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Microglia replacement by bone marrow transplantation (Mr BMT) in the central nervous system of adult mice.

ABSTRACT: Microglia are important immune cells in the central nervous system (CNS). Mutations in microglia may cause CNS disorders. Replacement of dysfunctional microglia with allogeneic wild-type microglia can correct the gene deficiency, thus treating the neurogenic diseases. However, traditional approaches cannot efficiently replace microglia at the adulthood. Here, we introduce a potentially clinical-feasible strategy named microglia replacement by bone marrow transplantation that achieves efficient microglia replacement at the whole CNS scale, including the brain, spinal cord, and retina in adult mice. For complete details on the use and execution of this protocol, please refer to Xu et al. (2020). The original abbreviation of this microglia replacement strategy is mrBMT. We hereby change the name to Mr BMT.

SUBMITTER: Xu Z

PROVIDER: S-EPMC8273422 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Microglia replacement by bone marrow transplantation (Mr BMT) in the central nervous system of adult mice.

Xu Zhen Z Zhou Xin X Peng Bo B Rao Yanxia Y

STAR protocols 20210707 3

Microglia are important immune cells in the central nervous system (CNS). Mutations in microglia may cause CNS disorders. Replacement of dysfunctional microglia with allogeneic wild-type microglia can correct the gene deficiency, thus treating the neurogenic diseases. However, traditional approaches cannot efficiently replace microglia at the adulthood. Here, we introduce a potentially clinical-feasible strategy named microglia replacement by bone marrow transplantation that achieves efficient m ...[more]

PMID: 34286294

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Microglia replacement by microglia transplantation (Mr MT) in the adult mouse brain.

Project description:Mutations in microglia may cause brain disorders. Replacement of dysfunctional microglia by allogeneic wild-type microglia from bone marrow transplantation (Mr BMT) or peripheral blood can correct the gene deficiency at the brain-wide scale but cannot achieve precise replacement at specific brain regions. Here, we introduce a strategy with potential clinical relevance-microglia replacement by microglia transplantation (Mr MT), combining tamoxifen-induced ablation of Mr BMT cells and intracranial injection of microglia to mouse brain, to achieve region-sepcific microglia replacement. The original abbreviation of this microglia replacement strategy is mrMT. We hereby change the name to Mr MT. For complete details on the use and execution of this protocol, please refer to Xu et al. (2020).

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Bone marrow transplantation increases efficacy of central nervous system-directed enzyme replacement therapy in the murine model of globoid cell leukodystrophy.

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Efficient strategies for microglia replacement in the central nervous system

Project description:Microglia are important immune cells in the central nervous system (CNS). Dysfunctions of gene-deficient microglia contribute to the development and progression of multiple CNS diseases. Microglia replacement by nonself cells has been proposed to treat microglia associated disorders. However, most of attempts are failed due to low replacement efficiencies, such as with the traditional bone marrow transplantation approach. In this study, we develop three efficient strategies for microglia replacement: microglia replacement by bone marrow transplantation (mrBMT), microglia replacement by peripheral blood (mrPB) and microglia replacement by microglia transplantation (mrMT). mrBMT and mrPB allow microglia-like cells to efficiently replace resident microglia in the whole CNS. On the other hand, mrMT achieves microglia replacement in brain regions of interest. In summary, the present study offers effective tactics for microglia replacement with diverse application scenarios, which potentially opens up a window on treating microglia-associated CNS disorders.

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Donor bone marrow-derived macrophage engraftment into the central nervous system of patients following allogeneic transplantation.

Project description:Hematopoietic 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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Bone marrow drives central nervous system regeneration after radiation injury.

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Potentially inappropriate medications in geriatric blood or marrow transplantation (BMT) survivors: A BMT Survivor Study report.

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Synergistic effects of central nervous system-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis.

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