Sex and donor shape retinal outcomes of bone marrow-mesenchymal stromal cell and extracellular vesicle therapy in systemic LPS-induced neuroinflammation

Sepsis-associated encephalopathy (SAE) is a frequent and disabling complication of sepsis without effective disease-modifying therapies. The retina provides an accessible window into neuronal responses to systemic inflammation and may reveal mechanisms relevant to the brain, while bearing in mind that retinal findings may not directly reflect therapeutic effects in the brain. Systemic lipopolysaccharide (LPS) administration induces retinal ganglion cell (RGC) loss and microglial activation with marked sexual dimorphism. Here, we evaluated bone marrow-derived mesenchymal stromal cells (BM-MSCs) and their extracellular vesicles (EVs) as therapies, focusing on sex and donor-recipient interactions. Following intravitreal delivery, BM-MSCs remained largely in the vitreous, whereas EVs entered the retina, were detected in the ganglion cell layer, and were observed within Iba1 + cells. In healthy tissue, EVs caused a small loss of RGCs, while BM-MSCs did not. Under LPS-induced inflammation, responses differed by sex. In males, both BM-MSCs and EVs were protective or neutral and also promoted contralateral neuroprotection. In females, these same treatments mainly worsened neuronal loss, regardless of compatibility. Donor sex further influenced outcomes, with male-derived BM-MSCs exacerbating injury in females. These findings identify recipient sex, and in females, donor sex, as key determinants of the retinal response to BM-MSCs and EVs following systemic LPS-induced inflammation. They support sex-aware evaluation of these approaches in retinal injury associated with systemic inflammation; their relevance to SAE requires direct assessment of brain and neurological outcomes.