# Resilient Calvarial Bone Marrow Supports Retinal Repair in Type 2 Diabetes

## TL;DR

Skull bone marrow in diabetic mice remains healthy and sends more immune cells to the eye, helping protect it from damage.

## Contribution

The study reveals that calvarial bone marrow in T2D mice maintains structural and functional integrity and supports retinal immune defense.

## Key findings

- Calvarial bone marrow in T2D mice retains structural integrity and hematopoietic capacity unlike long bone marrow.
- CSF in both mice and humans contains protective oxysterols, indicating a conserved neuroprotective profile.
- Calvarial bone marrow is a major source of immune cells for the retina, producing 20 times more than leg bones.

## 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.

Skull bone (calvarium) marrow in diabetic mice stay structurally intact and keeps making blood cells, unlike the bone marrow of the leg bones. The skull marrow is exposed to cerebrospinal fluid (CSF), which contains protective molecules called oxysterols. Similar molecules are found in human CSF, suggesting this protective environment exists across species. The skull marrow also sends far more immune cells to the retina (about 20 times more than leg bones), helping defend against injury or infection in the eye. In short, skull bone marrow remains strong in diabetes and plays a key role in eye health.