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Migration of bone marrow-derived cells into the central nervous system in models of neurodegeneration
Antoine Lampron1, Pedro M Pimentel-Coelho, Serge Rivest
1Laboratory of Neurosciences, CHU de Québec Research Center (CHUL), and Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, Canada, G1W 4G8.
Abstract:
Microglia are the brain-resident macrophages tasked with the defense and maintenance of the central nervous system (CNS). The hematopoietic origin of microglia has warranted a therapeutic potential for the hematopoietic system in treating diseases of the CNS. However, migration of bone marrow-derived cells (BMDC) into the CNS is a marginal event under normal, healthy conditions. A busulfan-based chemotherapy regimen was used for bone marrow transplantation in wild-type mice before subjecting them to a hypoxic-ischemic brain injury or in APP/PS1 mice prior to the formation of amyloid plaques. The cells were tracked and analyzed throughout the development of the pathology. The efficacy of a preventive macrophage colony-stimulating factor (M-CSF) treatment was also studied to highlight the effects of circulating monocytes in hypoxic-ischemic brain injury. Such an injury induces a strong migration of BMDC into the CNS, without the need for irradiation. These migrating cells do not replace the entire microglial pool but rather are confined to the sites of injury for several weeks, suggesting that they could perform specific functions. M-CSF showed neuroprotective effects as a preventive treatment. In APP/PS1 mice, the formation of amyloid plaques was sufficient to induce the entry of cells into the parenchyma, though in low numbers. This study confirms that BMDC infiltrate the CNS in animal models for stroke and Alzheimer's disease and that peripheral cells can be targeted to treat affected regions of the CNS.
Insights
Bone marrow-derived cells (BMDC) can infiltrate the brain after injury or during disease progression. This study shows that targeting these peripheral cells, like with M-CSF, offers neuroprotection and potential therapeutic strategies for CNS disorders.
Area of Science:
- Neuroscience
- Immunology
- Hematology
Background:
- Microglia, the brain's resident immune cells, originate from hematopoietic precursors.
- Migration of bone marrow-derived cells (BMDC) into the central nervous system (CNS) is limited in healthy conditions.
- Understanding BMDC infiltration is key for developing novel CNS therapies.
Purpose of the Study:
- To investigate BMDC infiltration into the CNS under pathological conditions.
- To evaluate the therapeutic potential of targeting peripheral cells for CNS diseases.
- To assess the neuroprotective effects of M-CSF in a stroke model.
Main Methods:
- Busulfan chemotherapy and bone marrow transplantation in mouse models.
- Induction of hypoxic-ischemic brain injury or use of APP/PS1 Alzheimer's disease model.
- Tracking and analysis of BMDC migration and M-CSF treatment efficacy.
Main Results:
- Hypoxic-ischemic injury significantly increased BMDC migration into the CNS without irradiation.
- Migrating BMDC localized to injury sites and did not fully replace resident microglia.
- Preventive M-CSF treatment demonstrated neuroprotective effects in hypoxic-ischemic injury.
- Amyloid plaque formation in APP/PS1 mice induced low-level BMDC entry into the brain parenchyma.
Conclusions:
- BMDC can infiltrate the CNS in animal models of stroke and Alzheimer's disease.
- Peripheral cell targeting represents a viable therapeutic strategy for CNS disorders.
- M-CSF shows promise as a preventive neuroprotective agent.
