In Vivo Transient and Partial Cell Reprogramming to Pluripotency as a Therapeutic Tool for Neurodegenerative Diseases.

In theory, human diseases in which a specific cell type degenerates, such as neurodegenerative diseases, can be therapeutically addressed by replacement of the lost cells. The classical strategy for cell replacement is exogenous cell transplantation, but now, cell replacement can also be achieved with in situ reprogramming. Indeed, many of these disorders are age-dependent, and "rejuvenating" strategies based on cell epigenetic modifications are a possible approach to counteract disease progression. In this context, transient and/or partial reprogramming of adult somatic cells towards pluripotency can be a promising tool for neuroregeneration. Temporary and controlled in vivo overexpression of Yamanaka reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc (OSKM)) has been proven feasible in different experimental settings and could be employed to facilitate in situ tissue regeneration; this regeneration can be accomplished either by producing novel stem/precursor cells, without the challenges posed by exogenous cell transplantation, or by changing the epigenetic adult cell signature to the signature of a younger cell. The risk of this procedure resides in the possible lack of perfect control of the process, carrying a potential oncogenic or unexpected cell phenotype hazard. Recent studies have suggested that these limits can be overcome by a tightly controlled cyclic regimen of short-term OSKM expression in vivo that prevents full reprogramming to the pluripotent state and avoids both tumorigenesis and the presence of unwanted undifferentiated cells. On the other hand, this strategy can enhance tissue regeneration for therapeutic purposes in aging-related neurological diseases as well. These data could open the path to further research on the therapeutic potential of in vivo reprogramming in regenerative medicine.