Repression of OSMR and FGFR1 by miR-1/133a prevents adult cardiomyocyte dedifferentiation and cell cycle entry in the adult heart
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Thomas Boettger
PROVIDER: E-MTAB-10226 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We have demonstrated previously that adult cardiomyocytes can dedifferentiate and proliferate when cultured in vitro. To determine if cardiomyocyte dedifferentiation and cell cycling/proliferation happens in vivo, we applied here a novel multi-reporter transgenic mouse model (aMH-CMerCreMer;mT/MG;aMHC-H2BBFP) carrying reporter genes for permanent cardiomyocyte lineage mapping and maturity (dedifferentiation) reporting. With this new model, we deciphered the cellular sources and processes of cardiomyocyte dedifferentiation and proliferation in adult hearts. In this study, we used single-nucleus RNA-sequencing to tackle the challenges in analyzing the highly heterogeneous heart cell populations, and obtained datasets for a large number of cardiac single nuclei (both myocytes and non-myocytes) for control and post-infarct hearts. We identified specific cell populations in the heart using distinct transcriptomic clusters, transgenic reporters for ACM lineage and dedifferentiation, as well as cell cycle markers. The results demonstrated that the dedifferentiation and cell cycle progression of pre-existing CMs was augmented in post-infarct hearts, with a number of signaling pathways and gene sets affected. This is the first study dissecting the transcriptomic profiles and signaling pathways associated with cardiomyocyte dedifferentiation and cycling/proliferation in vivo using unbiased high-throughput single-nucleus RNA-Seq analysis, in junction with novel cell lineage (e.g. cardiomyocyte) and phenotyping (e.g. dedifferentiation) transgenic model systems.
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Project description:In previous work we described a novel culture technique using a cholera toxin and PMA-free medium (Mel-mix) for obtaining pure melanocyte cultures from human adult epidermis. In Mel-mix medium the cultured melanocytes are bipolar, unpigmented and highly proliferative. Further characterization of the cultured melanocytes revealed the disappearance of c-Kit and TRP-1 and induction of nestin expression, indicating that melanocytes dedifferentiated in this in vitro culture. Cholera toxin and PMA were able to induce c-Kit and TRP-1 protein expressions in the cells, reversing dedifferentiation. TRP-1 mRNA expression was induced in dedifferentiated melanocytes by UV-B irradiated keratinocyte supernatants, however direct UV-B irradiation of the cells resulted in further decrease of TRP-1 mRNA expression. These dedifferentiated, easily accessible cultured melanocytes provide a good model for studying melanocyte differentiation and possibly transdifferentiation. Because melanocytes in Mel-mix medium can be cultured with human serum as the only supplement, this culture system is also suitable for autologous cell transplantation.
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Project description:For many oncogenes, increased expression resulting from copy number gain confers a selective advantage to cells that consequently make up the tumour bulk. To identify oncogenes of potential biological significance in cervical squamous cell carcinoma (SCC), 36 primary samples and ten cell lines were screened by array comparative genomic hybridization (CGH). The most commonly occurring regions of copy number gain that also showed amplification were 5p15.2–14.3 (59%), 5p13.3 (65%), and 5p13.2–13.1 (63%). Gene copy numbers were significantly associated with expression levels for three candidate oncogenes at these loci: OSMR (oncostatin M receptor) (p = 0.03), PDZK3 (PDZ domain containing protein 3) (p = 0.04), and TRIO (triple functional domain) (p = 0.03). Further examination by fluorescence in situ hybridization on a tissue microarray of 110 primary cervical SCC samples revealed copy number gain frequencies of 60.9%, 57.3%, and 54.5% for OSMR, PDZK3, and TRIO, respectively, with OSMR adversely influencing overall patient survival independently of tumour stage (p = 0.046). By array CGH, copy number gain of OSMR was not seen in any of 40 microdissected precursor cervical squamous intraepithelial lesions (SILs). Moreover, global mRNA expression analysis, using Affymetrix U133A 2.0 Arrays, showed no overexpression of OSMR in SILs, suggesting that OSMR gain and overexpression are relatively late steps in cervical carcinogenesis. In the cervical SCC cell lines CaSki and SW756, exogenous OSM activated downstream-signalling elements of OSMR including STAT3, p44/42 MAPK, and S6 ribosomal protein, and induced transcription of the angiogenic factor VEGF, effects that were reduced by OSMR depletion using RNA interference. We conclude that copy number gain of OSMR is frequently found in cervical SCC and is associated with adverse clinical outcome. As well as being a potential prognostic marker, OSMR is a candidate cell surface therapeutic target aCGH of high grade late stage primary cervical SCCs obtained from the archives of the Kidwai Memorial Institute of Oncology,
2011-02-16 | E-GEOD-27332 | biostudies-arrayexpress
