Unknown,Transcriptomics,Genomics,Proteomics

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Cardiogenic genes expressed in cardiac fibroblasts contribute to heart development and repair

ABSTRACT: Cardiac fibroblasts are critical to proper heart function through multiple interactions with the myocardial compartment. Loosely defined based on their mesenchymal origin, capacity to adhere to plastic and to secrete extracellular matrix, cardiac fibroblasts have been largely neglected due to heterogeneity and lack of proper markers. Objective: To identify genes uniquely expressed in the cardiac fibroblast pool, we performed an unbiased comparative analysis between cardiac and tail fibroblasts, and tracked cardiac fibroblasts after injury to determine their contribution to myocardial regeneration. Methods and Results: High-throughput cell surface and intracellular profiling identified homogeneously expressed MSC markers in cardiac fibroblasts, as well as a surprising number of cardiogenic markers, some expressed at higher levels than in cardiomyocytes. Genetically marked fibroblasts contributed to interstitial but not cardiomyocyte compartments in infarcted hearts. Conclusions: The core transcriptional identity of cardiac fibroblasts reflects their embryological origin, provoking novel interpretations for studies on more specialized cardiac progenitors, and offering a novel perspective for reinterpreting cardiac regenerative therapies 3 biological replicates plated over 5 days after isolation pooled out of 2 animals were used for both tail and heart fibroblasts (6 total samples analysed)

ORGANISM(S): Mus musculus

SUBMITTER: Milena Furtado

PROVIDER: E-GEOD-50531 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Cardiogenic genes expressed in cardiac fibroblasts contribute to heart development and repair.

Furtado Milena B MB Costa Mauro W MW Pranoto Edward A EA Salimova Ekaterina E Pinto Alexander R AR Lam Nicholas T NT Park Anthony A Snider Paige P Chandran Anjana A Harvey Richard P RP Boyd Richard R Conway Simon J SJ Pearson James J Kaye David M DM Rosenthal Nadia A NA

Circulation research 20140320 9

<h4>Rationale</h4>Cardiac fibroblasts are critical to proper heart function through multiple interactions with the myocardial compartment, but appreciation of their contribution has suffered from incomplete characterization and lack of cell-specific markers.<h4>Objective</h4>To generate an unbiased comparative gene expression profile of the cardiac fibroblast pool, identify and characterize the role of key genes in cardiac fibroblast function, and determine their contribution to myocardial devel ...[more]

PMID: 24650916

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Project description:1.1 Introduction Cardiac fibrosis occurs in a wide range of cardiac diseases and is characterised by the transdifferentiation of cardiac fibroblasts into myofibroblasts these cells produce large quantities of extracellular matrix, resulting in myocardial scar. The profibrotic process is multi-factorial, meaning identification of effective treatments has been limited. The antifibrotic effect of the bile acid ursodeoxycholic acid (UDCA) is established in cases of liver fibrosis however its mechanism and role in cardiac fibrosis is less well understood. 1.2 Methods In this study, we used cellular models of cardiac fibrosis and living myocardial slices to characterise the macroscopic and cellular responses of the myocardium to UDCA treatment. We complemented this approach by conducting RNA-seq on cardiac fibroblasts isolated from dilated cardiomyopathy patients. This allowed us to gain insights into the mechanism of action and explore whether the IL-11 and TGFβ/ WWP2 profibrotic networks are influenced by UDCA. Finally, we used fibroblasts from a TGR5 KO mouse to confirm the mechanism of action. 1.3 Results and Discussion We found that UDCA reduced myofibroblast markers in rat and human fibroblasts and in living myocardial slices, indicating its antifibrotic action. Furthermore, we demonstrated that the treatment of UDCA successfully reversed the profibrotic IL-11 and TGFβ/ WWP2 gene networks. We also show that TGR5 is the most highly expressed UDCA receptor in cardiac fibroblasts. Utilising cells isolated from a TGR5 knock-out mouse, we identified that the antifibrotic effect of UDCA is attenuated in the KO fibroblasts. This study combines cellular studies with RNA-seq and state-of-the-art living myocardial slices to offer new perspectives on cardiac fibrosis. Our data confirm that TGR5 agonists, such as UDCA, offer a unique pathway of action for the treatment of cardiac fibrosis. Medicines for cardiac fibrosis have been slow to clinic and have the potential to be used in the treatment of multiple cardiac diseases. UDCA is well tolerated in the treatment of other diseases, indicating it is an excellent candidate for further in-human trials.

Dataset Information

Cardiogenic genes expressed in cardiac fibroblasts contribute to heart development and repair

Publications

Cardiogenic genes expressed in cardiac fibroblasts contribute to heart development and repair.

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