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Bone-marrow-derived cell differentiation into microglia: a study in a progressive mouse model of Parkinson's disease
Manuel Rodriguez1, Lydia Alvarez-Erviti, Francisco J Blesa
1Laboratory of Neurobiology and Experimental Neurology, Department of Physiology, Faculty of Medicine, University of La Laguna, La Laguna, Tenerife, Canary Islands, Spain. mrdiaz@ull.es
Abstract:
The migration of peripheral bone-marrow-derived cells (BMDCs) to the brain was studied in a chronic mouse model of Parkinson's disease (PD). BMDCs expressing the enhanced green fluorescent protein (GFP) were aseptically obtained from C57 BL/6-EGFP-Tg mice and intravenously injected into C57 BL/6j mice which had received a total body irradiation of 8 Gy to induce bone marrow ablation. Implanted GFP-BMDCs replenished the bone marrow of irradiated mice, and progressively crossed the blood-brain barrier (BBB), penetrating different mesencephalic and telencephalic brain regions in the following months. The progressive degeneration of dopamine (DA) cells with a small daily dose (4 mg/kg/day for 20 days) of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) increased the penetration of GFP-BMDCs into the brain, particularly into those regions with marked DA innervation and which showed the clearest DA cell loss. BMDC penetration increased before the DA cell loss was evident and persisted for a long time after MPTP withdrawal. Under these conditions, most BMDCs differentiated into microglia (CD68 expression was observed in 50% of GFP cells 60 days after MPTP administration). BMDC-derived microglia showed morphological characteristics of cell activation, with the glial cell line-derived neurotrophic factor only being expressed in 3% of the cells. No differentiation into neurons (NeuN expression), astrocites (GFAP), cytotoxic lymphocytes (CD8) and T-helper lymphocytes (CD4) was observed. Taken together, the present data suggest that a significant portion of microglial cells is of a peripheral origin. Bearing in mind that microglial reaction is a significant part of the degenerative process in PD, the increase of BMDC penetration into DA-rich areas during DA cell degeneration and their differentiation into microglia suggest that cells coming across the BBB may participate in the neurodegeneration process. The precise role of such a cell inflow into the brain requires further study. Nevertheless, this may represent an opportunity to develop neuroprotective therapeutic strategies for PD.
Insights
Peripheral bone-marrow-derived cells migrate to the brain in a Parkinson
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Parkinson's disease (PD) involves dopamine (DA) cell degeneration.
- Microglial activation is a key feature of neurodegeneration in PD.
- The origin of reactive microglia in PD remains incompletely understood.
Purpose of the Study:
- To investigate the migration of peripheral bone-marrow-derived cells (BMDCs) to the brain in a mouse model of PD.
- To determine if BMDCs can cross the blood-brain barrier (BBB) and differentiate into brain cells.
- To explore the potential role of BMDC-derived cells in PD pathogenesis.
Main Methods:
- Used a chronic mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP).
- Injected enhanced green fluorescent protein (GFP)-labeled BMDCs into irradiated mice to track their fate.
- Analyzed cell migration, differentiation (e.g., CD68, NeuN, GFAP), and gene expression post-MPTP administration.
Main Results:
- MPTP-induced PD model increased GFP-BMDC penetration across the BBB into DA-rich brain regions.
- Most infiltrating BMDCs differentiated into microglia (CD68+), exhibiting activated morphology.
- BMDC infiltration preceded evident DA cell loss and persisted after MPTP withdrawal; no neuronal or astrocyte differentiation observed.
Conclusions:
- A significant proportion of microglia in this PD model originate from the periphery.
- Peripheral BMDCs infiltrate the brain and differentiate into microglia during DA neurodegeneration.
- This BMDC-derived microglial influx may contribute to PD pathogenesis, offering potential therapeutic targets.
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