Optogenetic and Endogenous Modulation of Ca Signaling in Schwann Cells: Implications for Autocrine and Paracrine Neurotrophic Regulation.

Schwann cells (SCs) are central players in peripheral nerve repair, facilitating axonal regrowth, remyelination, and modulation of the regenerative microenvironment. A pivotal driver of these functions is intracellular Ca signaling, regulated by both endogenous Ca-permeable ion channels and engineered optogenetic actuators. Recent developments in optogenetics, particularly the application of Ca-permeable channelrhodopsins such as CapChR2, have enabled precise, light-controlled activation of SCs, allowing for targeted investigation of Ca-dependent pathways in non-neuronal cells. This review synthesizes emerging evidence demonstrating that optogenetically or endogenously induced Ca influx in SCs leads to the release of a diverse set of neurotrophic and regulatory factors. These Ca-triggered secretomes modulate SC phenotypes and surrounding neurons, orchestrating axon regeneration and myelin repair via autocrine and paracrine mechanisms. We further discuss the roles of key endogenous Ca channels-including transient receptor potential (TRP) channels and store-operated Ca entry (SOCE; STIM/Orai)-in orchestrating SC activation under physiological and injury-induced conditions. By integrating insights from optogenetic manipulation and intrinsic signaling biology, this review proposes a conceptual framework in which Ca-triggered SC secretomes act as structural and functional scaffolds for nerve repair. We highlight how SC-derived factors shape the regenerative niche, influence adjacent neurons and glia, and modulate repair processes in peripheral and autonomic nerves.