Fig. 1: Comparison between indirect and direct conversion of somatic cells into neurons.

Somatic cells can be converted into neurons either indirectly or directly. In the indirect conversion technology, fibroblasts can be first converted into iPSCs, by over-expressing Yamanaka’s TFs or into iNPCs, by temporarily over-expressing Yamanaka’s TFs in the presence of specific exogenous differentiation factors. In turn, iPSCs and iNPCS, when cultured in specific lineage differentiation medium, can generate neurons. However, neurons obtained from iPSCs are reprogrammed to the embryonic stage, thus loosing specific age-related and epigenetic features. In the direct conversion technology, age equivalent neurons can be obtained from astrocytes and fibroblasts either by pro-neuronal transcription factors (TFs) plus differentiation and maturation factors (induced Neurons, iNs), or by chemicals/small molecules (chemical-induced neurons, ciNs). iNs and ciNs are mature and functional neurons rapidly obtainable but with limitative regenerative capacities. Despite the multiple neuronal phenotypes, iNs present health concerns