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Study Finds Unique Molecular Profile of Human, Mice Skull Bone Marrow

NEW YORK — Researchers in Germany have found that bone marrow from mouse and human skulls has a distinct molecular profile compared to that of other bones in the body.

In a study published in Cell on Wednesday, a team led by investigators at the Institute for Tissue Engineering and Regenerative Medicine (iTERM) at the Helmholtz Center in Munich described using transcriptomics, proteomics, and various imaging techniques on skull and other samples from both species.

Their data showed cross-talk of immune cells in the human skull and the brain, suggesting that the skull can reflect brain pathology, such as neuroinflammation associated with central nervous system disorders. 

"Our discovery holds immense potential, as it suggests that in the near future, portable devices or even small sensors like those found in smartwatches could be utilized for early diagnosis and continuous monitoring of brain diseases," corresponding author Ali Erturk, director of the institute, told GenomeWeb in an email.

In 2018, Erturk's team helped discover physical connections between the skull's bone marrow and the meninges. While it was already known that skull bone marrow is important in shaping immune responses in the brain and meninges, its molecular makeup and relevance in human disease was unclear until now.

For their study, the researchers first performed single-cell RNA-sequencing on cells from different types of bones, the dura, and the brain, taken from mice that were naive, had an induced middle cerebral artery occlusion to simulate a stroke, or were sham-operated without the artery occlusion.

Of note, healthy and injured skulls had a distinct transcriptomic profile compared with other uninjured and injured bones and were characterized by a late-stage neutrophil phenotype. This was confirmed using mass spectrometry, in which researchers investigated proteome profiles in mice bones, meninges, and brain tissues.

Moreover, the calvaria, the top part of the skull, had the highest number of differentially upregulated genes and ligand-receptor pairs among the bones tested and had a molecular profile related to migration and inflammation, especially in the myeloid lineage.

Next, using immunofluorescence and electron microscopy, the researchers further studied cellular details of the human skull-meninges connections (SMCs) and found that human SMCs might be filled with fat, unlike those of mice, allowing immune trafficking while serving as an energy source for hematopoietic stem cells.

They also collected 20 post-mortem human skull, vertebra, and pelvis samples from two independent autopsy centers for proteomic analysis. The human skull contained the largest number of unique proteins compared to other bones, several related to synapses.

The authors also noted increased levels of brain-related, especially synaptic, proteins in the human calvaria, suggesting communication along the skull-meninges-brain axis might occur in both directions.

Finally, the researchers employed translocator protein positron emission tomography (TSPO-PET) imaging, which can detect neuroinflammation in patients with various diseases, such as Alzheimer's and stroke, and saw that the skull bone marrow reflected inflammatory brain responses that had a disease-specific spatial distribution.

Erturk said this confirmed the link between brain inflammation and corresponding signals in the skull, adding that he is excited about using skull imaging and portable sensors as early diagnostic tools. "This approach would offer a much simpler and more accessible way to monitor brain health than traditional methods like large-scale PET imaging. Moreover, this research opens the door to targeting neuroinflammation through interventions focused on the skull itself, potentially offering a novel avenue for reducing brain inflammation," he said.

As next steps, Erturk's team wants to investigate if recently approved Alzheimer's disease drugs could reduce inflammation in the brain.

Meanwhile, the authors said they could not compare gene expression differences in mice and humans due to the limited number of samples from varying ages. Also, they could not obtain bone samples from healthy humans for comparison with pathological states for ethical reasons. "Different causes of death might also be affecting the molecular profile of the samples," they wrote.