Robust Cardiac Reprogramming Systems with Selectivity to Cardiac Fibroblasts
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ABSTRACT:
PROVIDER: PRJNA878785 | ENA |
REPOSITORIES: ENA
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Project description:Direct cardiac reprogramming to induce cardiomyocyte-like cells, e.g. by GMT (Gata4, Mef2c and Tbx5), is a promising route for regenerating damaged heart in vivo and disease modeling in vitro. Supplementation with additional factors and chemical agents can enhance efficiency but raises concerns regarding selectivity to cardiac fibroblasts and complicates delivery for in situ cardiac reprogramming. Here, we screened 2000 chemicals with known biological activities and found that a combination of 2C (SB431542 and Baricitinib) significantly enhances cardiac reprogramming by GMT. Without Gata4, MT (Mef2c and Tbx5) plus 2C could selectively reprogram cardiac fibroblasts with enhanced efficiency, kinetics and cardiomyocyte function. More importantly, 2C+MYOCD selectively reprograms human cardiac fibroblasts into cardiomyocyte-like cells. 2C enhances cardiac reprogramming by inhibiting Alk5, Tyk2 and downregulating Oas2, Oas3, Serpina3n and Tgfbi. 2C thus enables selective and robust cardiac reprogramming that can greatly facilitate disease modeling in vitro and advance clinical therapeutic heart regeneration in vivo.
2023-12-13 | GSE213021 | GEO
Project description:Direct cardiac reprogramming to induce cardiomyocyte-like cells, e.g., by GMT (Gata4, Mef2c and Tbx5), is a promising route for regenerating damaged heart in vivo and disease modeling in vitro. Supplementation with additional factors and chemical agents can enhance efficiency but raises concerns regarding selectivity to cardiac fibroblasts and complicates delivery for in situ cardiac reprogramming. Here, we screened 2000 chemicals with known biological activities and found that a combination of 2C (SB431542 and Baricitinib) significantly enhances cardiac reprogramming by GMT. Without Gata4, MT (Mef2c and Tbx5) plus 2C could selectively reprogram cardiac fibroblasts with enhanced efficiency, kinetics, and cardiomyocyte function. Moreover, 2C significantly enhanced cardiac reprogramming in human cardiac fibroblasts. 2C synergistically enhances cardiac reprogramming by inhibiting Alk5, Tyk2 and downregulating Oas2, Oas3, Serpina3n and Tgfbi. 2C enables selective and robust cardiac reprogramming that can greatly facilitate disease modeling in vitro and advance clinical therapeutic heart regeneration in vivo.
| S-EPMC10709133 | biostudies-literature
Project description:Cells were reprogrammed from cardiac fibroblasts to cardiomyocytes, in various conditions. These are the iCM cells (induced cardiomyocytes). There are both human and mouse arrays here, as seen below. Microarrays were used to measure the overall degree to which cellular repogramming was successful, by comparing the reprogrammed cells to reference populations of cardiomyocytes (CMs) and cardiac fibroblasts (CFs).
2013-07-26 | E-GEOD-49192 | biostudies-arrayexpress
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 Gata4, Hand2, Tbx5, 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 weeks, 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 non-myocyte 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. Human foreskin fibroblasts were transduced with 5 transcription factors and total RNA was obtained 4 weeks later. total RNA was also obtained from human foreskin fibroblasts as a negative control and adult human heart tissue as a positive control. The expression level of genes in each sample was compared.
2013-01-18 | E-GEOD-43588 | biostudies-arrayexpress
Project description:Cell Reprogramming experiment (reprogramming cardiac fibroblasts into cardiomyocytes)
| PRJNA213262 | ENA
Project description:Cells were reprogrammed from cardiac fibroblasts to cardiomyocytes, in various conditions. These are the iCM cells (induced cardiomyocytes). There are both human and mouse arrays here, as seen below.
2013-07-26 | GSE49192 | GEO
Project description:Direct cardiac reprogramming from fibroblasts holds great potential for disease modeling, drug screening, and regeneration. However, cardiac reprogramming remains inefficient in vitro, and induced cardiomyocytes (iCMs) generated in vitro are less mature than those in vivo, suggesting undefined biophysical factors may inhibit cardiac reprogramming. Previous studies mainly used conventional polystyrene dishes, and thus the effect of matrix rigidity on cardiac reprogramming remains unclear. Here, we developed a Matrigel-based hydrogel culture system to determine the effect of matrix rigidity and mechanotransduction on cardiac reprogramming. We found that soft matrix rigidity comparable to myocardium greatly enhanced cardiac reprogramming in combination with Gata4, Hand2, Mef2c, and Tbx5. Mechanistically, soft matrix enhanced cardiac reprogramming via inhibition of Rho/ROCK, actomyosin, and YAP/TAZ pathway, and suppression of fibroblast program, which were activated on rigid substrate. Intriguingly, inhibition of YAP/TAZ further suppressed integrin-mediated signaling to create a positive feedback loop for robust reprogramming. Thus, mechanotransduction may represent a new target for cardiac reprogramming.
2020-08-28 | GSE125811 | GEO
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 Gata4, Hand2, Tbx5, 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 weeks, 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 non-myocyte 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.
2013-01-18 | GSE43588 | GEO
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2011-10-24 | E-GEOD-33151 | biostudies-arrayexpress
Project description:Mouse adult cardiac fibroblasts were infected with doxycycline inducible, 11 cardiac factors. Addition of doxycycline resulted in appearance of proliferative cells that had high nuclear-to-cytoplasmic ratio. We called these cells iCPCs. iCPC were stably reporgrammed and could be maintined in proliferative state without doxycycline. Here we compared the transcriptome of iCPC with their parental cells; adult cardiac fibroblasts. We found that iCPCs have upregulated genes involved in cardiovascular development and downregulated fibroblasts specific genes. iCPCs did not expressed endoderm, ectoderm or pluripotency associated genes indicating that they were cardiac mesoderm restricted progenitors. We isolated RNA from low passage iCPCs, high passage iCPCs and cardiac fibroblasts and performed RNASeq analysis
2015-09-16 | E-GEOD-61486 | biostudies-arrayexpress