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Busulfan as a Myelosuppressive Agent for Generating Stable High-level Bone Marrow Chimerism in Mice
Published on: April 1, 2015
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Targeting myeloid cells to the brain using non-myeloablative conditioning.
Chotima Böttcher1, Francisco Fernández-Klett, Nadine Gladow
1Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany.
Plos One
|November 19, 2013
Summary
A new conditioning method using focal head irradiation (HI) effectively targets bone marrow-derived cells (BMDCs) to brain damage sites. This non-myeloablative approach minimizes hematopoietic disruption, unlike traditional methods like total body irradiation (TBI).
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Bone marrow-derived cells (BMDCs) can infiltrate the central nervous system (CNS) at injury sites, making them promising for CNS gene/molecule delivery.
- Current methods for engrafting BMDCs in the brain, such as total body irradiation (TBI) or chemotherapy (busulfan), severely impact the host's hematopoietic system.
Purpose of the Study:
- To establish a non-myeloablative conditioning protocol for targeting myeloid cells to CNS damage sites.
- To evaluate the efficacy and inflammatory profile of focal head irradiation (HI) compared to TBI and busulfan treatment.
Main Methods:
- Mice underwent focal head irradiation (HI) or total body irradiation (TBI), or received busulfan treatment, followed by bone marrow transplantation.
- Gene expression analysis of CNS cytokines/chemokines (CCL2, CXCL10, TNF-α, CCL5) was performed to assess inflammatory responses.
- Blood chimerism and myeloid cell recruitment to the brainstem following facial nerve axotomy were quantified.
Main Results:
- HI induced lower inflammatory responses in the CNS compared to TBI, despite similar cranial radiation doses.
- HI resulted in significantly lower peripheral blood chimerism (<5%) compared to TBI (>95%) or busulfan (>50%).
- HI effectively recruited myeloid cells to brainstem lesions within 7 days, whereas busulfan treatment showed no donor cell engraftment in lesions up to 2 weeks.
Conclusions:
- Myeloid cells can be effectively targeted to CNS damage sites with minimal peripheral blood chimerism.
- Focal head irradiation (HI) offers a novel, non-myeloablative conditioning strategy with reduced hematopoietic disturbance for targeted BMDC delivery to brain pathology.
