Aging-dependent reduction of KAT7/HBO1 activity impairs imMKCL-based platelet production by promoting immune properties

The master cell bank (MCB) system is essential for regenerative cell therapy. We have developed induced pluripotent stem cell (iPSC)-based immortalized megakaryocyte progenitor cell lines (imMKCLs) as an MCB for iPSC-derived platelet (iPSC-PLT) transfusion. However, imMKCLs exhibit both thrombopoietic and immune-skewed properties, with enhanced immune activity impairing platelet production. The link between immune properties and thrombopoietic efficiency remains unclear. Here, we demonstrate that proliferating imMKCLs in G1 and G2/M interphases contribute to platelet generation, while lysine acetyltransferase 7 (KAT7) suppresses immune-biased dominancy to maintain these interphases. KAT7 inhibition with WM3835 increases G0 cells, mimicking imMKCL aging, and induces cGAS-STING activation, chromatin instability, and the secretion of tumor necrosis factor (TNF)-α, interferon (IFN)-β, and other pro-inflammatory cytokines. Additionally, TNF-α treatment recapitulates the transition to G0 seen with KAT7 loss. These findings identify KAT7 as a key regulator of imMKCL proliferation by preventing immune-skewed properties, highlighting its potential as a quality control marker in iPSC-PLT manufacturing.