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The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE196127 | GEO | 2023/08/24

REPOSITORIES: GEO

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The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition [scRNA-seq]

Project description:Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds great promise for heart regeneration. Although great progress has been made in understanding the transcriptional and epigenetic mechanisms of iCM reprogramming, its translational regulation remains largely unexplored. Here we characterized the translational landscape of iCM reprogramming using integrative ribosome and transcriptomic profiling, and showed extensive translatome re-patterning during fibroblast conversion into iCM. Loss of function screening for translational regulators uncovered Ybx1 as a critical barrier to iCM induction. Knockdown of Ybx1 dramatically improved the efficiency and quality of iCM reprogramming. Mechanistically, Ybx1 directly bound the transcripts of Srf and Baf60c, both of which mediated, at least partially, the repressive effect of Ybx1 on iCM generation.and Depletion of Ybx1 de-repressed the translation of its targets including SRF and Baf60c. Interestingly, upon removing Ybx1, Tbx5 alone could reprogram fibroblasts into iCMs that exhibit classic iCM molecular features and reprogramming trajectories revealed by our single cell dual-omics. In sum, we presented here a global view of translatome dynamics of cardiac reprogramming and identified a novel translational barrier, Ybx1, to iCM generation. Removing this barrier allowed the single factor mediated iCM reprogramming.

2023-08-24 | GSE237267 | GEO

The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition [scRNA-seq and scATAC-seq]

2023-08-24 | GSE196125 | GEO

The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition [Ribo-seq and RNA-seq]

2023-08-24 | GSE196124 | GEO

The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition

Project description:The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition

| PRJNA803437 | ENA

The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition [scRNA-seq]

Project description:The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition [scRNA-seq]

| PRJNA994502 | ENA

The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition [scRNA-seq and scATAC-seq]

Project description:The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition [scRNA-seq and scATAC-seq]

| PRJNA803442 | ENA

The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition [Ribo-seq and RNA-seq]

Project description:The translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition [Ribo-seq and RNA-seq]

| PRJNA803443 | ENA

Direct Cardiac Cellular Reprogramming for Cardiac Regeneration.

Project description:Direct cardiac cellular reprogramming of endogenous cardiac fibroblasts directly into induced cardiomyocytes is a highly feasible, promising therapeutic option for patients with advanced heart failure. The most successful cardiac reprogramming strategy will likely be a multimodal approach involving an optimal combination of cardio-differentiating factors, suppression of fibroblast gene expression, and induction of angiogenic factors.

| S-EPMC5278776 | biostudies-other

Reprogramming of human fibroblasts toward a cardiac fate.

Project description:Reprogramming of mouse fibroblasts toward a myocardial cell fate by forced expression of cardiac transcription factors or microRNAs has recently been demonstrated. The potential clinical applicability of these findings is based on the minimal regenerative potential of the adult human heart and the limited availability of human heart tissue. An initial but mandatory step toward clinical application of this approach is to establish conditions for conversion of adult human fibroblasts to a cardiac phenotype. Toward this goal, we sought to determine the optimal combination of factors necessary and sufficient for direct myocardial reprogramming of human fibroblasts. Here we show that four human cardiac transcription factors, including GATA binding protein 4, Hand2, T-box5, and myocardin, and two microRNAs, miR-1 and miR-133, activated cardiac marker expression in neonatal and adult human fibroblasts. After maintenance in culture for 4-11 wk, human fibroblasts reprogrammed with these proteins and microRNAs displayed sarcomere-like structures and calcium transients, and a small subset of such cells exhibited spontaneous contractility. These phenotypic changes were accompanied by expression of a broad range of cardiac genes and suppression of nonmyocyte genes. These findings indicate that human fibroblasts can be reprogrammed to cardiac-like myocytes by forced expression of cardiac transcription factors with muscle-specific microRNAs and represent a step toward possible therapeutic application of this reprogramming approach.

| S-EPMC3619357 | biostudies-literature

Cardiac-mimetic cell-culture system for direct cardiac reprogramming.

Project description:Rationale: Cardiovascular diseases often cause substantial heart damage and even heart failure due to the limited regenerative capacity of adult cardiomyocytes. The direct cardiac reprogramming of fibroblasts could be a promising therapeutic option for these patients. Although exogenous transcriptional factors can induce direct cardiac reprogramming, the reprogramming efficiency is too low to be used clinically. Herein, we introduce a cardiac-mimetic cell-culture system that resembles the microenvironment in the heart and provides interactions with cardiomyocytes and electrical cues to the cultured fibroblasts for direct cardiac reprogramming. Methods: Nano-thin and nano-porous membranes and heart like electric stimulus were used in the cardiac-mimetic cell-culture system. The human neonatal dermal fibroblasts containing cardiac transcription factors were plated on the membrane and cultured with the murine cardiomyocyte in the presence of the electric stimulus. The reprogramming efficiency was evaluated by qRT-PCR and immunocytochemistry. Results: Nano-thin and nano-porous membranes in the culture system facilitated interactions between fibroblasts and cardiomyocytes in coculture. The cellular interactions and electric stimulation supplied by the culture system dramatically enhanced the cardiac reprogramming efficiency of cardiac-specific transcriptional factor-transfected fibroblasts. Conclusion: The cardiac-mimetic culture system may serve as an effective tool for producing a feasible number of reprogrammed cardiomyocytes from fibroblasts.

| S-EPMC6815967 | biostudies-literature

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