Tryptophanyl-tRNA synthetase (WRS), a novel damage-induced cytokine, significantly increases the therapeutic effects of endometrial stem cells

Abstract

Background & Aim Aminoacyl-tRNA synthetases (AARSs) are highly conserved and ubiquitously expressed enzymes that catalyze the first step of protein synthesis by covalently attaching amino acids to their corresponding tRNA to form an aminoacyl tRNA during mRNA translation in the nucleus. Importantly, in addition to their known canonical activities, several studies have recently shown that some AARS family members may have non-canonical cytokine-like functions under specific physiological conditions, such as apoptosis, cell proliferation, glucose homeostasis, and inflammatory response, and vascularization. More recently, particular attention has been focused on the non-canonical functions of the one of their family member tryptophanyl-tRNA synthetase (WRS) in inflammatory response as a cytokine, due to its rapidly secretion upon pathogen infection to activate host defense pathways. These observations have raised the possibility that in addition to its previous reported canonical functions, WRS may exert diverse biological activities as a novel secreted cytokine. Therefore, in the present study, we devoted our attention to the discovery of the previously unidentified cytokine functions of WRS that regulates multiple functions of human stem cells. However, its non-canonical functions and its underlying molecular mechanisms in stem cells still remain unknown. Methods, Results & Conclusion Indeed, we found for the first time that WRS is actively released from the site of injury in response to various damage signals both in vitro and in vivo and then acts as a potent non-enzymatic cytokine that facilitates the self-renewal, migratory, and differentiation capacities of endometrial stem cells to repair damaged tissues. Furthermore, we found that WRS, through its functional receptor cadherin-6 (CDH-6), is shown to activate major pro-survival signaling pathways, such as Akt and ERK1/2 signaling, which are implicated in diverse cellular functions, including, differentiation/pluripotency, recruitment, and self-renewal capacity of various stem cell types. Taken together, these results suggest that, in addition to its well-known canonical functions (catalyzing enzyme for protein synthesis), WRS is actively secreted in response to tissue injury and subsequently enhances the therapeutic effects of stem cells in vitro and in vivo as a novel non-enzymatic cytokine. tissue injury and subsequently enhances the therapeutic effects of stem cells in vitro and in vivo as a novel non-enzymatic cytokine.