Deciphering the Role of the MST1/2-YAP Axis in Irisin-Treated Aplastic Anemia: Implications for Mesenchymal Stem Cell Function

Abstract

Aplastic anemia (AA) is a debilitating hematological disorder characterized by bone marrow failure. Recent advancements in mesenchymal stem cell (MSC) research have highlighted potential therapeutic avenues, particularly through the modulation of cellular pathways influenced by novel agents like Irisin. This study investigates Irisin's effects on MSCs in the context of AA using advanced techniques such as single-cell sequencing and spatial transcriptomics. Irisin administration in AA model mice significantly altered gene expression in MSCs, particularly affecting 935 genes associated with the Hippo signaling pathway, notably the MST1/2-YAP axis. These changes were linked to decreased adipogenic differentiation and enhanced mitochondrial membrane system homeostasis. In vitro experiments supported these findings, showing Irisin's capability to inhibit the MST1/2-YAP signaling pathway and suppress adipogenesis in bone marrow stem cells (BMSCs). Corresponding in vivo studies demonstrated that Irisin treatment not only downregulated Mst1 and Mst2 but also upregulated Yap expression. Importantly, these molecular alterations led to reduced bone marrow adiposity and improved hematopoietic function in AA mice, showcasing Irisin's potential as an effective treatment option. The study underscores the critical role of the MST1/2-YAP pathway in mediating Irisin's therapeutic effects, suggesting promising strategies for AA management through targeted MSC pathway modulation.