Neuronal replacement: Concepts, achievements, and call for caution

Abstract

Regenerative approaches have made such a great progress, now aiming toward replacing the exact neurons lost upon injury or neurodegeneration. Transplantation and direct reprogramming approaches benefit from identification of molecular programs for neuronal subtype specification, allowing engineering of more precise neuronal subtypes. Disentangling subtype diversity from dynamic transcriptional states presents a challenge now. Adequate identity and connectivity is a prerequisite to restore neuronal network function, which is achieved by transplanted neurons generating the correct output and input, depending on the location and injury condition. Direct neuronal reprogramming of local glial cells has also made great progress in achieving high efficiency of conversion, with adequate output connectivity now aiming toward the goal of replacing neurons in a noninvasive approach.

Keywords: Neuronal replacement therapies; Transplantation and direct neuronal reprogramming.

Fig. 1

Neuronal replacement therapies.(a) Neuronal loss and network degeneration are major hallmarks of both acute brain injuries and neurodegenerative disorders. Regenerative approaches have made great progress, aiming nowadays toward replacing the exact lost neurons and restoring the correct network. Neuronal replacement therapies have mainly focused their efforts on two promising approaches: (b) cell transplantation takes advantage of different types of neuronal progenitors as sources of donor cells and (c) direct reprogramming of in loco glial cells to a neuronal fate by introducing proneural factors via viral vectors.

Fig. 2

Combinations of neurogenic factors used for in vivo reprogramming in the neocortex and striatum.In vivo direct reprogramming of glial cells can be achieved using different cocktails of factors promoting fate conversion into neurons [11∗∗, 12∗∗, 13∗∗,35,36,38,39,41,43, 44, 45,47,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66].

Fig. 3

Single-cell RNA-sequencing (scRNA-seq) and CRISPR-mediated gene activation (CRISPRa) technologies can improve in vivo reprogramming. With scRNA-seq, we can now examine the patterns of gene expression in glial cells (a), induced neurons (b), and endogenous neurons (c) at the single-cell level. The comparison of these data sets could ultimately highlight the differences between induced and endogenous neurons, improving the accuracy of reprogramming. This could be achieved by multiplexing viral-transduced gRNAs for selected genes, using CRISPRa (d).