosis after carotid injury.

Restenosis, a frequent complication of coronary angioplasty, is associated with increased superoxide (O2*(-)) production. Although the molecular identity of the responsible oxidase is unclear, an NAD(P)H oxidase appears to be involved. In smooth muscle, p22phox and 2 homologues of gp91phox, nox1 and nox4, are expressed, whereas fibroblasts contain gp91phox. To begin investigating the possibility that these oxidase components might contribute to the increased O2*(-) that accompanies neointimal formation, we measured their expression after balloon injury of the rat carotid artery. The increase in O2*(-) production 3 to 15 days after surgery was not due to inflammatory cell infiltration but appeared to be derived from medial and neointimal smooth muscle cells and adventitial fibroblasts. Nox1 and p22phox mRNAs were increased 2.7- and 3.6-fold, respectively, at day 3 after injury and remained elevated for 15 days. gp91Phox was increased 7 to 15 days after injury, and nox4 expression was increased 2-fold, but only at day 15 after surgery. These results confirm and extend our previous in vitro data and suggest that in the vasculature, the nox-based NAD(P)H oxidases serve different functions. This dynamic regulation of oxidase components may be critical to smooth muscle phenotypic modulation in restenosis and atherosclerosis.

Animals↗

PubMed2005

Ocular surface reconstruction using autologous rabbit oral mucosal epithelial sheets fabricated ex vivo on a temperature-responsive culture surface.

PURPOSE: Autologous stem cell transplantation for total limbal stem cell deficiency is immunologically preferable, to avoid allograft rejection. This study was undertaken to investigate the possibility of a novel tissue engineering approach for ocular surface reconstruction, using autologous oral mucosal epithelial stem cells expanded ex vivo on temperature-responsive cell culture surfaces. METHODS: Rabbit oral mucosal epithelial cells cultured on temperature-responsive culture surfaces with mitomycin-C-treated 3T3 feeder cells for 2 weeks produced confluent epithelial cell sheets. Putative progenitor cell populations were estimated by colony-forming assays. Autologous transplantation of these cell sheets to surgically manipulated eyes was performed, and ocular surface reconstruction and cell phenotypic modulation were examined. RESULTS: All cultured oral epithelial cells were nonenzymatically harvested as transplantable intact cell sheets by reducing culture temperature to 20 degrees C. Oral epithelial cells were stratified in three to five cell layers more similar to corneal epithelium than to oral mucosal epithelium. Colony-forming assays and immunofluorescence for p63, beta1-integrin, and connexin 43 indicated retention of viable stem and/or progenitor cell populations in cell sheets. Autologous transplantation to rabbit corneal surfaces successfully reconstructed the corneal surface, with restoration of transparency. Four weeks after transplantation, epithelial stratification was similar to that in the corneal epithelium, although the keratin expression profile retained characteristics of the oral mucosal epithelium. CONCLUSIONS: Cell sheet harvest technology enables fabrication of viable, transplantable, tissue-engineered epithelial cell sheets that retain putative progenitor cells from autologous oral mucosal epithelial cells. Promising clinical capabilities for autologous tissue-engineered epithelial cell sheets for ocular surface reconstruction are indicated.

Animals↗

PubMed2007

Macrophage heterogeneity and tissue lipids.

Macrophages are present as resident cells in adipose tissue, and blood monocytes are recruited in increased numbers to sites of lipid accumulation in atherosclerosis, a modified form of inflammation in the arterial wall. Recent findings reported by 3 separate groups in this issue of the JCI provide evidence for distinct monocyte subsets, differential chemokine receptor usage, and phenotypic modulation of macrophages in murine models of genetic and high-fat diet-induced disease (see the related articles beginning on pages 175, 185, and 195). These studies raise prospects for selective therapeutic targets to ameliorate macrophage hyperinflammatory responses, while sparing host defense and repair mechanisms.

Adipose Tissue↗

PubMed1999

Satellite cells on isolated myofibers from normal and denervated adult rat muscle.

