Abstract
AbstractHematopoietic stem cell transplantation is a well-known treatment for hematologic malignancies, wherein nascent stem cells provide regenerating marrow and immunotherapy against the tumor. The progeny of hematopoietic stem cells also populate a wide spectrum of tissues, including the brain, as bone marrow–derived macrophages similar to microglial cells. We developed a sensitive and novel combined immunohistochemistry (IHC) and XY fluorescence in situ hybridization assay to detect, quantify, and characterize donor cells in the cerebral cortices of 19 female patients who underwent allogeneic stem cell transplantation. We showed that the number of male donor cells ranged from 0.14% to 3.0% of the total cells or from 1.2% to 25% of microglial cells. Using tyramide-based fluorescent IHC, we found that at least 80% of the donor cells expressed the microglial marker ionized calcium-binding adapter molecule-1, consistent with bone marrow–derived macrophages. The percentage of donor cells was related to pretransplantation conditioning; donor cells from radiation-based myeloablative cases averaged 8.1% of microglial cells, whereas those from nonmyeloablative cases averaged only 1.3%. The number of donor cells in patients conditioned with busulfan- or treosulfan-based myeloablation was similar to that in total body irradiation-based conditioning; donor cells averaged 6.8% of the microglial cells. Notably, patients who received multiple transplantations and those with the longest posttransplantation survival had the highest level of donor engraftment, with donor cells averaging 16.3% of the microglial cells. Our work represents the largest study characterizing bone marrow–derived macrophages in patients after transplantation. The efficiency of engraftment observed in our study warrants future research on microglial replacement as a therapeutic option for disorders of the central nervous system.
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