An irradiation-free platform for localized skull bone marrow manipulation to dissect the skull-brain axis.

The skull bone marrow (SBM) has recently emerged as a crucial regulator of brain physiology and pathology. However, its direct impact on the brain remains elusive, as existing methods cannot isolate local SBM functions from systemic confounds. Here, we developed an irradiation-free cranial bone flap transplantation platform that enables localized SBM replacement and niche-preserving engraftment. Our method establishes exclusive chimerism within CNS compartments, achieving a "peripherally clean" profile that cleanly separates SBM-brain communication from systemic variables. Comprehensive characterization of this model revealed age- and sex-dependent chimerism patterns specifically within central nervous system (CNS) niches. In contrast to conventional long bone marrow (LBM) transplantation, our model achieved robust CNS-targeted engraftment with minimal peripheral involvement. Proof-of-concept functional studies further demonstrated its functional utility by attenuating brain aging and neuroinflammation through young SBM transplantation into old recipients. Our model provides a targeted approach to dissect the skull-brain axis in health and disease, opening avenues to decipher its role in neurological disorders and to identify niche-specific therapeutic targets.