Satellite cells (SCs) in normal adult muscle are quiescent. They can enter the mitotic program when stimulated with growth factors such as basic FGF. Short-term denervation stimulates SC to enter the mitotic cycle in vivo, whereas long-term denervation depletes the SC pool. The molecular basis for the neural influence on SCs has not been established. We studied the phenotype and the proliferative capacity of SCs from muscle that had been denervated before being cultured in vitro. The expression of PCNA, myogenin, and muscle (M)-cadherin in SCs of normal and denervated muscle fibers was examined at the single-cell level by immunolabeling in a culture system of isolated rat muscle fibers with attached SCs. Immediately after plating (Day 0), neither PCNA nor myogenin was present on normal muscle fibers, but we detected an average of 0.5 M-cadherin(+) SCs per muscle fiber. The number of these M-cadherin(+) cells (which are negative for PCNA and myogenin) increased over the time course examined. A larger fraction of cells negative for M-cadherin underwent mitosis and expressed PCNA, followed by myogenin. The kinetics of SCs from muscle fibers denervated for 4 days before culturing were similar to those of normal controls. Denervation from 1 to 32 weeks before plating, however, suppressed PCNA and myogenin expression almost completely. The fraction of M-cadherin(+) (PCNA(-)/myogenin(-)) SCs was decreased after 1 week of denervation, increased above normal after denervation for 4 or 8 weeks, and decreased again after denervation for 16 or 32 weeks. We suggest that the M-cadherin(+) cells are nondividing SCs because they co-express neither PCNA or myogenin, whereas the cells positive for PCNA or myogenin (and negative for M-cadherin) have entered the mitotic cycle. SCs from denervated muscle were different from normal controls when denervated for 1 week or longer. The effect of denervation on the phenotypic modulation of SCs includes resistance to recruitment into the mitotic cycle under the conditions studied here and a robust extension of the nonproliferative compartment. These characteristics of SCs deprived of neural influence may account for the failure of denervated muscle to fully regenerate. (J Histochem Cytochem 47:1375-1383, 1999)

Animals↗

PubMedDate not supplied

Mechanical stress-induced orientation and ultrastructural change of smooth muscle cells cultured in three-dimensional collagen lattices.

The effect of tensile stress on the orientation and phenotype of arterial smooth muscle cells (SMCs) cultured in three-dimensional (3D) type I collagen gels was morphologically investigated. Ring-shaped hybrid tissues were prepared by thermal gelation of a cold mixed solution of type I collagen and SMCs derived from bovine aorta. The tissues were subjected to three different modes of tensile stress. They were floated (isotonic control), stretched isometrically (static stress) and periodically stretched and recoiled by 5% above and below the resting tissue length at 60 RPM frequency (dynamic stress). After incubation for up to four wk, the tissues were investigated under a light microscope (LM) and a transmission electron microscope (TEM). Hematoxylin and eosin-stained LM samples revealed that, irrespective of static or dynamic stress loading, SMCs in stress-loaded tissues exhibited elongated bipolar spindle shape and were regularly oriented parallel to the direction of the strain, whereas those in isotonic control tissues were polygonal or spherical and had no preferential orientation. In Azan-stained samples, collagen fiber bundles in isotonic control tissues were somewhat retracted around the polygonal SMCs to form a random network. On the other hand, those in statically and dynamically stressed tissues were accumulated and prominently oriented parallel to the stretch direction. Ultrastructural investigation using a TEM showed that SMCs in control and statically stressed tissues were almost totally filled with synthetic organelles such as rough endoplasmic reticulums, free ribosomes, Golgi complexes and mitochondria, indicating that the cells remained in the synthetic phenotype. On the other hand, SMCs in dynamically stressed tissues had increased fractions of contractile apparatus, such as myofilaments, dense bodies and extracellular filamentous materials equivalent to basement membranes, that progressed with incubation time. These results indicate that periodic stretch, in concert with 3-D extracellular collagen matrices, play a significant role in the phenotypic modulation of SMCs from the synthetic to the contractile state, as well as cellular and biomolecular orientation.

Animals↗

PubMed1998

Ca2+ signaling in fowl aortic smooth muscle increases during maturation but is impaired in neointimal plaques.

Many bird species show the spontaneous development of high arterial pressure and vascular lesions in the aorta and other large arteries. In chickens, arterial pressure tends to increase with age/maturation (particularly in males), and subendothelial hyperplasia (neointima) in the abdominal aorta is often seen prior to sexual maturation. The mechanisms involved, however, are not known. Our aim, therefore, was to determine (1) whether cytosolic Ca2+ signaling (CCS) responses to vasoactive substances in fowl aortic smooth muscle differ among chickens at different maturation stages and (2) whether CCS responses to Ca2+ channel agonists in neointimal plaques differ from those in normal aortic smooth muscle. K+ increased CCS in a dose-dependent manner in isolated and superfused abdominal aortic smooth muscle tissue from chicks (5-9 weeks old), pullets (11-18 weeks old) and adult hens (20 weeks and older); CCS responses increased as chickens matured. The addition of Bay K 8644 (10(-6)mol l-1) to Ringer's solution containing 50 mmol l-1 K+ further increased CCS, and this response was reduced to half by nifedipine (10(-6)mol l-1). Norepinephrine did not alter CCS in chicks, whereas marked dose-dependent increases in CCS were noted in pullets. In contrast to the CCS responses to K+, the norepinephrine-induced CCS responses became smaller in adult hens. Isolated neointimal plaques showed only slight increases in CCS in response to 50 mmol l-1 K+ plus Bay K 8644, whereas clear responses were noted in aortic smooth muscle tissue underlying the plaques. These results suggest (1) that CCS responses to Ca2+ channel agonists increased with sexual maturation in fowl, but (2) that CCS responses to norepinephrine were low in mature hens and to K+ plus Bay K 8644 were low in spontaneously developed neointima, suggesting that phenotypic modulation of Ca2+ channel/norepinephrine receptors may have occurred during maturation/aging and in neointima.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1991

Endothelial cells create a hematopoietic inductive microenvironment preferential to erythropoiesis in the mouse spleen.

