Transdifferentiation or direct reprogramming of fibroblasts to oligodendrocyte progenitors

Back-to-back papers (here and here) in Nature Biotechnology report the transdifferentiation (now often simply referred to as “direct reprogramming”) of plain old fibroblasts into brain cells called oligodendrocyte progenitor cells (OPCs).

OPCs are a remarkably useful kind of brain cell that generates myelin, which insulates nerves. OPCs are thought to have great therapeutic potential for a number of pathological conditions including Multiple Sclerosis (MS) and spinal cord injury (SCI).

The two teams included one from Case Western Reserve University School of Medicine led by Paul J Tesar (Najm, et al paper) and one from Stanford (Yang, et al paper) led by transdifferentiation guru, Marius Wernig. The teams worked independently but made very similar, complimentary discoveries.

Both teams honed in on transcription factors that are specifically expressed in OPCs and the oligodendrocyte lineage or when deleted cause defects in this lineage.

Najm, et al screened using the following factors: Olig1, Olig2, Nkx2.2, Nkx6.2, Sox10, ST18, Gm98 (Myrf) and Myt1.  They found that all 8 factors when introduced together could make OPCs, but that Sox10, Olig2, and Nkx6.2 could do the same thing by themselves without the other five factors.

Yang, et al found that Sox10, Olig2, and Zfp536 could directly reprogram fibroblasts into OPCs after screening through the following: Ascl1, Gm98, Myt1, Nkx2.2, Nkx6.1, Nkx6.2, Olig1, Olig2, Sox10 and Zfp536.

Taken together these findings would suggest that Sox10 and Olig2 are the most important OPC-inducing factors. It is interesting that the teams each found a distinct 3rd factor makes up an effective 3-part cocktail.

It is particularly notable that Najm’s cocktail uses the homeodomain transcription factor Nkx6.2 because it seems that the Yang team tried Nkx6.2 as well, but in combination with Sox10 and Olig2, it didn’t work in their hands. Instead, a zinc-finger transcription factor Zfp536 did the trick for Wernig’s team.

The difference may be explainable by other different conditions and assays used in the two labs.

Part of Figure 2 from the Najm paper (above) shows that in the presence of Dox, which turns on the 8 transgenes, the morphology changes from normal fibroblasts (spindly in a) to the characteristic bipolar morphology of OPCs (b). With differentiation, the cells adopt the beautifully intricate morphology of oligodendrocytes, stain for the GFP (green) marker indicating the transgenes are “on”, and also importantly stain in red for Maltose Binding Protein (MBP), a marker of mature oligodendrocytes.

Very cool!

In both cases with the two teams, the studies were done using rodent cells and each of papers notes in the discussion that human studies are critical. Wernig’s team stated:

Given the strong clinical interest in OPCs for regenerative therapies, one of the most important next steps is to translate our findings to human fibroblasts. Based on our experience with iPS and iN cells, we predict that generation of human iOPCs is possible but may require additional reprogramming factors, such as other transcriptional regulators or microRNAs

I see these papers as a major advance in transdifferentiation technology. In theory if these technologies can be adapted for human use, then transdifferentiation can be used to make OPCs from any given patient that could be given back to that same patient as an autologous transplant. Thus, these studies have huge clinical implications.

I am happy to say that this discovery also now makes me have a perfect 100% record so far for my 2013 stem cell predictions (you can check them out here).

I am now correct on #8, #6, #3 (so far), and #1.

Fingers crossed on the rest.