Dysbacteriosis-induced LPS elevation disturbs the development of muscle progenitor cells by interfering with retinoic acid signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): mouse gut metagenome Gallus gallus
PROVIDER: GSE139526 | GEO | 2020/05/08
REPOSITORIES: GEO
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Project description:Whether myogenesis is affected by the maternal gut dysbacteriosis still remains ambiguous. In this study, firstly we show elevated level of lipopolysaccharides (LPS) in a gut microbiota dysbiosis mouse model. Secondly, we demonstrate that the diameter of muscle fibres, limb development and somitogenesis were inhibited in both gut microbiota dysbiosis and LPS exposed mice and chicken embryos. These might be due to LPS disturbed the cell survival and the key genes which regulating the somitogenesis and myogenesis. RNA sequencing and subsequent validation experiments verified that retinoic acid (RA) signaling perturbation was mainly responsible for the aberrant somite formation and differentiation. Subsequently, we found that LPS-induced Roxidative stress (ROS generation and antioxidant genes such as Nrf2, AKR) contributed to the above-mentioned interference with RA signaling. These findings highlight that the gut microbiota homeostasis also involved in regulating the development of muscle progenitor cells during pregnancy.
2020-05-08 | GSE139525 | GEO
Project description:Whether myogenesis is affected by the maternal gut dysbacteriosis still remains ambiguous. In this study, firstly we show elevated level of lipopolysaccharides (LPS) in a gut microbiota dysbiosis mouse model. Secondly, we demonstrate that the diameter of muscle fibres, limb development and somitogenesis were inhibited in both gut microbiota dysbiosis and LPS exposed mice and chicken embryos. These might be due to LPS disturbed the cell survival and the key genes which regulating the somitogenesis and myogenesis. RNA sequencing and subsequent validation experiments verified that retinoic acid (RA) signaling perturbation was mainly responsible for the aberrant somite formation and differentiation. Subsequently, we found that LPS-induced Roxidative stress (ROS generation and antioxidant genes such as Nrf2, AKR) contributed to the above-mentioned interference with RA signaling. These findings highlight that the gut microbiota homeostasis also involved in regulating the development of muscle progenitor cells during pregnancy.
2020-05-08 | GSE139422 | GEO
Project description:Dysbacteriosis-induced LPS elevation disturbs the development of muscle progenitor cells by interfering with retinoic acid signaling
| PRJNA580051 | ENA
Project description:Dysbacteriosis-induced LPS elevation disturbs the development of muscle progenitor cells by interfering with retinoic acid signaling [RNA-seq]
| PRJNA580058 | ENA
Project description:Dysbacteriosis-induced LPS elevation disturbs the development of muscle progenitor cells by interfering with retinoic acid signaling [16S rRNA sequencing]
| PRJNA579597 | ENA
Project description:The first and second branchiomeric (branchial arch) muscles are craniofacial muscles that derive from branchial arch mesoderm. In mammals, this set of muscles is indispensable for jaw movement and facial expression. Defects during embryonic development that result in congenital partial absence of these muscles can have significant impact on patients' quality of life. However, the detailed molecular and cellular mechanisms that regulate branchiomeric muscle development remains poorly understood. Herein we investigated the role of retinoic acid (RA) signaling in developing branchiomeric muscles using mice as a model. We administered all-trans RA (25 mg/kg body weight) to Institute of Cancer Research (ICR) pregnant mice by gastric intubation from E8.5 to E10.5. In their embryos at E13.5, we found that muscles derived from the first branchial arch (temporalis, masseter) and second branchial arch (frontalis, orbicularis oculi) were severely affected or undetectable, while other craniofacial muscles were hypoplastic. We detected elevated cell death in the branchial arch mesoderm cells in RA-treated embryos, suggesting that excessive RA signaling reduces the survival of precursor cells of branchiomeric muscles, resulting in the development of hypoplastic craniofacial muscles. In order to uncover the signaling pathway(s) underlying this etiology, we focused on Pitx2, Tbx1, and MyoD1, which are critical for cranial muscle development. Noticeably reduced expression of all these genes was detected in the first and second branchial arch of RA-treated embryos. Moreover, elevated RA signaling resulted in a reduction in Dlx5 and Dlx6 expression in cranial neural crest cells (CNCCs), which disturbed their interactions with branchiomeric mesoderm cells. Altogether, we discovered that embryonic craniofacial muscle defects caused by excessive RA signaling were associated with the downregulation of Pitx2, Tbx1, MyoD1, and Dlx5/6, and reduced survival of cranial myogenic precursor cells.
