Store-Operated Ca2+ Entry in Fibrosis and Tissue Remodeling

Abstract

Fibrosis is a pathological condition characterized by excessive tissue deposition of extracellular matrix (ECM) components, leading to scarring and impaired function across multiple organ systems. This complex process is mediated by a dynamic interplay between cell types, including myofibroblasts, fibroblasts, immune cells, epithelial cells, and endothelial cells, each contributing distinctively through various signaling pathways. Critical to the regulatory mechanisms involved in fibrosis is store-operated calcium entry (SOCE), a calcium entry pathway into the cytosol active at the endoplasmic reticulum-plasma membrane contact sites and common to all cells. This review addresses the multifactorial nature of fibrosis with a focus on the pivotal roles of different cell types. We highlight the essential functions of myofibroblasts in ECM production, the transformation of fibroblasts, and the participation of immune cells in modulating the fibrotic landscape. We emphasize the contributions of SOCE in these different cell types to fibrosis, by exploring the involvement of SOCE in cellular functions such as proliferation, migration, secretion, and inflammatory responses. The examination of the cellular and molecular mechanisms of fibrosis and the role of SOCE in these mechanisms offers the potential of targeting SOCE as a therapeutic strategy for mitigating or reversing fibrosis.

Keywords: Orai1; calcium release activated channel (CRAC) (ICRAC); calcium signaling; fibrosis; stromal-interaction molecule (STIM); tissue remodeling.

Graphical abstract

This is a visual representation of the abstract.

Figure 1.

Cell types involved in the fibrotic process and the putative functions of SOCE, in each cell type, in regulating transcription, cytokine secretion, cell function and tissue remodeling (generated with BioRender).