Are the hopes of a direct conversion of astrocytes into neurons dashed?

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In 2013, Xiang-Dong Fu of the University of California, San Diego, and colleagues found that deleting a single gene converts a variety of cells, including fibroblasts, directly into neurons. This procedure represents one of the simplest methods of generating neurons to date. Since it does not require any foreign DNA, it can bring in-vivo direct cells conversion closer to the clinic.

Cellular reprogramming technology, including the generation of induced pluripotent stem cells, had raised hopes that scientists might one day replace dying cells with new ones derived from patient's healthy tissues. New presentations in 2019 had really made people think that a clinical solution for neurodegenerative diseases like Parkinson's, Alzheimer's or ALS (Charcot's disease) was at hand.

Fu's group proceeded by injecting directly into the substantia nigra of mice, an adeno-associated virus (AAV) carrying an RNA that inhibited PTBP1. To mark infected astrocytes, the vector they used included a fluorescent tag that could only be activated in cells infected with the virus (because it was under the control of the GFAP promoter). Researchers reported that fluorescent cells carrying neural markers formed connections with nearby striatum and reversed motor deficits in an animal model of Parkinson's disease. Obviously we could already be wondering why AAV viruses would only infect astrocytes, and not other cells and among these, neurons.

Indeed, several recent studies suggest that the apparently converted astrocytes would in fact have been neurons. These recent studies have used different cell lineage mapping approaches to label astrocytes. This type of lineage can be studied by marking a cell (with fluorescent molecules or other traceable markers) and following its progeny after cell division. In fact, it is a method quite similar to that used by the San Diego group.

Two of the studies, published in Cell Reports on June 14, reported that Müller's glia (a source of retinal stem cells that can replenish neuronal loss and restore vision) failed to convert into neurons when PTBP1 was deleted (Xie and al., 2022; Hoang et al., 2022). Two others – one published in Life on May 10 and the other published on bioRxiv on May 13 – came to similar conclusions with astrocytes in the substantia nigra and striatum (Chen et al., 2022; Yang et al ., 2022).

Their findings are consistent with a similar report published last year (Wang et al., 2021). Some have also found GFAP promoter expression in neurons, giving the mistaken impression that they were ancient astrocytes.

We can ask ourselves some serious questions, for example why the scientific community did not express as soon as the 2013 announcement was made, the fairly obvious fact that astrocytes were probably not the only ones to be infected, why did they wait 9 years to highlight this point?

Another question concerns the cell lines, these are different in the different studies, the cells are at different stages of maturation, and their phenotype is very different from that of astrocytes, so can we really draw general conclusions?

In addition, Müller's glia are derived from the development of two distinct populations of cells, which are we talking about in these new studies? Finally, they are the only retinal glial cells that share a common cell line with retinal neurons. From a certain point of view Müller's glia are neurons not astrocytes, and therefore this greatly diminishes the value of the analyzes carried out, but this should be known to scientists who have done these contradictory studies?

In response to these and other studies that challenge data for conversion of astrocytes to neurons, Fu recognized that some expression of the GFAP promoter occurs in neurons infected with AAV viruses. For him, about 5% of cells expressing AAV genes soon after infection were neurons. Yet this percentage seems very low.

On the other hand, Fu said that lineage tracing experiments performed in the new studies may have preferentially marked mature Müller cells, leaving open the possibility that the conversion of more immature cells into neurons may have been missed. .

Finally, knocking out PTBP1 effectively restored dopamine levels and boosted motor function in a mouse model of Parkinson's disease. If not by the creation of new neurons, what could e


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