Let’s take a look at the latest in a series of high-profile studies focused on retinal regeneration. This one describes small molecule-based reprogramming cocktail that can turn fibroblasts into rod photoreceptors and restore vision. https://www.nature.com/articles/s41586-020-2201-4

The authors use a small molecule cocktail to induce formation of GFP-positive cells from MEFs obtained from Nrl-GFP mice, use RNA-Seq to show that they express many rod-specific genes, and identify Axin2, Nkfb, and Ascl1 as regulators of this conversion. So far, so good./2

Similar approaches have been used for directed differentiation of other cell types, with the main problem being that this process is inefficient, and typically does not result in full conversion into the target cell type./3

This also appears to be the case here, as treated cells continue to express many fibroblast-specific genes, and express photoreceptor-specific genes at much lower levels than immature photoreceptor precursors. /4

So, what makes this study different? The claim that transplanted rod photoreceptor-like cells can restore visual function in rd1 mice. Here’s where things get dicey./5

The evidence here amounts to a modest and transient rescue of the scotopic b-wave at P30 and a more persistent, yet equally modest, rescue of light-induced pupillary constriction (PLR), but only under photopic conditions, when rods are not normally active./6

No cellular e-phys or ultrastructural data is present to support this claim. Few surviving GFP-positive transplanted cells are observed, and IHC analysis does not convincingly show expression photoreceptor-specific genes or synaptic connections with bipolar cells./7

Rescue is most likely to reflect neurotrophic effects of the transplanted cells, with the PLR potentially due to improved survival or function of cones. This is not directly tested, nor are the effects of MEF transplantation (only PBS and sham controls are included)./8

Even if transplantation of treated cells does result in rescued scotopic b-wave or PLR relative to MEFs alone, this does not rule out the possibility that treatment simply enhances the neurotrophic function of these cells./9

With this in mind, the central and most spectacular claim of the study is questionable. It’s yet another case where submission to bioRxiv, and resulting feedback, could have made a big difference. /end