Schwann cells modified to secrete MANF is a potential cellular therapy for peripheral nerve regeneration

Despite several decades of research, an effective therapy for peripheral nerve regeneration is still lacking. The lack of knowledge of molecular candidates that equally promote axon regeneration and glial cell dynamics essential for regeneration poses challenges in developing effective therapies. Improper optimization of potential therapies leading to failures in ensuring their local availability in nerves also poses additional challenges. Here, we showed that the neurotrophic factor, the mesencephalic astrocyte-derived neurotrophic factor (MANF), equally promotes axon regeneration and glial cell dynamics favorable for nerve regeneration. We showed that while endogenous expression of MANF is primarily restricted to non-peptidergic sensory neurons in adult rats, exogenous MANF promotes the growth of all subtypes of adult rat sensory neurons. We also demonstrated that exogenous MANF promotes the proliferation and migration of adult rat primary Schwann Cells (SCs). Further, we found that local and repeated administration of exogenous MANF to injured mouse nerve promote axon regeneration. Finally, we devised a therapeutic approach by programming nerve resident SCs to locally and continuously deliver MANF to injured rat nerves and showed that this approach improved nerve regeneration indices. Overall, this work developed a therapeutic approach by harnessing the power of SCs as a local delivery system of MANF for improving nerve regeneration.