Stable fusion of bone marrow-derived cells with Purkinje neurons enables long-term nuclear integration and neuronal repair

Developing effective strategies to replace or restore injured neurons could significantly revolutionise the treatment of currently incurable neurodegenerative disorders. Studies have shown that bone marrow-derived cells (BMDCs) can migrate into the brain and fuse with damaged Purkinje neurons (PNs), restoring their structure and function. Yet, despite over two decades of research, the temporal dynamics and functional stability of these fusion events in vivo remain poorly defined, largely due to reliance on static, post-mortem histological analyses that provide only a single snapshot in time. Here, using in vivo two-photon imaging of the intact cerebellum in EGFP-bone marrow chimeric mice, we visualised the dynamics of BMDC-PN interactions both in real time and longitudinally to monitor the physiological characteristics of fused PNs. Notably, we provide definitive evidence that fused cells are not transient but remain stable over extended periods in the living brain. Moreover, we demonstrate sustained transcriptional activity of donor-derived genes within fused PNs, indicating partial or complete functional integration of the BMDC nucleus. Given their accessibility and genetic tractability, BMDCs represent a practical and promising platform for targeted delivery of therapeutic genes to PNs, opening new avenues for treating neurodegenerative disease.