Abstract
Migration of transplanted allogeneic myeloid cells into the brain following systemic hematopoietic stem and progenitor cells transplantation (HCT) holds great promise as a therapeutic modality to correct genetic deficiencies in the brain such as lysosomal storage diseases.1–3 However, the toxic myeloablation required for allogeneic HCT can cause serious, life-threatening side effects limiting its applicability. Moreover, transplanted allogeneic myeloid cells are highly vulnerable to rejection even in an immune-privileged organ like the brain. Here we report a brain-restricted, high-efficiency microgliareplacement approach without myeloablative preconditioning. Unlike previous assumptions, we found that hematopoietic stem cells are not required to repopulate the myeloid compartment of the brain environment. In contrast, Sca1-committed progenitor cells were highly efficient to replace microglia following intracerebral injection. This finding enabled the development of brain-restricted preconditioning and avoided long-term peripheral engraftment thus eliminating complications such as graft-vs-host disease. Evaluating its therapeutic potential, we found that our allogeneic microglia replacement method rescues the murine model of Sandhoff disease, a lysosomal storage disease caused by hexosaminidase B deficiency. In support of the translational relevance of this approach, we discovered that human induced pluripotent stem cell-derived myeloid progenitor cells display a similar engraftment potential following brain-restricted conditioning. Our results overcome current limitations of conventional HCT and may pave the way for the development of allogeneic microglial cell therapies for the brain.
Therapeutic genetic restoration through allogeneic brain microglia replacement - Nature
Migration of transplanted allogeneic myeloid cells into the brain following systemic hematopoietic stem and progenitor cells transplantation (HCT) holds great promise as a therapeutic modality to correct genetic deficiencies in the brain such as lysosomal storage diseases.1–3 However, the toxic...
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