Oligodendrocyte Precursor Cells as source of neurons via direct neuronal reprogramming

• Applicants: Professorin Silvia Cappello, Ph.D.; Giacomo Masserdotti, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Biology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575467845

Direct neuronal reprogramming is a promising avenue for cell-based replacement therapies aimed at replacing neurons lost in neurodegeneration or traumatic injuries. This is achieved via the conversion of local, differentiated non-neuronal cells into functional neurons without passing through a proliferative and pluripotent stage, thus eliminating the possibility of neoplastic formation. In the context of direct reprogramming, oligodendrocyte precursor cells (OPCs) are a poorly explored yet very interesting population to be targeted to generate new functional neurons. In fact, OPCs derive from radial glia cells, which during development give rise first to neurons. They are widespread in the central nervous system; they can shift from a glycolytic to a more oxidative phosphorylation metabolism, required for proper function of neurons; in the adult brain they proliferate both in homeostatic as well as in disease, thus reconstituting their pool to homeostatic condition. In this grant, we propose to investigate the reprogramming potential of OPCs, both of mouse and human origin, into functional neurons, analyse the mechanisms underlying the conversion process using different transcription factors and assess their survival and integration in a complex 3D environment, namely human brain organoids. This will involve the molecular analysis of the cells undergoing the conversion, including transcriptional as well as chromatin changes, but also of the newly generated neurons, to assess their final neuronal identity. The transplantation of human iPSCs-derived OPCs-iNs will allow to evaluate whether such induced neurons further acquire a more mature phenotype when exposed to the enriched 3D brain organoid environment. Finally, the comparison of the data generated in this grant with data recently obtained for human astrocyte-to-neuron direct reprogramming will allow for the first time a systematic interrogate different reprogramming paradigm to identify general reprogramming principles as well as pathways specifically associated to given starter cells or to a defined neuronal subtype generated. Overall, the proposed project aims to advance our understanding of the mechanisms underlying direct conversion of glial cells into functional neurons, unravelling the reprogramming potential of oligodendrocyte precursor cells and providing a solid ground for more translational approaches towards the replacement of neurons in the central nervous system.

• DFG Programme: Research Grants