Pre–hematopoietic stem cell transplantation (HSCT) chemotherapy creates a permissive niche in the brain for peripheral macrophage engraftment.
Major Finding: Pre–hematopoietic stem cell transplantation (HSCT) chemotherapy creates a permissive niche in the brain for peripheral macrophage engraftment.
Concept: Host brain microglia undergo cell-cycle arrest and senescence leading to engraftment of donor macrophages.
Impact: HSCT chemotherapy disrupts brain regenerative populations and leads to the irreversible loss of adult neurogenesis.
Chemotherapy agents are often used for myeloablation prior to hematopoietic stem cell transplantation (HSCT) in many malignant and nonmalignant diseases to create a permissive niche in the recipient's bone marrow for donor cell engraftment. Peripheral engrafted parenchymal macrophages have been found in the post-HSCT brain, but the mechanism behind this phenomenon remains undefined. Therefore, Sailor and colleagues used a clinical dose of busulfan chemotherapy for myeloablation to address this issue and showed that, at 6 weeks post-HSCT, donor-derived cells first appeared in the brain parenchyma and continued to increase over the next 18 weeks. Single-cell 3D tracking indicated the persistence of these cells, suggesting that most donor cells become resident. Tracking of host microglial changes after busulfan chemotherapy revealed a loss of microglial density that was sustained for up to 24 weeks; however, their coverage area was doubled, indicating the enlargement of the remaining microglia in response to this reduced density. Investigation into the effects of busulfan chemotherapy treatment on cell proliferation of adult neurogenesis, which are persistently mitotic stem/progenitor cells, uncovered a complete loss of proliferation within the first week, which was sustained to 24 weeks post-HSCT. Additional analyses demonstrated that microglia undergo cell-cycle arrest, leading to the activation of p21 and subsequent senescence. Furthermore, these post-HSCT microglia lost their capacity for regeneration, and treatment of mice with the CSF1R antagonist PLX3397 to deplete microglia revealed that, with HSCT, recovery of host microglia did not occur after PLX3397 withdrawal, whereas donor macrophages demonstrated almost complete engraftment in the entire brain. Overall, this study reveals the mechanisms behind peripheral engraftment of macrophages in the brain after pre-HSCT chemotherapy, which was discovered to be likely noninflammatory as well as did not involve clear disruption of the blood–brain barrier. Investigation into these phenotypes in the clinic, as well as the potential effect they may have on the cognitive deficits observed post-HSCT, represent next steps for the field.
Sailor KA, Agoranos G, López-Manzaneda S, Tada S, Gillet-Legrand B, Guerinot C, et al. Hematopoietic stem cell transplantation chemotherapy causes microglia senescence and peripheral macrophage engraftment in the brain. Nat Med 2022 Feb 21 [Epub ahead of print].
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