Cardiac fibroblasts and cardiac fibrosis
Cardiac fibroblasts are a group of tissue resident mesenchymal cells. These cells stay largely quiescent in the interstitial area between cardiomyocytes under normal condition. However, when heart is injured such as after myocardial infarction (MI), these cells quickly start to proliferate and then differentiate to myofibroblasts expressing high levels of extracellular matrix (ECM) proteins and highly organized α smooth muscle actin (αSMA). Previous research mainly focused on myofibroblasts due to their obvious importance in most-injury tissue repair. And it is believed that myofibroblasts either dedifferentiate back to fibroblast or undergo apoptosis when the tissue repair is finished. However, we recently found that cardiac fibroblasts persist in the infarct scar long term after MI likely due to the nonregenerative nature of heart. These persistent cardiac fibroblasts do not express αSMA, the hallmark of myofibroblasts, but express moderate levels of some typical heart ECM proteins and some unique proteins that are usually expressed in bone and cartilage. These cells also lack the ability to proliferate in response to additional stimuli. We, therefore, named these cells matrifibrocytes. The unique properties of these cells suggest an important role of them in maintaining the post-MI infarct stability.
We are currently studying the function of these cells and the mechanism responsible for the change in their differentiation states through lineage tracing-based research and transcriptome analysis.
Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar.
Highlights
Acta2 deletion in cardiac fibroblasts does not affect the post-MI cardiac function.
Acta2-null cardiac fibroblasts can undergo normal myofibroblast differentiation.
Non-Acta2 actin isoforms compensate for the loss of Acta2 deletion.
www.sciencedirect.com/science/article/pii/S0022282822001596?via%3Dihub
After myocardial infarction, the massive death of cardiomyocytes leads to cardiac fibroblast proliferation and myofibroblast differentiation, which contributes to the extracellular matrix remodelling of the infarcted myocardium. We recently found that myofibroblasts further differentiate into matrifibrocytes, a newly identified cardiac fibroblast differentiation state. Cardiac fibroblasts of different states have distinct gene expression profiles closely related to their functions. However, the mechanism responsible for the gene expression changes during these activation and differentiation events is still not clear. In this study, the gene expression profiling and genome-wide accessible chromatin mapping of mouse cardiac fibroblasts isolated from the uninjured myocardium and the infarct at multiple time points corresponding to different differentiation states were performed by RNA sequencing (RNA-seq) and the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), respectively. ATAC-seq peaks were highly enriched in the promoter area and the distal area where the enhancers are located. A positive correlation was identified between the expression and promoter accessibility for many dynamically expressed genes, even though evidence showed that mechanisms independent of chromatin accessibility may also contribute to the gene expression changes in cardiac fibroblasts after MI. Moreover, motif enrichment analysis and gene regulatory network construction identified transcription factors that possibly contributed to the differential gene expression between cardiac fibroblasts of different states.
https://www.tandfonline.com/doi/full/10.1080/15592294.2021.1982158