Reprogramming of Pericyte-Derived Cells of the Adult Human Brain into Induced Neuronal Cells

Abstract

Reprogramming of somatic cells into neurons provides a new approach toward cell-based therapy of neurodegenerative diseases. A major challenge for the translation of neuronal reprogramming into therapy is whether the adult human brain contains cell populations amenable to direct somatic cell conversion. Here we show that cells from the adult human cerebral cortex expressing pericyte hallmarks can be reprogrammed into neuronal cells by retrovirus-mediated coexpression of the transcription factors Sox2 and Mash1. These induced neuronal cells acquire the ability of repetitive action potential firing and serve as synaptic targets for other neurons, indicating their capability of integrating into neural networks. Genetic fate-mapping in mice expressing an inducible Cre recombinase under the tissue-nonspecific alkaline phosphatase promoter corroborated the pericytic origin of the reprogrammed cells. Our results raise the possibility of functional conversion of endogenous cells in the adult human brain to induced neuronal fates.

Leptomeninges: a novel stem cell niche with neurogenic potential

“…Therefore, it is likely that adult brain pericytes have the features of somatic cells rather than those of tissue-committed stem cells. However, reprogramming has been reported to cause adult brain pericytes to become non-pericytic lineages, such as neuronal lineages (10). In support of this notion, we showed that adult brain pericytes, which do not possess stem cell activity under normal conditions, reacquired stemness in response to ischemia, presumably through cellular reprogramming by mesenchymal-epithelial transition (11,12).…”

Vers une régénération induite du système nerveux

“…En parallèle de ces travaux ciblant les astrocytes, d'autres ont décrit l'obtention de neurones glutamatergiques et GABAergiques par conversion directe de cellules gliales NG2 (NG2 glia, progéniteurs d'oligodendrocytes immunoréactifs pour NG2) de souris et de rats [31,33] (Tableau I), faisant des divers sous-types de glies autant de candidats potentiels à la génération de néo-neurones in vivo. Afin de valider notre approche chez l'homme, nous avons tenté de reproduire la conversion astrocytesneurones sur des cellules de cortex humain cultivées à partir de prélèvements chirurgicaux [34]. De manière inattendue, les cellules cultivées se sont avérées être des péricytes, une population cellulaire non gliale, [33] Astrocyte humain NeuroD1…”

“…GABAergique [34] Tableau I. Conversion directe de cellules gliales et péricytes en neurones in vitro.…”

Epigenetic setting and reprogramming for neural cell fate determination and differentiation

“…Regarding glial cells, we have previously shown that activation of the JAK/STAT signalling pathway can induce transdifferentiation from oligodendrocytes into astrocytes [98]. Pericytes, a cell type implicated in the establishment and maintenance of the blood-brain barrier, isolated from human cerebral cortex were also reported to be transdifferentiated into neurons by the ectopic coexpression of SOX2 and ASCL1 [99]. In addition, ectopic expression of PAX6 or NEUROG2 in astrocytes could induce their conversion to immature neurons in mice [100].…”