Cardiovascular disease (CVD) represents the leading cause of death and disability worldwide. A consistent feature of CVD is fibrosis, which leads to excessive deposition of disorganised extracellular matrix (ECM) due to unrestrained or inappropriate activation of cardiac reparative pathways. In humans, heart failure is the devastating end-stage of fibrotic progression. The notion that pathological fibrosis represents dysregulated tissue repair presents a duality that has implications for how we think about, study, and treat cardiac fibrosis, and the notable failure of anti-fibrotic drug discovery efforts to date reinforces the need to reconsider current models.
Single cell genomics has revealed unexpected heterogeneity of cardiac cell populations, and one key hope from this new data is that pro-regenerative and pathological fibrosis become distinguishable at cellular and molecular levels such that they could be targeted selectively. An intermediary goal is to develop high dimensionality single cell atlases and virtual 3D tissues that will drive forward new biology and drug discovery. This requires the generation of integrated reference maps of single cell and spatial transcriptomics data drawn from different studies which harmonise disparate experimental designs, analytical pipelines, and taxonomies. Towards this end, we have generated a comprehensive single cell, time-resolved transcriptome integration map of cardiac fibrosis after myocardial infarction and used it to interrogate the fibrotic process in diverse CVD states. Key findings include the high similarity between fibroblast identities and dynamics in ischaemic and hypertensive models of cardiomyopathy, timelines for engagement of activated fibroblasts for proliferation and myofibrogenesis, the co-existence of pro- and anti-fibrotic states within myofibroblasts and their descendants, and illustration of the self-limiting nature of fibrosis.
We have developed new genetic tools for defining, isolating, and manipulating select fibroblast subsets, and show how integrated data can be used to gain insights into models of run-away fibrosis and augmented cardiac repair. These data invoke a degree of fibroblast plasticity governed by cell state stability thresholds. Preliminary spatial transcriptomics data support key roles for distinct fibroblast spatial microenvironments. Overall, these studies will hopefully contribute to a refined conceptual framework for cardiac fibrosis, allowing better interpretation of CVD progression and new points for intervention through knowledge-based therapeutics.
