Mesenchymal stem cells (MSCs) hold great promise for the treatment of Sjögren disease (SjD) owing to their potent immunomodulatory capacity. However, the precise molecular mechanism by which MSCs regulate the characteristic B cell dysregulation in SjD remains largely unknown. In this study, we found that Pik3cb expression was significantly upregulated in submandibular glands (SMGs) of NOD mice, a well-established SjD model. Notably, genome-wide microarray profiling identified Pik3cb as a pivotal mediator of the therapeutic efficacy of allogeneic MSCs in NOD mice, suggesting it plays a role in SjD pathogenesis and treatment. Systematic investigation of the role of Pik3cb in MSC therapy and B cell regulation revealed that MSC administration and pharmacological inhibition of Pik3cb (using TGX-221) significantly attenuated SjD progression. This attenuation was characterised by the robust suppression of B cell responses, including activation, chemotaxis, plasma cell differentiation, and antibody production. Both interventions effectively restored salivary secretion and alleviated lymphocytic infiltration and fibrosis in the SMGs. Concurrently, a significant shift in the cytokine profile was observed, with diminished pro-inflammatory cytokines (IL-4, IL-6, IFN-γ) and upregulated anti-inflammatory factors (IL-10, TGF-β1) in the SMGs and spleens. Additionally, Pik3cb overexpression in B cells abrogated the MSC-induced therapeutic benefits, confirming the specificity of Pik3cb as a target. Finally, mechanistic studies revealed that MSC efficacy was correlated with Pik3cb suppression, resulting in the subsequent downregulation of Akt/mTOR signalling. In conclusion, this study provides mechanistic evidence that MSC therapy mitigates B cell dysfunction in SjD through the Pik3cb/Akt/mTOR pathway. Furthermore, our data identified Pik3cb as a hitherto unrecognized molecular target in SjD pathogenesis, suggesting that its pharmacological inhibition may represent a promising complementary therapeutic avenue for SjD meriting further investigation.
Wu et al. (Thu,) studied this question.