Toward better functional recovery:
Restoring impaired function by regulating extrinsic/intrinsic cell fate in the CNS
Kinichi Nakashima
Department of Stem Cell Biology and Medicine,
Graduate School of Medical Sciences, Kyushu University
nakashima.kinichi.718(at)m.kyushu-u.ac.jp
The usefulness of neural stem cell (NSC) transplantation to replenish neurons has been extensively investigated. However, because of the gliogenic environment in the lesion site, effective neuronal production has not been satisfactorily successful. We have previously found that the antiepileptic drug valproic acid, also known as a histone deacetylase inhibitor, induced neuronal differentiation of NSCs, and reported that combinatorial treatment with VPA and NSC transplantation could supply newly generated neurons in the injured spinal cord, leading to dramatic functional recovery after spinal cord injury (SCI)1). In the subsequent study, we have also shown that human iPSC-derived NSCs, which are epigenetically restricted not to differentiate into glial cells, efficiently give rise to neurons in the injured spinal cord, inducing recovery of locomotor functions of mice after SCI2). Although it is now understood that the supply of new neurons has beneficial effects on functional recovery, critical problems remain, such as tumorigenicity and time-consuming preparation of cells if we utilize iPSC-derived cells. As an alternative strategy to replenish new neurons in vivo, direct conversion from endogenous cells in non-neuronal lineages has recently attracted much attention. In this regard, we have found that microglia, which converge at the lesion site after injury, can be converted to functional neurons in vitro and in vivo by expressing a single proneural transcription factor NeuroD1 (ND1) 3). In this talk, we will demonstrate that this microglia-to-neuron conversion reinstates neurological function after stroke4), shedding light on developing therapies for ischemic brain injury by intravital neuronal conversion technology.
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