The spleen is an erythropoietic organ in mouse. To reconstruct a microenvironment essential for erythropoiesis in vitro, the stroma (MSS31) cell line had been established from a newborn mouse spleens. MSS31 cells exhibited properties of endothelial cells: (a) the cells showed the activity to uptake acetylated low-density lipoprotein (Ac-LDL) and (b) the cells can form a capillarylike structure by a phenotypic modulation in collagen matrices. MSS31 cells selectively supported the proliferation and differentiation of the erythroid progenitor cells by direct cell-to-cell contact in a semisolid medium in the presence of erythropoietin. These layers also supported erythrocyte maturation and enucleation of erythroblasts. This suggests that spleen endothelial cells are a new type of stromal cell with erythropoietic stimulation activity and may have a critical function in the hemopoietic inductive microenvironment of the mouse spleen.

Animals↗

PubMed1999

The unique 5-flanking region of the human basic calponin gene.

Calponin has been implicated in the regulation of smooth muscle contraction. Basic calponin, one of the calponin isoforms, is expressed exclusively in smooth muscle cell (SMC)-rich tissues, and is considered to be a phenotypic marker of differentiated SMC. To define the molecular mechanism of SMC-specific gene transcription in humans, we isolated and characterized the 5'-flanking region of this gene. Sequence analysis revealed that several putative cis-acting elements were clustered within a 500-bp sequence upstream of the transcription start site. However, the 1.9-kb promoter region obtained herein lacked a completely matched consensus sequence of the CArG box that is commonly identified in the promoter region of other SMC-specific genes. A luciferase assay demonstrated that the 1.9-kb promoter region was sufficient to drive a basal transcriptional activity not only in human vascular smooth muscle cells (VSMC) but also in HeLa cells. In particular, the sequence between positions -1,906 and -867 had a significantly higher transcriptional activity in VSMC than in HeLa cells. In contrast, the promoter activity was drastically decreased between positions -327 and -257 in both types of cells. These results indicate that the sequence spanning from position -327 to -257 contains an essential domain involved in the basal transcriptional activity of the human basic calponin gene, and that the distal region of the 1.9-kb 5'-flanking sequence presented herein may play a pivotal role in the phenotypic modulation of VSMC.

5' Untranslated Regions↗

PubMed2003

Informatics center for mouse genomics: the dissection of complex traits of the nervous system.

In recent years, there has been an explosion in the number of tools and techniques available to researchers interested in exploring the genetic basis of all aspects of central nervous system (CNS) development and function. Here, we exploit a powerful new reductionist approach to explore the genetic basis of the very significant structural and molecular differences between the brains of different strains of mice, called either complex trait or quantitative trait loci (QTL) analysis. Our specific focus has been to provide universal access over the web to tools for the genetic dissection of complex traits of the CNS--tools that allow researchers to map genes that modulate phenotypes at a variety of levels ranging from the molecular all the way to the anatomy of the entire brain. Our website, The Mouse Brain Library (MBL; http://mbl.org) is comprised of four interrelated components that are designed to support this goal: The Brain Library, iScope, Neurocartographer, and WebQTL. The centerpiece of the MBL is an image database of histologically prepared museum-quality slides representing nearly 2000 mice from over 120 strains--a library suitable for stereologic analysis of regional volume. The iScope provides fast access to the entire slide collection using streaming video technology, enabling neuroscientists to acquire high-magnification images of any CNS region for any of the mice in the MBL. Neurocartographer provides automatic segmentation of images from the MBL by warping precisely delineated boundaries from a 3D atlas of the mouse brain. Finally, WebQTL provides statistical and graphical analysis of linkage between phenotypes and genotypes.

Analysis of Variance↗

PubMed2006

The low-density lipoprotein receptor-related protein is a pro-survival receptor in Schwann cells: possible implications in peripheral nerve injury.

