Human life expectancy has increased more than two-fold over the past two centuries, resulting in a dramatic increase in the elderly population. Advanced age is associated with physiological decline, which ultimately lead to an enhanced predisposition to diseases. Aging is the highest risk factor for neurodegenerative diseases. Remarkably, Alzheimer disease and other dementias are among the most common causes of death. The World Health Organization reported that up to 1 billion people, nearly one in six of the world’s population, suffer from neurological diseases, which make these disorders a growing burden for aged societies worldwide (1).
Many of these neurological disorders have in common the malfunction of neurons, but most neurons are not replaced during normal life or pathological situations. The formation of neurons or neurogenesis is rare in postnatal life, and only occurs in two confined areas of the mammalian brain. Because adult neurogenesis is limited, the regenerative capacity of the brain is restrained and the possibilities of recovery from damage are almost absent. Current clinical interventions for neurological dysfunction are very limited, highlighting the need for strategies to palliate the loss of functional neurons occurring in these conditions.
This project, 4F4REJUVENGLIA (short for: 4 Factors for rejuvenating glia)focuses on a novel approach to address regeneration in the nervous system, based on nuclear cell reprogramming technology, to generate new neurons in regions naturally devoid of neurogenesis. Current methods of reprogramming use direct conversion from glial cells to neurons by the expression of proneural factors I proposed an alternative approach, partial reprogramming, based in the short expression of the Yamanaka factors, to facilitate the conversion from glia to neuron through an intermediate progenitor state. We hypothesise that this “rewinding” to a neural progenitor-like state may rearrange the local environment and remodel it towards a stem cell niche that help instruct and integrate new neurons within the preexisting circuits.
The project is guided by the objective of harnessing the potential offered by cell reprogramming technology to manipulate tissue regeneration and explore its applications to promote brain repair. The strategy is to use reprogramming to reinstall neurogenesis in brain areas, such as the cerebral cortex, which are naturally devoid of neurogenesis once embryogenesis is completed. The formation of new neurons aims to compensate for the degeneration of these cells occurring in pathophysiological conditions and to promote the regeneration of damaged brain areas.
