Repeated Mild Head Injury Establishes a Senescent Cranial Bone Marrow Niche that Impairs Brain Metabolism

Abstract

Traumatic brain injury (TBI) of any severity is associated with long-term systemic inflammation and increased risk of peripheral comorbidities, yet the mechanisms driving immune dysregulation and accelerated aging after repeated mild head impacts remain poorly defined. Here, we investigated the acute and chronic effects of repeated mild TBI (rmTBI) on distal and proximal bone marrow compartments in the femur and calvaria, respectively. Using a modified weight-drop mouse model delivering rotational and acceleration-deceleration forces (3 hits/week for up to 16 weeks), rmTBI produced no mortality, skull fracture, hemorrhage, or brain leukocyte infiltration. One day after three consecutive impacts, rmTBI induced robust proliferation of LSK stem/progenitor cells in both femoral and calvarial marrow, evidenced by Ki67 expression, BrdU incorporation, and increased monocyte output. By 8 weeks (24 impacts), injury-induced proliferation subsided and LSK cells exhibited increased senescence-associated {beta}-galactosidase activity and upregulation of tumor suppressor genes. At 16 weeks (48 impacts), LSK populations were depleted at both sites, displaying reduced proliferative capacity, telomere shortening, and pancytopenia in otherwise young adult mice. Calvarial bone marrow cells exposed to rmTBI released a distinct cytokine and proteomic secretome marked by elevated IL-6, suppressed mitochondrial and metabolic signaling, and enhanced DNA repair pathways. Notably, skull-derived secretome factors impaired cortical and hippocampal mitochondrial metabolism, and reduced microglial mitochondrial membrane potential. Together, these findings identify replicative senescence of the brain-adjacent bone marrow niche as an early and progressive consequence of repeated mild head injury, linking rmTBI to long-lasting metabolic dysfunction, impaired immunity, and accelerated aging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/699107v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@683c8eorg.highwire.dtl.DTLVardef@15fc42forg.highwire.dtl.DTLVardef@48f398org.highwire.dtl.DTLVardef@170bbcc_HPS_FORMAT_FIGEXP M_FIG C_FIG