Project description:PurposeThe purpose of this study was to characterize the injury response of extraocular muscles (EOMs) in adult zebrafish.MethodsAdult zebrafish underwent lateral rectus (LR) muscle myectomy surgery to remove 50% of the muscle, followed by molecular and cellular characterization of the tissue response to the injury.ResultsFollowing myectomy, the LR muscle regenerated an anatomically correct and functional muscle within 7 to 10 days post injury (DPI). Following injury, the residual muscle stump was replaced by a mesenchymal cell population that lost cell polarity and expressed mesenchymal markers. Next, a robust proliferative burst repopulated the area of the regenerating muscle. Regenerating cells expressed myod, identifying them as myoblasts. However, both immunofluorescence and electron microscopy failed to identify classic Pax7-positive satellite cells in control or injured EOMs. Instead, some proliferating nuclei were noted to express mef2c at the very earliest point in the proliferative burst, suggesting myonuclear reprogramming and dedifferentiation. Bromodeoxyuridine (BrdU) labeling of regenerating cells followed by a second myectomy without repeat labeling resulted in a twice-regenerated muscle broadly populated by BrdU-labeled nuclei with minimal apparent dilution of the BrdU signal. A double-pulse experiment using BrdU and 5-ethynyl-2'-deoxyuridine (EdU) identified double-labeled nuclei, confirming the shared progenitor lineage. Rapid regeneration occurred despite a cell cycle length of 19.1 hours, whereas 72% of the regenerating muscle nuclei entered the cell cycle by 48 hours post injury (HPI). Dextran lineage tracing revealed that residual myocytes were responsible for muscle regeneration.ConclusionsEOM regeneration in adult zebrafish occurs by dedifferentiation of residual myocytes involving a muscle-to-mesenchyme transition. A mechanistic understanding of myocyte reprogramming may facilitate novel approaches to the development of molecular tools for targeted therapeutic regeneration in skeletal muscle disorders and beyond.
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Project description:For many oncogenes, increased expression resulting from copy number gain confers a selective advantage to cells that consequently make up the tumour bulk. To identify oncogenes of potential biological significance in cervical squamous cell carcinoma (SCC), 36 primary samples and ten cell lines were screened by array comparative genomic hybridization (CGH). The most commonly occurring regions of copy number gain that also showed amplification were 5p15.2–14.3 (59%), 5p13.3 (65%), and 5p13.2–13.1 (63%). Gene copy numbers were significantly associated with expression levels for three candidate oncogenes at these loci: OSMR (oncostatin M receptor) (p = 0.03), PDZK3 (PDZ domain containing protein 3) (p = 0.04), and TRIO (triple functional domain) (p = 0.03). Further examination by fluorescence in situ hybridization on a tissue microarray of 110 primary cervical SCC samples revealed copy number gain frequencies of 60.9%, 57.3%, and 54.5% for OSMR, PDZK3, and TRIO, respectively, with OSMR adversely influencing overall patient survival independently of tumour stage (p = 0.046). By array CGH, copy number gain of OSMR was not seen in any of 40 microdissected precursor cervical squamous intraepithelial lesions (SILs). Moreover, global mRNA expression analysis, using Affymetrix U133A 2.0 Arrays, showed no overexpression of OSMR in SILs, suggesting that OSMR gain and overexpression are relatively late steps in cervical carcinogenesis. In the cervical SCC cell lines CaSki and SW756, exogenous OSM activated downstream-signalling elements of OSMR including STAT3, p44/42 MAPK, and S6 ribosomal protein, and induced transcription of the angiogenic factor VEGF, effects that were reduced by OSMR depletion using RNA interference. We conclude that copy number gain of OSMR is frequently found in cervical SCC and is associated with adverse clinical outcome. As well as being a potential prognostic marker, OSMR is a candidate cell surface therapeutic target 36 primary cervical SCC samples, and 10 cervical SCC cell lines were subject to 1 Mb aCGH using a dye swapped approach. Two samples were subject to repeat. (J Pathol. 2007 Jul;212(3):325-34.)
2011-02-16 | E-GEOD-27331 | biostudies-arrayexpress
Project description:The type II Oncostatin M receptor (OSMR) serves as the main binding site for the pleiotropic cytokine OSM. We have previously demonstrated a positive correlation between copy number driven OSMR over-expression and adverse clinical outcome in cervical tumours and have also established enhanced angiogenic, migratory and invasive potential as major consequences of OSMR over-expression using cell-line models of cervical cancer. By analysis of gene expression patterns in cell lines and tumours, this study now systematically defines cohorts of genes that are implicated for the phenotypes observed. Importantly, we have identified 15 OSM induced genes that are involved in at least one of these key functions and are up-regulated in both OSMR over-expressing cell-lines and tumours. These genes can serve as markers of OSM signalling in OSMR over-expressing SCCs and represent suitable targets for functional characterisation. Gene expression of 4 cervical SCC cell lines analysed (2 with and 2 without OSMR overexpression) at 6 different time-points, with 3 replicates at each time-point.
2011-09-29 | E-GEOD-27480 | biostudies-arrayexpress