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Promoting donor microglial replacement through augmented conditioning or radiation sensitivity
Troy C Lund1, Willa Durose1, Emma Schindhelm1
1Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Minneapolis, MN 55455, USA.
Abstract:
Donor myeloid cells engraft the brain after hematopoietic cell transplantation (HCT), partially replacing native microglia. The conditions which promote or maintain engraftment are not well known. Previously, we demonstrated that mice receiving double HCT using radiation-based conditioning had higher brain engraftment but also mortality of 70%. We now show that mice that undergo double HCT with busulfan preconditioning have nearly 70%-80% brain engraftment and lower mortality of 8%. Using the radiation-sensitive NSG mouse model, we found up to 15% donor myeloid (CX3CR1+) brain engraftment after low-dose radiation (450 cGy) vs. 0.1% in C57BL/6 mice treated similarly. NBSGW mice engraft the marrow without the need for conditioning, and we found that in these mice the addition of radiation boosted brain engraftment greater than 10-fold, from 0.3% (no conditioning) to 4.8% after HCT. A further increase in brain engraftment (median 22.5%) was observed when animals were pretreated with PLX3397, a microglia inhibitor, which indicated that myeloid niche clearance promotes brain engraftment. In conclusion, preconditioning and niche clearance play an important role in brain engraftment. New ways of microglia replacement are needed if we are to avoid the use of preconditioning.
Insights
Hematopoietic cell transplant (HCT) can engraft donor myeloid cells in the brain. Busulfan preconditioning significantly improves brain engraftment after HCT while reducing mortality, offering a safer alternative.
Area of Science:
- Neuroscience
- Immunology
- Hematology
Background:
- Donor myeloid cells can engraft the brain post-hematopoietic cell transplant (HCT), partially replacing resident microglia.
- Understanding conditions that promote or maintain brain engraftment is crucial for therapeutic applications.
- Previous studies showed high brain engraftment with radiation conditioning but also high mortality.
Purpose of the Study:
- To investigate methods for improving brain engraftment after HCT with reduced mortality.
- To explore the role of preconditioning agents and microglia inhibition in enhancing donor cell engraftment in the brain.
Main Methods:
- Compared busulfan preconditioning with radiation preconditioning for double HCT in mice.
- Assessed donor myeloid cell brain engraftment in NSG and NBSGW mouse models using varying radiation doses.
- Investigated the effect of PLX3397 (microglia inhibitor) on brain engraftment.
Main Results:
- Busulfan preconditioning achieved 70-80% brain engraftment with only 8% mortality, unlike radiation conditioning (70% mortality).
- Low-dose radiation (450 cGy) increased donor myeloid brain engraftment in NSG mice (15%) and NBSGW mice (>10-fold increase).
- Pretreatment with PLX3397 further enhanced brain engraftment (median 22.5%), indicating niche clearance is beneficial.
Conclusions:
- Preconditioning strategies, such as busulfan, are vital for successful brain engraftment after HCT.
- Microglial niche clearance, potentially via inhibitors like PLX3397, significantly promotes donor cell engraftment in the brain.
- Developing preconditioning-free methods for microglia replacement is essential to avoid toxicity.
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