Intranasal L-MYC Neural Stem Cells Restore Neurovascular and Neuroimmune Homeostasis After TBI via CX3CL1 Upregulation and ICAM-1 Downregulation

Traumatic brain injury (TBI) results in lasting neuroimmune and neurovascular issues that exacerbate secondary brain damage and impede recovery. Researchers explored if an intranasal single dose of LMNSC01 could reprogram neuroinflammatory and neurovascular reactions after TBI, and if these effects were consistent across genders.

Immunocompetent male and female rats experienced a controlled cortical impact (CCI) or sham surgery and seven days later received either LMNSC01 (6 x10^6 cells/dose) or a vehicle. Both histological and transcriptomic assessments, along with multiplex tissue ELISA, were employed to evaluate injury and treatment-related responses.

CCI led to enduring yet gender-specific transcriptional alterations. Males showed primary innate immune, adhesion, extracellular matrix, and tissue remodeling responses, while females displayed broader activation of microglial, interferon, complement, MHC/antigen presentation, and humoral/adaptive immune pathways. LMNSC01 treatment altered these injury states through somewhat gender-specific means.

In males, LMNSC01 enhanced endogenous immune-regulatory factors, such as Il1rn, and diminished genes linked to adhesion and immune cell migration. In females, treatment lowered expression of genes associated with microglial, leukocyte, MHC/antigen presentation, cytokine, and adhesion pathways, and decreased macrophage- and CD45 positive cell markers.

Despite these gender-specific transcriptional differences, LMNSC01 induced comparable protein modifications in both genders, lowering injury-linked ICAM-1 and restoring CX3CL1 proteins. This suggests a novel molecular mechanism for LMNSC01 adjusting endothelial activation and neuron-microglia communication post-injury. The study sheds light on gender disparities in injury response and treatment outcomes after TBI and identifies potential repair pathways, supporting further LMNSC01 development as a non-invasive treatment for TBI.