Transient Induction of Actin Cytoskeletal Remodeling Associated With Dedifferentiation, Proliferation, and Redifferentiation Stimulates Cardiac Regeneration
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ABSTRACT:
PROVIDER: PRJNA1032122 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26525725_1.fastq.gz | Fastqsanger.gz | |||
| SRR26525725_2.fastq.gz | Fastqsanger.gz | |||
| SRR26525726_1.fastq.gz | Fastqsanger.gz | |||
| SRR26525726_2.fastq.gz | Fastqsanger.gz |
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Project description:The formation of new and functional cardiomyocytes requires a 3-step process: dedifferentiation, proliferation, and redifferentiation, but the critical genes required for efficient dedifferentiation, proliferation, and redifferentiation remain unknown. In our study, a circular trajectory using single-nucleus RNA sequencing of the pericentriolar material 1 positive (PCM1+) cardiomyocyte nuclei from hearts 1 and 3 days after surgery-induced myocardial infarction (MI) at postnatal day (P) 1 was reconstructed and demonstrated that actin remodeling contributed to the dedifferentiation, proliferation, and redifferentiation of cardiomyocytes after injury. We identified four top actin-remodeling regulators, namely Tmsb4x, Tmsb10, Dmd, and Ctnna3, which we collectively referred to as 2D2P. Transiently expressed changes of 2D2P, using a polycistronic non-integrating lentivirus driven by Tnnt2 (cardiac-specific troponin T) promoters (Tnnt2-2D2P-NIL), efficiently induced transiently proliferative activation and actin remodeling in P7 cardiomyocytes and adult hearts. Furthermore, the intramyocardial delivery of Tnnt2-2D2P-NIL resulted in a sustained improvement in cardiac function without ventricular dilatation, thickened septum, or fatal arrhythmia for at least 4 months. In conclusion, this study highlights the importance of actin remodeling in cardiac regeneration and provides a foundation for new gene-cocktail-therapy approaches to improve cardiac repair and treat heart failure using a novel transient and cardiomyocyte-specific viral construct.
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Project description:The actin cytoskeleton is a highly conserved structural network that supports diverse cellular processes, but its contribution to organismal aging is not well understood. This project investigates how genetic and pharmacological perturbations of actin and actin-binding proteins influence global gene expression and aging phenotypes in Caenorhabditis elegans. Whole-animal RNA interference was used to knock down key actin regulatory genes, including arx-2 (Arp2/3 complex), unc-60 (cofilin), and lev-11 (tropomyosin). Here Bulk RNA sequencing was performed to assess transcriptional responses to actin cytoskeletal disruption using genetic knockdown (RNAi) of actin-binding proteins and actin de/stabilizing molecules. These datasets capture transcriptomic signatures associated with actin dysfunction, aging trajectories, and stress responses, and provide a resource for exploring the molecular links between cytoskeletal integrity and longevity regulation.
2026-05-11 | E-MTAB-16193 | biostudies-arrayexpress
Project description:Background: Adipocyte hypertrophy, the unique ability of adipocytes to expand in response to positive energy balance, is a key determinant of metabolic health during obesity. However, the molecular mechanisms that govern this adaptive growth are not fully understood. Methods: We performed super-enhancer profiling to identify transcriptional regulators activated in adipocytes under obesogenic conditions. Functional roles of the identified regulator were assessed through in vitro and in vivo analyses, including adipocyte-specific deletion of target gene and subsequent single-nucleus RNA sequencing. Results: Serum Response Factor (SRF) was identified as a pivotal driver of actin cytoskeletal remodeling in adipocytes during obesity. SRF was both necessary and sufficient for the expression of actin cytoskeletal genes in vitro. In vivo, adipocyte-specific SRF deletion reduced actin cytoskeletal gene expression, disrupted filamentous actin networks, and impaired adipocyte enlargement following high-fat diet feeding. Despite similar body weights, mice lacking adipocyte SRF exhibited exacerbated insulin resistance and ectopic lipid accumulation in the liver and brown adipose tissues, reflecting compromised adipocyte integrity and lipid storage capacity. Single-nucleus RNA-seq further revealed that defective actin cytoskeletons in adipocytes disrupted tissue homeostasis, resulting in impaired vascularization and elevated inflammation. Conclusion: These findings establish SRF as a central regulator of actin cytoskeletal organization in adipocytes, essential for supporting healthy hypertrophic expansion and proper tissue remodeling during obesity. SRF emerges as a critical determinant of metabolic health and a potential therapeutic target for obesity-related disorders.
