Tumor cells undergoing direct lineage conversion to neurons: unnatural but useful?

Dear Editor, In 2011, Son et al. （2011） reported that the forced expression of selected transcription factors is sufficient to convert mouse and human fibroblasts into induced motor neurons （iMNs）. The authors used three factors （Ascll, Brn2, and Mytll） to convert fibroblasts into neuronal-like ceils. After confirming that the cells had neuronal morphology, but with absence of motor neuron markers, eight candidate transcription factors were added, which participate in various stages of motor neuron specification. As expected, a significant number of motor cells emerged with known characteristics of cultured embryonic motor neurons.

Two-photon live imaging of direct glia-to-neuron conversion in the mouse cortex

Over the past decade,a growing number of studies have reported transcription factor-based in situ reprogramming that can directly conve rt endogenous glial cells into functional neurons as an alternative approach for n euro regeneration in the adult mammalian central ne rvous system.Howeve r,many questions remain regarding how a terminally differentiated glial cell can transform into a delicate neuron that forms part of the intricate brain circuitry.In addition,concerns have recently been raised around the absence of astrocyte-to-neuron conversion in astrocytic lineage-tra cing mice.In this study,we employed repetitive two-photon imaging to continuously capture the in situ astrocyte-to-neuron conversion process following ecto pic expression of the neural transcription factor NeuroD1 in both prolife rating reactive astrocytes and lineage-tra ced astrocytes in the mouse cortex.Time-lapse imaging over several wee ks revealed the ste p-by-step transition from a typical astrocyte with numero us short,tapered branches to a typical neuro n with a few long neurites and dynamic growth cones that actively explored the local environment.In addition,these lineage-converting cells were able to migrate ra dially or to ngentially to relocate to suitable positions.Furthermore,two-photon Ca2+imaging and patch-clamp recordings confirmed that the newly generated neuro ns exhibited synchronous calcium signals,repetitive action potentials,and spontaneous synaptic responses,suggesting that they had made functional synaptic connections within local neural circuits.In conclusion,we directly visualized the step-by-step lineage conversion process from astrocytes to functional neurons in vivo and unambiguously demonstrated that adult mammalian brains are highly plastic with respect to their potential for neuro regeneration and neural circuit reconstruction.

Direct lineage conversion of astrocytes to induced neural stem cells or neurons

Since the generation of induced pluripotent stem cells in 2006, cellular reprogramming has attracted increasing attention as a revolutionary strategy for cell replacement therapy. Recent advances have revealed that somatic cells can be directly converted into other mature cell types, which eliminates the risk of neoplasia and the generation of undesired cell types. Astrocytes become reactive and undergo proliferation, which hampers axon regeneration following injury, stroke, and neurodegenerative diseases. An emerging technique to directly reprogram astrocytes into induced neural stem cells （iNSCs） and induced neurons （iNs） by neural fate determinants brings potential hope to cell replacement therapy for the above neurological problems. Here, we discuss the development of direct reprogramming of various cell types into iNs and iNSCs, then detail astrocyte-derived iNSCs and iNs in vivo and in vitro. Finally, we highlight the unsolved challenges and opportunities for improvement.