Transcriptional respose to Wnt activation regulates the regenerative capacity of the murine postnatal cochlea
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PROVIDER: PRJNA453779 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: Wnt activation can induce regeneration in the early postnatal cochlea, but the regenerative capacity of the postnatal cochlea diminishes between P0 to P5. The goal of this study was to utilize RNA-Seq for the overall evaluation of expression patterns, comparing P1 and P4 newborn cochlea with and without Wnt activation. Methods: Sox2-CreER; β-cateninflox(Exon3)/+ mice were used to stabilize β-catenin in Sox2+ cochlear supporting cells. Tamoxifen was injected to the mother at either P1 or P4 to induce Cre activation in the pups. mRNA libraries were generated from treated and untreated pups 3 days after injection in triplicates (overall 12 samples) using ThruPLEX DNA-seq kit (Rubicon Genomics) and then sequenced using Illumina NextSeq500 Single-End 75bp. Reads were aligned to mm10 and quality control was assessed using FastQC and Qualimap followed by FeatureCounts, Sailfish v0.10.1 and tximport. Differential expression was evaluated using DESeq2 and subsequent pathway analysis was performed using Ingenuity Pathway Analysis Software (Qiagen). Results: 40-50 million reads were detected per sample. PCA and Pearson correlation demonstrated a clear segragation of the samples by age that was supported by the identification of 2914 differentially expressed genes between P1 and P4 samples. Additional affect of treatment resulted is 530 differentially expressed genes between treated and untreated samples at P1 and 304 genes were differentially expressed between treated and untreated samples at P4. Clear activation of the Wnt pathway was apparent at both time-points after treatment. However, activation of downstream pathways that may be involved in regeneration was detected at P1 but not at P4, mainly the involvement of cell-cycle and proliferation as well as Erbb2 associated genes. Conclusions: Our results suggest that the Wnt pathway is still active and can be further induced at early and late postnatal stages in a similar manner. However, at early stages, exogenous Wnt activation potentially promotes an arrest of maturation progression or even partial dedifferentiation of supporting cells into a less mature state that enables regeneration, while the downstream affect is not as prominenet later on. Proliferative capacity in the early postnatal cochlea is correlated with a unique transcriptional response that diminishes in the older cochlea, including a robust increase in the expression of cell cycle genes and cellular growth and development genes. Our results suggest that the downstream transcriptional response to Wnt activation is the key factor mediating a regenerative response, or a lack-thereof, in the mammalian cochlea and that efforts to stimulate regeneration in the adult auditory organ may require recapitulating the transcriptional response of the early neonatal cochlea to exogenous Wnt activation and subsequent alterations of silenced state of Wnt target genes. .
2018-12-01 | GSE113719 | GEO
Project description:Early regenerative capacity in the porcine heart
| PRJNA475704 | ENA
Project description: Not available
| S-EPMC6288390 | biostudies-literature
Project description:Background: The adult mammalian heart has limited ability to repair itself following injury. Zebrafish, newts and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown if hearts of young large mammals can regenerate. Methods: We examined the regenerative capacity of the pig heart in neonatal animals (ages: 2, 3 or 14 days postnatal) after myocardial infarction (MI) or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry and Western blotting were performed to study cell proliferation, sarcomere dynamics and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. Results: After MI, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls and did not recover function. Genome wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day old animals that was absent in 2-day old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the MI showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. Conclusions: Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.
2018-09-12 | GSE115665 | GEO
Project description:Our studies showed that Wnt activation influenced patterning of the mouse cochlea across the radial axis. To identify genes responding to Wnt activation, mouse embryonic cochleas were treated in the presence and absence of the GSK 3beta inhibitor, CHIR99021. Cochleas were harvested on E12.5 and cultured in vitro for 24 hours. On the next day (day 1), cochleas were treated with either DMSO vehicle control or CHIR99021. The 6-hour treatment helped to identify the immediate genes transcribed following Wnt activation.
