Neurogenin-2 Reprograms Human Microglial Lineage Cells into Neurons In Vitro and in Chimeric Brains

Singlenucleus RNA sequencing reveals a continuous, directionally ordered reprogramming trajectory marked by suppression of myeloid transcriptional programs, progression through intermediate remodeling states, and progressive activation of neuronal gene regulatory networks, consistent with a regulated lineage conversion rather than partial identity switching. Using a xenotransplantation-based human microglia chimeric brain model, we further demonstrate that inducible NEUROG2 expression reprograms donor-derived human microglia toward a neuronal identity in vivo, with stable neuronal marker expression maintained for up to eight months.

Together, these findings establish human microglial lineage cells as a previously unexplored substrate for neuronal reprogramming, providing a conceptual framework for microglia-based strategies aimed at neuronal replacement and neural repair.