Resilient Calvarial Bone Marrow Supports Retinal Repair in Type 2 Diabetes

Abstract

Using micro-computed tomography, we identified a network of skull channels in the calvarium of type 2 diabetic (T2D) mice that remained structurally intact and numerically stable despite long-standing disease. The retention of calvaria bone marrow structural integrity was associated with preserved hematopoietic capacity under chronic diabetic conditions, which was not observed in the bone marrow of long bones. A distinctive feature of the calvarial bone marrow compartment was its direct exposure to cerebrospinal fluid (CSF), a property not shared by tibial bone marrow. To characterize the biochemical environment of the murine calvarium, we profiled oxysterols in CSF using mass spectrometry. The CSF exhibited elevated levels of neurotrophic and anti-inflammatory oxysterols, including 22-hydroxycholesterol (22-OHC) and 27-hydroxycholesterol (27-OHC). To assess whether this protective oxysterol signature was conserved in humans, we analyzed CSF samples from diabetic and non-diabetic individuals with obesity-associated idiopathic intracranial hypertension (IIH). Human CSF contained 7α-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA), a metabolite of 27-OHC, supporting the conservation of this neuroprotective profile across species. Given the anatomical proximity of the calvarium to the eye, we hypothesized that calvaria bone marrow may serve as a reservoir for immune cells recruited to the injured or infected retina. The calvaria bone marrow was the predominant source of myeloid angiogenic cells (MACs) and neutrophils, mobilizing these cells at levels approximately 20-fold higher than long bones. These findings demonstrate that calvarial bone marrow plays a critical role in retinal immune defense, while maintaining both structural integrity and functional capacity despite chronic T2D.

Keywords: calvarium marrow; ischemia‐reperfusion; long bones; myeloid angiogenic cells; neutrophils; retina; skull; stem/progenitor cells.