# Skull marrow crosstalk with the central nervous system

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $669,146

## Abstract

Leukocytes protect against pathogens; however, these cells are also protagonists of acute and chronic
diseases of the central nervous system (CNS). While the steady-state brain relies on locally sourced innate
immune cells such as microglia which enables recruitment of immune cells that arise from hematopoietic
organs. In particular, innate immune cells such as neutrophils and monocytes migrate to the diseased brain.
These cells are produced by hematopoietic stem and progenitor cells (HSPC) in the bone marrow.
Inflammatory conditions, including brain ischemia, increase the production of myeloid cells, which are
subsequently recruited to the ischemic brain. Similarly, chronic inflammatory CNS disorders may lead to
leukocyte recruitment. Emerging data indicate that recruited leukocytes pursue functions with high relevance to
brain recovery and function. The current dogma states that in response to systemic stimuli, hematopoietic
marrow homogenously releases leukocytes into the systemic circulation and that these leukocytes migrate to
the injured brain via the carotid and vertebral arteries. We discovered small vascularized channels that connect
the skull bone marrow with the surface of the brain. These 20µm sized channels through the inner skull cortex
are clad with endothelial cells and frequented by neutrophils and monocytes. Our unpublished preliminary data
document that this leukocyte migration increases in inflammatory conditions. We developed imaging tools,
including intravital microscopy, to interrogate cellular traffic in these channels. Here we propose to characterize
this hypothetical alternative leukocyte migration route in the steady state, as a function of aging and
development, after ischemic stroke and in hypertension. We will test the overarching hypothesis that small
vascular channels serve as a "short cut" for leukocytes from skull marrow to sites of CNS inflammation. Since it
is currently unknown whether the skull bone marrow functions in synchrony with the marrow in vertebrae,
pelvis and long bones, or alternatively exhibits regionally unique properties that may be important due to its
proximity to the brain, we will compare the function of skull marrow derived leukocytes to cells made in other
hematopoietic sites in steady state, hypertension and after brain ischemia. This application unites an
interdisciplinary team with expertise in neuroscience, hematology, immunology, vascular biology and imaging
to investigate novel microvasculature that may connect the hematopoietic skull tissue with the dura, the CNS
surface and possibly parenchyma. The gained insight may inform novel anti-inflammatory therapeutic
approaches for the treatment of inflammatory CNS disorders.

## Key facts

- **NIH application ID:** 10445009
- **Project number:** 5R01NS108419-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Michael A. Moskowitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $669,146
- **Award type:** 5
- **Project period:** 2018-09-30 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445009

## Citation

> US National Institutes of Health, RePORTER application 10445009, Skull marrow crosstalk with the central nervous system (5R01NS108419-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10445009. Licensed CC0.

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