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Project description:Airway smooth muscle (ASM) is a dynamic and complex tissue involved in regulation of bronchomotor tone, but the molecular events essential for the maintenance of ASM homeostasis are not well understood. Observational and genome-wide association studies in humans have linked airway function to the nutritional status of vitamin A and its bioactive metabolite retinoic acid (RA). Here, we provide evidence that ongoing RA signaling is critical for the regulation of adult ASM phenotype. By using dietary, pharmacologic, and genetic models in mice and humans, we show that (a) RA signaling is active in adult ASM in the normal lung, (b) RA-deficient ASM cells are hypertrophic, hypercontractile, profibrotic, but not hyperproliferative, (c) TGF-β signaling, known to cause ASM hypertrophy and airway fibrosis in human obstructive lung diseases, is hyperactivated in RA-deficient ASM, (d) pharmacologic and genetic inhibition of the TGF-β activity in ASM prevents the development of the aberrant phenotype induced by RA deficiency, and (e) the consequences of transient RA deficiency in ASM are long-lasting. These results indicate that RA signaling actively maintains adult ASM homeostasis, and disruption of RA signaling leads to aberrant ASM phenotypes similar to those seen in human chronic airway diseases such as asthma.
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Project description:Centroacinar cells (CACs) are ductal Notch-responsive progenitors that in the larval zebrafish pancreas differentiate to form new islets and ultimately contribute to the majority of the adult endocrine mass. Uncovering the mechanisms regulating CAC differentiation will facilitate understanding how insulin-producing β cells are formed. Previously we reported retinoic acid (RA) signaling and Notch signaling both regulate larval CAC differentiation, suggesting a shared downstream intermediate. Sox9b is a transcription factor important for islet formation whose expression is upregulated by Notch signaling in larval CACs. Here we report that sox9b expression in larval CACs is also regulated by RA signaling. Therefore, we hypothesized that Sox9b is an intermediate between both RA- and Notch-signaling pathways. In order to study the role of Sox9b in larval CACs, we generated two cre/lox based transgenic tools, which allowed us to express full-length or truncated Sox9b in larval CACs. In this way we were able to perform spatiotemporal-controlled Sox9b gain- and loss-of-function studies and observe the subsequent effect on progenitor differentiation. Our results are consistent with Sox9b regulating CAC differentiation by being a downstream intermediate of both RA- and Notch-signaling pathways. We also demonstrate that adult zebrafish with only one functional allele of sox9b undergo accelerated β-cell regeneration, an observation consistent with sox9b regulating CAC differentiation in adults.
| S-EPMC5031550 | biostudies-literature
Project description:Vitamin A deficiency has been shown to exacerbate allergic asthma. Previous studies have postulated that retinoic acid (RA), an active metabolite of vitamin A and high-affinity ligand for RA receptor (RAR), is reduced in airway inflammatory condition and contributes to multiple features of asthma including airway hyperresponsiveness and excessive accumulation of airway smooth muscle (ASM) cells. In this study, we directly quantified RA and examined the molecular basis for reduced RA levels and RA-mediated signaling in lungs and ASM cells obtained from asthmatic donors and in lungs from allergen-challenged mice. Levels of RA and retinol were significantly lower in lung tissues from asthmatic donors and house dust mite (HDM)-challenged mice compared to non-asthmatic human lungs and PBS-challenged mice, respectively. Quantification of mRNA and protein expression revealed dysregulation in the first step of RA biosynthesis consistent with reduced RA including decreased protein expression of retinol dehydrogenase (RDH)-10 and increased protein expression of RDH11 and dehydrogenase/reductase (DHRS)-4 in asthmatic lung. Proteomic profiling of non-asthmatic and asthmatic lungs also showed significant changes in the protein expression of AP-1 targets consistent with increased AP-1 activity. Further, basal RA levels and RA biosynthetic capabilities were decreased in asthmatic human ASM cells. Treatment of human ASM cells with all-trans RA (ATRA) or the RARγ-specific agonist (CD1530) resulted in the inhibition of mitogen-induced cell proliferation and AP-1-dependent transcription. These data suggest that RA metabolism is decreased in asthmatic lung and that enhancing RAR signaling using ATRA or RARγ agonists may mitigate airway remodeling associated with asthma.
| S-EPMC9361782 | biostudies-literature
Project description:BACKGROUND:Despite compelling data describing pro-regenerative effects of all-trans retinoic acid (ATRA) in pre-clinical models of chronic obstructive pulmonary disease (COPD), clinical trials using retinoids for emphysema patients have failed. Crucial information about the specific role of RA signaling in adult rodent and human lung epithelial progenitor cells is largely missing. METHODS:Adult lung organoid cultures were generated from isolated primary mouse and human lung epithelial cells, and incubated with pharmacological pathway modulators and recombinant proteins. Organoid number and size were measured, and differentiation was assessed with quantitative immunofluorescence and gene expression analyses. FINDINGS:We unexpectedly found that ATRA decreased lung organoid size, whereas RA pathway inhibition increased mouse and human lung organoid size. RA pathway inhibition stimulated mouse lung epithelial proliferation via YAP pathway activation and epithelial-mesenchymal FGF signaling, while concomitantly suppressing alveolar and airway differentiation. HDAC inhibition rescued differentiation in growth-augmented lung organoids. INTERPRETATION:In contrast to prevailing notions, our study suggests that regenerative pharmacology using transient RA pathway inhibition followed by HDAC inhibition might hold promise to promote lung epithelial regeneration in diseased adult lung tissue. FUND: This project is funded by the Lung Foundation Netherlands (Longfonds) grant 6.1.14.009 (RG, MK, JS, PSH) and W2/W3 Professorship Award by the Helmholtz Association, Berlin, Germany (MK).
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