Single-Cell Transcriptome Dynamics of the Autotaxin-Lysophosphatidic Acid Axis During Muscle Regeneration Reveal Proliferative Effects in Mesenchymal Fibro-Adipogenic Progenitors

Abstract

Lysophosphatidic acid (LPA) is a growth factor-like bioactive phospholipid. As such, it has recently become an attractive target during tissue inflammation, repair, and regeneration, demonstrating biomedical relevance. LPA and LPA receptor-mediated signalling pathways regulate embryonic development, wound healing, carcinogenesis, and fibrosis, inducing cell migration, proliferation, and differentiation. Extracellular LPA is produced by the secreted hydrolase ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2, Autotaxin/ATX) and hydrolyzed by different membrane-bound phospholipid phosphatases (PLPPs). This study uses bulk and single-cell RNA sequencing to explore the gene expression dynamics of LPA receptors (LPARs), ENPP2, and PLPPs in skeletal muscle cells in homeostatic conditions and regeneration. Here, I show that skeletal muscle differentially expresses LPAR-Enpp2/ATX-PLPP coding genes, being Lpar1 the highest expressed member among LPARs. Lpar1 was highly expressed by FAPs and tenocytes, whereas Enpp2/ATX was mainly by FAPs. Clustering stromal fibro-adipogenic progenitors (FAPs) identified different populations representing distinct cell states with robust LPAR and Enpp2/ATX transcriptome signatures in homeostasis or resting-like cell states, including Dpp4+ and Hsd11b1+ FAPs. Tissue injury induces strong and fast repression of LPA receptors and Enpp2/ATX, indicating activated and proliferative FAP cell states are partly defined by a strong downregulation of LPAR and Enpp2/ATX gene expression. Hence, our results highlight the presence of the ATX-LPAR-PLPP axis in different muscle cells and FAP lineage in homeostasis and injury, providing a robust entry point for profound research on the role of LPA signalling skeletal muscle and other organs and tissues.