Regional heterogeneity in astrocytes to neurons reprogramming

The repair of the damaged neuronal circuits is one of the major challenges of modern neuroscience. In the mammalian adult brain a subpopulation of astrocytes act as neural stem cells through life. Brain lesions can activate a latent neurogenic potential in parenchymal astrocytes. This potential, however, is activated only in specific conditions and do not show any regenerative capacity as the fate of the newborn neurons differ from that of the degenerated neurons. An alternative solution to extend the adult brain neurogenic potential is represented by in vivo reprogramming. Reprogramming exploits the expression of master transcription factor involved in the cell development to force their transition to a different cell lineage. Adult astrocytes share many features with embryonic progenitors and their neurogenic potential make them a suitable target for reprogramming. However, it is important to understand if astrocytes regional heterogeneity can affect the efficiency of the process and the fate of the obtained neurons. To address this issue, Hu and colleagues (2019) isolated in vitro astrocytes from cerebral cortex, cerebellum and spinal cord and assessed their susceptibility to be reprogrammed by two TFs, NGN2 and ASCL1. The reprogramming efficiency was much higher in the cortex and lower in the spinal cord. Concerning the fate of the generated neurons, regional differences have a major role in the susceptibility of adult astrocytes to be reprogrammed. NGN2 and ASCL1 drive neurons to a glutamatergic and GABAergic fate, respectively. However, the in vitro set-up and the limited phenotypic analysis performed by the authors did not allowed to more precisely analyze the neuronal subtype identity of the induced neurons. To perform more in depth analyses of the fate of induced neurons, Mattugini and colleagues (2019) reprogrammed astrocytes in the lesioned neocortex in vivo. To this aim, they induced in these cells the expression of NGN2 and Nurr1 TF. They observed that the induced neurons (iNs) were all pyramidal and acquired a specific layer molecular identity, as assessed by molecular, morphological and electrophysiological analyses. The reprogrammed neurons acquired the new phenotype gradually and integrated in pre-existing neuronal circuits. Altogether, these studies highlight the importance of the regional factors in the recombining efficiency and fate choice of the reprogrammed cells. In vivo reprogramming may thus represent a promising approach for cells replacement in the lesioned adult brain.