Schwann cells undergo phenotypic modulation in peripheral nerve injury. In the adult rodent, Schwann cells are resistant to death-promoting challenges. The responsible receptors and signaling pathways are incompletely understood. In this study, we demonstrate that low-density lipoprotein receptor-related protein-1 (LRP-1) is expressed in adult sciatic nerve. After crush injury, LRP-1 is lost from the axoplasm and substantially upregulated in Schwann cells. Increased LRP-1 mRNA expression was observed locally at the injury site in multiple forms of sciatic nerve injury, including crush injury, chronic constriction injury, and axotomy. Endogenously produced tumor necrosis factor-alpha (TNF-alpha) was mostly responsible for the increase in LRP-1 expression; this activity was reproduced by direct injection of TNF-alpha into injured nerves in the TNF-alpha gene knock-out mouse. TNF receptor II was primarily involved. TNF-alpha also increased LRP-1 mRNA in Schwann cells in primary culture. Silencing of Schwann cell LRP-1 with siRNA decreased phosphorylated Akt and increased activated caspase-3. Equivalent changes in cell signaling were observed in LRP-1-deficient murine embryonic fibroblasts. Schwann cell death was induced in vitro by serum withdrawal or TNF-alpha, to a greater extent when LRP-1 was silenced. Schwann cell death was induced in vivo by injecting the LRP-1 antagonist, receptor-associated protein, into axotomy sites in adult rats. These results support a model in which LRP-1 functions as a pro-survival receptor in Schwann cells.

Animals↗

PubMed2026

Microrna Expression in Aurelia aurita Metamorphosis.

INTRODUCTION: In animal taxa and jellyfish, the same genome encodes for the different phenotypes that characterize life stages that follow each other during ontogeny. This situation underscores the existence of profound regulation of genomic information at the epigenetic level. MicroRNAs are fundamental epigenetic regulators. The aim of this study is to evaluate the role of microRNA regulation during jellyfish metamorphosis and to explore the existence of evolutionarily conserved microRNAs. METHODS: Specimens belonging to the 4-metamorphosis stages of A. aurita (polyps, ephyra, young, and adult jellyfish) were bred and collected. The expression of 2,549 miRNAs for each stage was tested using microarray technology. The comparison of microRNA expression for each phase was performed using line plot analysis and Principal Component Analysis of variance (PCA), while the identification of microRNA clusters was performed via volcano plot analysis. RESULTS: A remarkable number of A. aurita miRNAs specifically hybridize with a human miRNA library. Each metamorphosis stage is characterized by a different level of expression of miRNAs: 1) Polyp vs. Ephyra stage: 128 upregulated, 2 downregulated; 2) Ephyra vs. Young stage: 2 upregulated, 135 downregulated; 3) Young vs. Adult stage: 69 upregulated, 6 downregulated. Specific functions inferred from known activities of corresponding miRNAs in higher animals (PubMed database) appear to be coherent with the correlated experimental model. DISCUSSION: Present results reveal that microRNAs with human homologs undergo specific expression changes throughout Aurelia aurita metamorphosis. This observation reinforces the hypothesis of a shared evolutionary origin of certain miRNA families between Cnidaria and Bilateria. The dynamic and stage-specific regulation pattern observed suggests that miRNAs play a key role in orchestrating the complex transitions involved in jellyfish development. These findings point to a broader conservation of epigenetic mechanisms, such as miRNA-mediated gene silencing, which may have emerged early in metazoan evolution and contributed to the regulation of cell differentiation and phenotype modulation. CONCLUSION: The present study highlights the importance of Aurelia aurita as a model for investigating miRNA-driven epigenetic regulation in non-bilaterian animals. The identification of human-homologous miRNAs provides novel insights into the evolutionary stability of the epigenetic machinery and suggests conserved regulatory functions across distant taxa. Although limited by the use of a human-based microarray platform, the data presented here lay a solid foundation for future studies employing sequencing and functional assays to further explore the role of miRNAs in cnidarian development and evolution.

Animals↗

PubMed2006

Airway remodeling and airway smooth muscle in asthma.

Airway remodeling in asthma has been recognized as structural changes of airways such as smooth muscle hypertrophy (an increase in size of airway smooth muscle cells) and hyperplasia (an increase in the number of airway smooth muscle cells), thickening and fibrosis of sub-epithelial basement membrane, hypertrophy of bronchial glands, goblet cell hyperplasia, and thickening of airway epithelium. In these pathological changes, airway smooth muscle remodeling has been recognized as one of the most important factors related to in vitro and in vitro airway responsiveness and the severity of asthma. Both hypertrophy and hyperplasia have been shown in asthmatic airways by morphometrical analyses, although there is a wide variation in the contribution of each mechanism in each patient. Such changes could also be recognized as a phenotypic modulation of airway smooth muscle. On the background of airway smooth muscle remodeling, the existence of several contributing factors, such as inflammatory mediators, growth factors, cytokines, extra-cellular matrix proteins, and genetic factors have been suggested. On the other hand, recent studies revealed that airway smooth muscle could also be a source of inflammatory mediators promoting airway inflammation. In this article, the recent understanding in the mechanisms of airway smooth muscle remodeling in asthma, its relations to airway inflammation and airway physiology, and possible usefulness of early intervention with inhaled glucocorticoids have been discussed.

Animals↗