Reprogramming glia to neurons

I must admit that I have pretty much avoided reading about reprogramming anything (fetal cells, fibroblasts, glia) to neurons to cure neurologic disease.  It seems light years away, and transplantation work to cure Parkinsonism never really worked.

However a gigantic amount of work (all experimental) has been done on reprogramming glia to neurons while my reading was elsewhere.  You can read all about it in a similarly gigantic review [ Neuron vol. 110 pp. 366 – 393 ’22 ].

But the review potentially is about much more than that, because it talks about what keeps a differentiated cell in its differentiated state.  To reprogram glia (or any cell) that must be broken, and the review contains a good deal of molecular biology on this point.

There is applicability to cancer (although this isn’t mentioned in the review).  The focus of nearly all cancer research is on stopping proliferation.  We were all taught that cancer also involves dedifferentiation.  Wouldn’t it be good if we could REdifferentiate the cancer back to its cell of origin.   The reprogramming literature and this review extensively deals with these issues (but only in the context of glia –> neurons).

Close study of one example (introduction of NeuroD1 to mouse microglia by a lentivirus) converts them to neurons (in vivo and in vitro).   Initially NeuroD1 occupies closed chromatin regions associated with bivalent epigenetic marks.

Bivalency just means two marks, one of which is associated with gene activation, the other associated with gene repression (respectively trimethylation of histone H3 on lysine 4 { H3K4Me3 } and H3K27Ac associated with repression).  Bivalent genes are thought to be in a primed state for activation although still repressed.  So this leads to the idea that cell fate may be stabilized by stringently shutting down transcription factors specifying alternative states.  Perhaps we could do something like this with neoplastic cells.

At lter stages of thei reprogramming model, bivalent regions are ‘resolved’ to a monoalent H3K4Me1 histone mark to establish neuronal identity. NeuroD1 also induces the expression of Brn2 which supports acquisition of neuronal gene expression.

The review delves further in to REST, which represses neuronal genes in nonNeuronal cells.  It binds and represses the microRNAs miR-124 and miR-9/9* which reduce the expression of SCP1 a phosphatase, which is recruited by REST on neuronal genes.  The review is full of detailed mechanistic stuff at this level.

Be prepared for a long slog through the review, there is a ton of dense information, densely presented.  It took me a week or so to get through it.

The amount of work already done is impressive.  Table 1 is a list of 32 in vivo studies (with controls) which show direct reprogramming of glia to neurons.

The techniques of introducing the reprogramming factors are discusssed:  retroviruses, lentiviruses and AdenoAssociated Viruses (AAVs).

It’s a long way from the clinic but a lot of work is ongoing.  Fascinating stuff

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