In Vivo Reprogramming for CNS Repair: Regenerating Neurons from Endogenous Glial Cells

Abstract

Neuroregeneration in the central nervous system (CNS) has proven to be difficult despite decades of research. The old dogma that CNS neurons cannot be regenerated in the adult mammalian brain has been overturned; however, endogenous adult neurogenesis appears to be insufficient for brain repair. Stem cell therapy once held promise for generating large quantities of neurons in the CNS, but immunorejection and long-term functional integration remain major hurdles. In this perspective, we discuss the use of in vivo reprogramming as an emerging technology to regenerate functional neurons from endogenous glial cells inside the brain and spinal cord. Besides the CNS, in vivo reprogramming has been demonstrated successfully in the pancreas, heart and liver, and may be adopted in other organs. Although challenges remain for translating this technology into clinical therapies, we anticipate that in vivo reprogramming may revolutionize regenerative medicine by using a patient’s own internal cells for tissue repair.

Regeneration of dorsal spinal cord neurons after injury viain situNeuroD1-mediated astrocyte-to-neuron conversion

“…Neuronal conversion can be achieved by several neurogenic transcription factors (Li and Chen, 2016). Besides NeuroD1, Sox2, Ngn2, and Ascl1 have all been reported to convert glial cells into neurons (Gascon et al, 2016;Grande et al, 2013;Guo et al, 2014;Heinrich et al, 2014;Liu et al, 2015;Niu et al, 2013;Su et al, 2014).…”

“…Neuronal conversion can be achieved by several neurogenic transcription factors (Li and Chen, 2016 ). An earlier report also showed that Ngn2-expressing retrovirus was able to promote neurogenesis in the injured spinal cord, but the number of newly generated neurons greatly decreases over time even when combined with growth factor treatment (Ohori et al, 2006).…”

“…In vivo neuronal reprogramming has recently emerged as a novel technology to regenerate functional new neurons from endogenous glial cells by overexpressing neurogenic transcription factors in the CNS (Barker et al, 2018;Gascon et al, 2016;Grande et al, 2013;Guo et al, 2014;Lei et al, 2019;Li and Chen, 2016;Liu et al, 2015;Niu et al, 2013). In the injured spinal cord, a combination of growth factor treatment and forced expression of the neurogenic transcription factor Neurogenin 2 (Ngn2) has been reported to stimulate neurogenesis from neural progenitors (Ohori et al, 2006).…”

Direct reprogramming of astrocytes to neurons leads to functional recovery after stroke

“…Here we demonstrated that NeuroD1-mediated astrocyte reprogramming results in the production of mature, active and regionally appropriate neurons that survive long term and correlate with motor improvement following cortical stroke. Previous studies have demonstrated the feasibility of direct cellular conversion in vivo [7,9,[12][13][14][22][23][24][25] but few have demonstrated improved behavioural outcomes following injury [12,17]. Using a foot fault task and gait analysis, we demonstrate that astrocyte-to-neuron reprogramming leads to functional improvement as early as three weeks post-reprogramming, and sustained long-term recovery.…”

Selective transduction of astrocytic and neuronal CNS subpopulations by lentiviral vectors pseudotyped with Chikungunya virus envelope

“…or of astrocytes through in vivo reprogramming [68] is a field under intense study and these vectors might have a distinct utility in this. Furthermore the stability of production and the lack of toxicity in producer cell lines or inactivation in human sera confers to these vectors the great advantage of being easily amenable for clinical use.…”