Genome-wide transcriptomes of adult mouse cardiomyocytes (CMs) with ectopic expression of reprogramming factors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE172192 | GEO | 2024/04/09
REPOSITORIES: GEO
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Project description:The cardiomyocytes (CMs) differentiation of 12 validated iPSC lines were induced using the Gibco PSC Cardiomyocyte Differentiation Kit and following manufacturer method with minor modifications (Thermo Fisher Scientific, Waltham, MA, USA). The differentiation kit consists of a set of serum-free and xeno-free media that enable efficient differentiation of human iPSCs into spontaneously contracting functional cardiomyocytes in 14 days. On day 14 of the differentiation, spontaneously contracting CMs were characterized by immunocytochemistry (ICC) analysis of cardiac mesoderm marker NKX2-5, and mature cardiomyocyte marker TNNT2 and genome-wide mRNA sequencing of the 12 iPSC lines and generated 12 CM lines were performed. The CMs differentiated from all the 12 iPSC lines expressed NKX2-5 and TNNT2 cardiomyocyte markers. Based on the criteria normalized read count (NRC) ≥ 20 in all 12 CM samples, a total of 12280 genes were found expressed. The average correlation coefficient at 95% CI between 12 CM samples, calculated based on all expressed genes, was 0.92 ± 0.02, suggesting a uniform differentiation of generated CMs across 12 samples. The expression of the well-known CMs genes/markers MYH6, MYL4, MYL3, MYL7, NPPA, NPPB, MYH7, NKX2-5, TBX5, TNNT2, ACTN2, TNNC1 and MB, was significantly up-regulated across all 12 CM samples (FDR corrected p-value ≤ 0.05 and fold change absolute (FC-abs) ≥ 2.0); whereas the expression of pluripotency markers and the ectodermal markers was significantly down regulated. The endodermal markers SOX17 and CLDN6 were below the expression threshold of NRC ≥ 20. A differential gene expression analysis of iPSC’s and CM’s expressed transcription identified 4,191 genes that were significantly differentially expressed (DE) between iPSCs and differentiated CMs. The 2,116 DE genes that were significantly up regulated in differentiated CMs showed significantly high enrichment in cardiovascular system development and functions (571 mRNAs; FDR adjusted p-value range: 1.75x10-66 – 1.61x10-14) and predicted activation of the functions associated with development of human heart and cardiovascular system.
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Project description:Tissue regeneration after injury is thought to involve the dedifferentiation of somatic cells, which is often understood as evidence for natural adaptative reprogramming in vivo. In the intestinal epithelium, acute tissue damage triggers the rapid emergence of injury-responsive cells with fetal-like characteristics, a sign of dedifferentiation. However, there is no direct evidence that tissue regeneration involves a shared molecular mechanism with direct cellular reprogramming. It is also not known whether dedifferentiation shares a single (de)differentiation pathway or consists of multiple parallel routes between adult and fetal states. Here, we induced dedifferentiation of intestinal epithelial cells by forced partial reprogramming in vivo using the “Yamanaka factors” (Oct4, Sox2, Klf4 and c-Myc: OSKM). The induced dedifferentiation showed shared molecular features of intestinal regeneration, with rapid transition from homeostatic intestinal cell types to injury-responsive-like cells sharing a common gene signature of revival stem cells and atrophy-induced villus epithelial cells. When applied to intestinal organoids, induced dedifferentiation allowed the organoids to adopt fetal characteristics ex vivo, suggesting a direct effect on the intestinal epithelium. In vivo, induced dedifferentiation promoted regeneration from acute tissue injury caused by ionizing radiation (IR) via the formation of injury-responsive-like cells. Taken together, in the intestinal epithelium, in vivo reprogramming shares the same molecular pathway as damage-induced tissue regeneration and facilitates the repair process.
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Project description:The generation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offers an unlimited source of patient-specific human cardiomyocytes. However, the use of iPSC-CM in vitro-models to guide the clinic selection of particular drugs for individual patients remains a vision. A major limitation represents the immature phenotype of iPSC-CMs, which alters their sensitivity towards physiological and pathophysiological stimuli, cardioactive drugs or toxic substances, in comparison to adult cardiomyocytes (CMs). In this study, we aim to generate iPSC-CMs with an advanced maturation state by combining the use of MM with the alignment of the cells on nanopatterned surfaces (NP) and induction of an increased contractile workload by electrical stimulation (ES). Under the combined influence of MM, NP and ES, iPSC-CMs develop a more complex cellular structure, increased mitochondrial content and enhanced electrophysiological properties. Furthermore, the response of iPSC-CMs matured under influence of MM, NP and ES to isoprenaline as well as verapamil differs to less mature iPSC-CMs cultured in B27-medium. Taken together, our results reveal that the combination of MM, NP and ES strongly improves the maturation state of iPSC-CMs and that this advanced maturation state critically affects the cell behavior in functional studies as well as response to cardioactive drugs.
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Project description:Contrary to adult mammals, zebrafish are able to regenerate their heart after cardiac injury. This regenerative response relies, in part, on the endogenous ability of cardiomyocytes (CMs) to dedifferentiate and proliferate to replenish the lost muscle. However, CM heterogeneity and population dynamics during development and regeneration remain poorly understood. Through comparative transcriptomic analyses of the developing and adult zebrafish heart, we identified tnnc2 and tnni4b.3 expression as markers for CMs at early and late developmental stages, respectively. Using newly developed reporter lines for these genes, we investigated their expression dynamics during development and regeneration, and observed interesting expression patterns. tnnc2 reporter lines label most CMs at embryonic stages, and this labeling declines rapidly during larval stages; in adult hearts expression is only detectable in a subset of CMs. Conversely, expression of a tnni4b.3 reporter is initially visible in outer curvature CMs at larval stages, and it is subsequently present in a vast majority of the CMs in adult hearts. Interestingly, we find that the adult CMs labeled by the embryonic reporter display higher levels of Tg(tp1:EGFP) expression, which indicates active Notch signaling. To further characterize this CM population, we performed transcriptomic analysis and found that it expresses genes encoding components of the Notch signaling pathway as well as markers of immature CMs. Moreover, during heart regeneration, proliferating CMs in the injured area activate the embryonic CM reporter. Overall, our findings provide further evidence of cardiomyocyte heterogeneity in the adult zebrafish heart.
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