Global human myeloid replacement with peripheral progenitors induces interferonopathy and neurodegeneration

The research addresses the paradigm in neuroimmunology and regenerative medicine which posits that replacing dysfunctional brain microglia with healthy, peripherally-derived hematopoietic stem cells (HSCs) is a viable therapeutic strategy for neurodegenerative diseases. This prevailing model is largely founded on evidence from murine studies suggesting that such replacement is beneficial, with only modest functional differences between native and replacement cells.

This paper precipitates a model crisis by revealing a critical anomaly that invalidates the core therapeutic assumption of the current paradigm. Using a humanized mouse model, the study demonstrates that transplanted human peripheral myeloid progenitors do not restore brain homeostasis as predicted. Instead, they trigger a harmful inflammatory state, characterized by interferonopathy, which leads to astrogliosis, demyelination, and neurodegeneration. These findings directly contradict the beneficial outcomes observed in murine models, exposing a fundamental failure of the existing paradigm to predict effects in a human context and creating a crisis for this entire therapeutic approach.