Muse cell transplantation attenuates neuroinflammation and preserves endothelial reparative responses after radiation-induced brain injury.

Abstract

Radiation-induced brain injury (RIBI) is a serious complication of cranial radiotherapy and currently lacks effective disease-modifying treatment. Persistent neuroinflammation and neurovascular dysfunction are considered central to RIBI progression, making them attractive therapeutic targets for regenerative intervention. Multilineage-differentiating stress-enduring (Muse) cells are a non-tumorigenic pluripotent-like cell population with reported reparative and immunomodulatory properties, but their therapeutic potential in RIBI has not been defined. In this study, we evaluated the effects of Muse cell transplantation in experimental RIBI using in vitro neurovascular co-culture systems and in an vivo rat model. Irradiation induced marked activation of inflammasome-related signaling, endothelial injury, and neurological impairment. Muse cells suppressed the expression of NLRP3, AIM2, ASC, Caspase-1, IL-1β, and IL-18 in irradiated co-culture systems, while preserving endothelial proliferative and angiogenic responses. Transcriptomic analysis identified stress-related pathways associated with Muse cell-mediated protection, and PPAN emerged as a candidate regulator linked to the reparative phenotype. In vivo, intracarotid transplantation of Muse cells reduced [18F] DPA-714 uptake in irradiated brain tissue and was accompanied by supportive behavioral trends suggestive of functional improvement. These findings provide exploratory preclinical evidence that Muse cell transplantation attenuates neuroinflammatory activation and preserves endothelial reparative responses after radiation-induced brain injury. Muse cells may therefore represent a potential cell-based strategy for RIBI, although their therapeutic efficacy, neurovascular repair-related effects, and long-term functional benefits require further validation in larger and more comprehensive preclinical studies.