Revolutionary Microglial Replacement Therapy: A New Hope for Deadly Brain Diseases!

After systemic hematopoietic stem/progenitor cell transplantation (HCT), transplanted allogeneic myeloid cells migrate to the brain, holding great promise as a therapeutic modality to correct brain genetic defects, such as lysosomal storage diseases. However, prior to allogeneic HCT, myeloablation is required—intensive chemotherapy or systemic radiation therapy to eliminate the patient's own bone marrow to prevent rejection of the transplanted HSCs and to make room for the transplanted cells. However, this procedure can cause severe, life-threatening side effects, limiting its applicability. Furthermore, even in immune-privileged organs like the brain, transplanted allogeneic myeloid cells are highly susceptible to rejection.

On August 6, 2025, researchers from the Stanford University School of Medicine published a research paper in Nature titled "Therapeutic genetic restoration through allogeneic brain microglia replacement". This study has reported a brain-restricted, highly efficient microglia replacement approach without myeloablative preconditioning. This approach avoids the many risks of traditional bone marrow transplantation and offers new hope for developing "off-the-shelf" therapies for neurological diseases.

Unlike previous assumptions, the study found that hematopoietic stem cells are not required to repopulate the myeloid compartment of the brain environment. Instead, Sca1+ committed progenitor cells (but not traditional hematopoietic stem cells) can efficiently replace microglia in the brain following intracerebral injection, completely bypassing the need for systemic myeloablation. This discovery enables the development of brain-restricted preconditioning, avoiding long-term peripheral engraftment and thus eliminating complications such as graft-versus-host disease (GvHD).

To evaluate its therapeutic potential, the research team validated this approach in a mouse model of Sandhoff disease, a lysosomal storage disorder caused by hexosaminidase B deficiency.

The results showed that these Sca1+ committed progenitor cells, after injection, were able to colonize the brain and develop into microglia without migrating to other parts of the body or being attacked by the immune system. Eight months after these cells were transplanted, over 85% of the microglia in the brain had been replaced. Untreated Sandhoff disease mice survived an average of 135 days, with no mice surviving beyond 155 days. However, five of the Sandhoff disease mice that received brain-specific microglia replacement therapy survived for 250 days, until the experiment was terminated.

To demonstrate the translational relevance of this approach, the research team further found that myeloid progenitor cells derived from human induced pluripotent stem cells (iPSCs) exhibited similar engraftment potential after brain-restricted conditioning, confirming their cross-species conservation.

Overall, this study overcomes the current limitations of traditional HCT and may pave the way for the development of allogeneic microglial cell therapies for the brain.

Nature published back-to-back papers from the University of Freiburg titled "Microglia–neuron crosstalk via Hex–GM2–MGL2 maintains brain homeostasis".

This study discovered that under homeostatic conditions, microglia deliver the lysosomal enzyme β-hexosaminidase (Hex) to neurons to degrade the ganglioside GM2, a key component in maintaining neuronal membrane structure and function. Deletion of Hexb (the gene encoding the β subunit of Hex) leads to abnormal accumulation of GM2 metabolites in specific spatiotemporal patterns in mice and humans with Sandhoff disease. Accumulated GM2 gangliosides bind to microglial MGL2 receptors via their N-acetylgalactosamine (GalNAc) residues, triggering lethal neurodegeneration. This vicious cycle leads to neuronal damage and imbalanced microglial function.

The research team further developed a therapeutic approach that, by replacing diseased microglia with peripherally derived microglia-like cells (MLCs), can completely interrupt the degenerative cycle and restore central nervous system homeostasis. These findings provide potential treatments for neurodegenerative diseases such as Sandhoff disease.