2024-03-01 | GSE256069 | GEO
Project description:Cis-Regulatory Accessibility Directs Muller Glial Development and Regenerative Capacity
| PRJNA565157 | ENA
Project description:To identify which miRNAs are involved in the onset and progression of age-related hearing loss in the mammalian cochlea We used miRNA microarrays to screen the miRNAs which exhibit the drastic changes in their expressing level during the aging of the cochlea The organ of Corti (OC), the major pathological sites of presbycusis in cochlea, was collected separately at 3 timepoints during the life span. Two strains were selected: C57bl/6j (as accelerated prebycusis model) and CBA/J (as naturally occured presbycusis model). The selected timepoints were: Postnatal 21 days (P21), 3 month (3m) and 9 month (9m) for C57 mice, and P21, 9m, 16m for CBA mice.
2013-03-12 | E-GEOD-45026 | biostudies-arrayexpress
Project description:Our work describes the application of mass spectrometry-based label-free quantitative proteomics for the identification of differentially expressed proteins between different-aged cochlea. We report proteins exclusively present as well as up- and downregulated in the cochlear sensory epithelium at significant developmental stages. Additionally, we report proteins exclusively present on P3 that were recently identified in the cochlea for the first time. We use bioinformatics to provide insight on biological functions and potential primary and secondary partners of the differentially expressed proteins. This study provides the first differentially expressed proteome in the mammalian cochlea at significant developmental stages; before hearing, during the onset of hearing, and when hearing is fully developed. We believe that these results will provide insights into the function of proteins that change during development and identify potential protein biomarkers related to hearing impairments.
2018-08-29 | PXD001973 | Pride
Project description:Irreversible blindness from glaucoma and optic neuropathies is attributed to retinal ganglion cells (RGCs) losing the ability to regenerate axons. While several transcription factors and proteins have demonstrated enhancement of axon regeneration after optic nerve injury, mechanisms contributing to the age-related decline in axon regenerative capacity remains elusive. Here, we show that microRNAs are differentially expressed during RGC development, and identify microRNA-19a (miR-19a) as a heterochronic marker; developmental decline of miR-19a relieves suppression of PTEN, a key regulator of axon regeneration, and serves as a temporal indicator of decreasing axon regenerative capacity. Intravitreal injection of miR-19a promotes axon regeneration after optic nerve crush in adult mice, and increases axon extension in RGCs isolated from aged human donors. This uncovers a previously unrecognized involvement of the miR-19a-PTEN axis in RGC axon regeneration, and demonstrates therapeutic potential of microRNA-mediated restoration of axon regenerative capacity via intravitreal injection in patients with optic neuropathies.
2020-07-04 | GSE102458 | GEO
Project description:Tissue stem cells preserve a certain level of potency to maintain intact tissue integrity after various injury. Postnatal dermal fibroblasts lose differentiation potential for regenerative healing that recreates normal tissue including functional hair follicles (HFs), however, their intrinsic cellular changes are not understood yet. Here, we uncover a postnatal maturation process in papillary fibroblasts (PFs) mediated by Twist2-driven chromatin and transcriptional remodeling. Within 4 days after birth, dermal PFs lost WNT transcription factors (TFs) and target gene expressions accompanied by loss of H3K27ac expression. Through single-cell transcriptomics, ATAC-seq and ChIP-seq profiling, we define a postnatal maturation trajectory of PFs, in addition to loss of regenerative trajectory, triggered by decrease of H3K27ac and chromatic accessibility. In vivo inhibition of histone deacetylation delays the postnatal chromatin remodeling and maintains developmental signaling and differentiation potential in PFs. TF motif analysis on the chromatin regions losing accessibility identifies TWIST as a potential regulator specifying these regions. Using Twist2 conditional knock-out mouse model, we unearth a postnatal role of Twist2 TF as governing the postnatal maturation process resulting in switch-off of developmental pathways after birth. Together, our findings expose a comprehensive intracellular mechanism driving postnatal maturation in dermal fibroblasts with profound implications for regenerative medicine.
2022-05-17 | GSE181390 | GEO