# Hematopoietic cell mobilization from distinct bone marrow compartments following retinal injury

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $379,250

## Abstract

Abstract
Bone marrow (BM)-derived vascular reparative cells, called myeloid angiogenic cells or MACs, are critical in
vascular repair due to their ability to release growth factors and immunomodulatory proteins that promote
endothelial survival and proliferation. MAC dysfunction in diabetes may lead to the imbalance between
physiological repair and pathological inflammation. Cholesterol levels are pathologically increased in MACs
from diabetic humans and mice leading to their dysfunction. Liver X receptor (LXR) activation restores
membrane fluidity in the diabetic MACs and facilitates cell migration and vascular repair preventing
vasodegenerative damage in the retinas of db/db mice (type 2 diabetes model). Recently, we made the novel
observation that MACs are preferentially mobilized to the injured retina from the calvaria BM and not the long
bones, while proinflammatory myeloid cells (myelopoiesis) are preferentially mobilized from the long bones.
Calvaria BM does not increase in fat content with increasing age, whereas the long bones do (promoting
myelopoiesis), supporting that the calvarium may be resilient to the adverse metabolic consequences of
chronic diabetes. While we showed denervation in the long bones in STZ-induced T1D, T2D db/db mice and
T2D rats (promoting myeloidosis), Ferraro et. al. identified neurogenesis in the calvarium of diabetic mice
suggesting a differential response to diabetes in these two distinct BM compartments. Importantly, unlike the
long bones, the calvarium is directly connected to the cerebral spinal fluid (CSF), a source of neurotropic and
growth factors including endogenous LXR ligands. Hypothesis: In contrast to the long bones, the calvaria
BM compartment is resistant to the adverse impact of diabetes because the CSF provides it with
neurotrophic and growth factors sustaining hematopoiesis and adequate levels of MACs needed for
vascular repair of the retina. In contrast, long bones succumb to denervation and myelopoiesis.
Overtime, however, the calvarium loses this protective response shifting the balance towards systemic
inflammation and development of DR. To evaluate this hypothesis, we propose the following aims.
Aim 1: To interrogate the calvarium microenvironment (stromal cells, resident BM macrophages, and
hematopoietic cells) by examining innervation by the sympathetic nervous system and changes in
hematopoiesis over the time course of diabetes.
Aim 2: To determine the time course of diabetes-induced changes in the release of BM compartment-specific
myeloid cells and MACs that are recruited to the retina.
Aim 3: To restore calvaria BM compartment in late-stage diabetes using targeted delivery of LXR agonists.

## Key facts

- **NIH application ID:** 10875561
- **Project number:** 5R01EY012601-24
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Julia V Busik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $379,250
- **Award type:** 5
- **Project period:** 1998-09-30 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875561

## Citation

> US National Institutes of Health, RePORTER application 10875561, Hematopoietic cell mobilization from distinct bone marrow compartments following retinal injury (5R01EY012601-24). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10875561. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*