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Project description:About 20-30% of patients with metastatic non-medullary thyroid cancer (TC) have persistent or recurrent disease resulting from tumor dedifferentiation. Tumor redifferentiation to restore sensitivity to radioactive iodine therapy is considered a promising strategy to overcome RAI resistance. Autophagy has emerged as an important mechanism in cancer dedifferentiation. Here, we demonstrate the therapeutic potential of autophagy activation for redifferentiation in thyroid cancer cell lines. Five, all digitalis-like compounds, restored hNIS expression and iodine uptake in TC cell lines. Upregulation of hNIS was mediated by intracellular Ca2+ and cFOS activation. Cell proliferation was inhibited by downregulating Akt1 and by induction of autophagy and p21-dependent cell cycle arrest. All together, digitalis-like compounds could represent a promising treatment modality for patients with dedifferentiated TC.
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Project description:In vitro expansion of adult human islet β cells is an attractive solution for the shortage of tissue for cell replacement therapy of type 1 diabetes. Using a lineage tracing approach, we have demonstrated that β-cell-derived (BCD) cells rapidly dedifferentiate in culture and can proliferate for up to 16 population doublings. Dedifferentiation is associated with changes resembling epithelial-mesenchymal transition (EMT). The WNT pathway has been shown to induce EMT and plays key roles in regulating replication and differentiation in many cell types. Here we show that BCD cell dedifferentiation is associated with β-catenin translocation into the nucleus and activation of the WNT pathway. Inhibition of β-catenin expression in expanded BCD cells using short hairpin RNA resulted in growth arrest, mesenchymal-epithelial transition, and redifferentiation, as judged by activation of β-cell gene expression. Furthermore, inhibition of β-catenin expression synergized with redifferentiation induced by a combination of soluble factors, as judged by an increase in the number of C-peptide-positive cells. Simultaneous inhibition of the WNT and NOTCH pathways also resulted in a synergistic effect on redifferentiation. These findings, which were reproducible in cells derived from multiple human donors, suggest that inhibition of the WNT pathway may contribute to a therapeutically applicable way for generation of functional insulin-producing cells following ex-vivo expansion.
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Project description:Remodeling of the actin cytoskeleton through actin dynamics (assembly and disassembly of filamentous actin) is known to be essential for numerous basic biological processes. In addition, recent in vitro studies provided evidence that actin dynamics participate in the control of gene expression. A spontaneous mouse mutant, corneal disease 1 (corn1), is deficient for a regulator of actin dynamics, destrin (DSTN; also known as actin depolymerizing factor or ADF), and develops epithelial hyperproliferation and neovascularization in the cornea. Dstncorn1 mice exhibit the actin dynamics defect in the corneal epithelial cells as evidenced by increased filamentous actin, offering an in vivo model to investigate the physiological significance of the transcriptional regulation by actin dynamics. To examine the effect of the Dstncorn1 mutation on gene expression, we performed a microarray analysis using the cornea from Dstncorn1 and wild-type control mice. A dramatic alteration of gene expression was observed in the Dstncorn1 cornea, with 1,226 annotated genes differentially expressed. Functional annotation of these genes revealed that most significantly enriched functional categories are associated with actin and/or cytoskeleton. Among genes that belong to these categories, a considerable number of serum response factor (SRF) target genes were found, indicating the existence of the actin-SRF pathway of transcriptional regulation in vivo. A comparative study using an allelic mutant strain, Dstncorn1-2J, with milder corneal phenotypes also suggested that the severity of the actin dynamics defect correlates with the level of gene expression changes. Our study provides evidence that actin dynamics have a strong impact on gene expression in vivo. Keywords: Comparative gene expression
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