Generation of induced neurons via direct conversion in vivo

TLDR

Cellular reprogramming allows somatic cells to be converted into other cell types by expressing specific genes, and direct neural conversion of fibroblasts or astrocytes into induced neurons offers a non‑proliferative alternative to induced pluripotent stem cells that could be applied in vivo. The study aims to demonstrate that human fibroblasts and astrocytes engineered to express inducible neural reprogramming genes can be transplanted and then activated to convert into neurons. Using a transgenic mouse model that drives reprogramming gene expression specifically in striatal astrocytes, the authors show that endogenous mouse astrocytes can be directly converted into NeuN‑positive neurons in situ. These results provide proof of principle that direct neural conversion occurs in the adult rodent brain from both transplanted human cells and endogenous mouse cells.

Abstract

Cellular reprogramming is a new and rapidly emerging field in which somatic cells can be turned into pluripotent stem cells or other somatic cell types simply by the expression of specific combinations of genes. By viral expression of neural fate determinants, it is possible to directly reprogram mouse and human fibroblasts into functional neurons, also known as induced neurons. The resulting cells are nonproliferating and present an alternative to induced pluripotent stem cells for obtaining patient- and disease-specific neurons to be used for disease modeling and for development of cell therapy. In addition, because the cells do not pass a stem cell intermediate, direct neural conversion has the potential to be performed in vivo. In this study, we show that transplanted human fibroblasts and human astrocytes, which are engineered to express inducible forms of neural reprogramming genes, convert into neurons when reprogramming genes are activated after transplantation. Using a transgenic mouse model to specifically direct expression of reprogramming genes to parenchymal astrocytes residing in the striatum, we also show that endogenous mouse astrocytes can be directly converted into neural nuclei (NeuN)-expressing neurons in situ. Taken together, our data provide proof of principle that direct neural conversion can take place in the adult rodent brain when using transplanted human cells or endogenous mouse cells as a starting cell for neural conversion.