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

Abstract

Neuroregeneration in the 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.

Fig. 1. Different approaches to generate new neurons in vitro and in vivo

The in vitro approaches include: 1) Using somatic cells such as skin fibroblasts to first reprogram into stem cells and then differentiate into neurons; 2) Using somatic cells to directly transdifferentiate into neurons; 3) Isolating stem cells or progenitor cells and differentiating into neurons in culture. These in vitro differentiated neurons or progenitor cells need to be transplanted into the CNS for neural repair. The in vivo approaches include modulating endogenous neural stem cells and in vivo reprogramming of internal glial cells to generate new neurons.

Fig. 2. In vivo reprogramming is fundamentally different from killing reactive glial cells

In vivo reprogramming is a constructive strategy to regenerate functional neurons out of reactive glial cells, whereas killing reactive glial cells is a destructive process.