Who's who? A similarities game in the context of the myocardial infarction

The application of single cell transcriptomics technology continues to confirm a fundamental reality for Cellular and Developmental Biologists: the complexity of the cellular landscape and trajectories are incredibly intricate. While changes of cellular stages, cellular activation or transdifferentiating processes are clear in Development textbooks, when interpreting single cell transcriptomics data, the differences between these terms are diffuse. As an example, we describe here two recent high-quality papers, published 6 weeks apart, and focused on the role of one of the most forgotten cardiac cell types, the cardiac pericyte (CP). CPs are a population of perivascular cells defined by their intimate association with the underlying coronary endothelium. They are responsible for keeping vascular integrity, permeability and contractibility, and have an active role in blood flow regulation. However, there is a lack of knowledge of cell-specific markers of pericytes. As consequence, their heterogeneity, arising from their diverse origins depending on the organ and developmental stage, has been a matter of study over years (1).

Now, Quijada et al (2) and Alex et al (3) have, for the first time, described the diversification of cardiac pericytes into a profibrotic population in response to myocardial ischemia, using the same transgenic Cspg4/NG2-lineage tracing tool. This population acquires a cardiac fibroblast (CF) transcriptional profile, characterized by an overexpression of extracellular matrix and fibrotic related genes 7 days post-injury, coinciding with the reparative and inflammatory phase window. Both studies agree that the accumulation of this population in response to MI is driven by proliferation. In addition, both studies consistently describe that the diversification of the CP and subsequent contribution to the infarct area could be mediated by TGF- β. However, the genetic ablation of Tgfbr1 in the NG2-lineage leads to a slight improvement in cardiac function with a reduction of the infarct size (2). In contrast, Tgfbr2 deletion in NG2-lineage does not impact in cardiac function nor the post-injury fibrosis process (3).

Interestingly, whereas both groups perform similar experimental approaches, they interpret the acquisition of a profibrotic phenotype by CP by different biological explanations. Based on their scRNASeq data, Alex et al identifies various subsets of pericytes that appear specifically after the injury. In contrast, Quijada et al. does not identify specific subpopulations of pericytes but an overall response of pericytes upregulating genes related to vascular permeability, proliferation, extracellular matrix production and fibrosis. The individual interpretation about the functional diversification of CP after an MI disagrees each other, although both are convincingly used to argue their hypothesis. On one hand, Quijada et al. propose that CP do not lose their pericyte identity but describe a transition from a quiescent to an activated stage for pericytes, defining the process as non-transdifferentiation (2). By contrast, Alex et al., suggest that a subset of CP undergoes dedifferentiation, giving rise to a subpopulation of pericytes-derived CF which transcriptional profile is distinguishable of the resident interstitial CF (3).

Deciding which definition is correct is not the objective of this comment, but we consider that the use of both terms is at least debatable. Transdifferentiation was originally associated with a switch in the phenotype (4), and denote the conversion of one cellular phenotype to another. Dedifferentiation implies taking a step back in the maturation to transform into a more undifferentiated state (5). Importantly, both definitions require functional changes in a cell, and a modification of a transcriptomic profile may be not a biological argument. This overestimation is highly frequent in the new era of -omics, with a clear tendency to distinguish who is who in a specific biological context without supporting, deeper experimental validations.

In summary, these two high-quality research papers provide intriguing insights into the heterogeneity and functional diversification of pericytes following myocardial infarction and their potential role contributing to fibrosis progression. They also set ground for the discussion of cellular states, which are especially difficult in cell types such as pericytes or fibroblasts. As enthusiastic readers about good science, we encourage you to read both excellent papers and make your own conclusions.

Link to original articles:

Cardiac pericytes mediate the remodeling response to myocardial infarction

Cardiac Pericytes Acquire a Fibrogenic Phenotype and Contribute to Vascular Maturation After Myocardial Infarction