Paper sparks renewed interest in transdifferentiation & clinical potential

There was a time when I thought transdifferentiation based approaches might quickly move into clinical trials. Then things kind of cooled off. We didn’t see many papers reporting methods to transdifferentiate cells.

I still think that this technology, sometimes called direct reprogramming, has major potential.

A new paper on making human brain cells this way got me thinking more about transdifferentiation again.

Where is this field of research these days more generally? First, I’ll give some background and then talk about the new paper.

transdifferentiation, iOPCS
Evidence of engraftment and function of transplanted cells following transdifferentiation. “Engraftment and myelination in vivo and disease modeling capability of iOPCs. (C) Electron microscopy of the transplantation area. Top row: only thinly and loosely myelinated axons were found in Shiverer mouse. Bottom row: electron microscopy of the area transplanted with iOPCs revealed multi-layer, compact myelin (arrows).” Tanabe, et al. Development, 2022. Fig. 4C.

What is transdifferentiation?

Stem cells, by definition, are special cells that can be differentiated into other cell types. For instance, pluripotent stem cells can make any other kind of cell in the body. Some adult stem cells have the ability to be differentiated into several other cell types. This is called potency.

Transdifferentiation is defined as a process of making one new type of cell from an entirely different kind of cell, without stem cells being involved as intermediaries. A good example of transdifferentiation is making brain cells from skin cells directly.

Using more conventional methods, we would instead first reprogram skin cells into iPS cells and then differentiate the iPS cells into neurons.

How does one transdifferentiate cells? Typically this is done using cocktails of master transcription factors. These factors normally function to direct differentiation of cell types such as during development but can be used in the lab to change cell identity.

How transdifferentiation could have unique benefits

You can see how direct reprogramming is, well, more direct than using iPS cells.

It’s simpler. Having fewer steps also means that transdifferentiation might give less room for things to go awry.

What could go wrong? One concern with some stem cell-based therapies is a pluripotency-related tumor called teratoma. Research shows that iPS or ES cells can spark teratoma formation. A possible advantage of direct reprogramming is that it might avoid the concern over teratoma formation from iPS cells.

For instance, let’s say you want to make a specific kind of retinal cell to use in a new cell therapy. If you go the iPS cell route then after you make the eye cells you have to be sure you have as close to zero residual iPS cells as possible in the product. We don’t want any teratoma showing up.

Both positive and negative selection can help get nearly pure differentiated cells from pluripotent stem cells.

Still it can be difficult to be sure out of potentially hundreds of millions of differentiated cells whether you might have 1 or 100 or even 1000 iPS cells hanging around. Or maybe some cells that aren’t iPS cells still are there but they are some intermediate type of precursor cell that could have tumor-forming potential.

So by avoiding the iPS cell step, transdifferentiation could be safer on the tumor front, but we can’t be sure about that yet. I have some concerns in that regard that I discuss at the end of the post.

Also, it’s possible that using iPS cells might give a much wider range of specific useful cell types than transdifferentiation.

New transdifferentiation paper

The new paper that caught my eye is entitled Generation of functional human oligodendrocytes from dermal fibroblasts by direct lineage conversion. It is coming out in the journal Development.

Human oligodendrocytes are special brain cells that have key roles in protecting neurons. These cells make the myelin coating around nerves. Disruptions of this protective system can cause diseases such as MS.

So having an unlimited supply of healthy, functional oligodendrocytes would be a big deal clinically.

While researchers can already make oligodendrocytes by differentiating human iPS cells or ES cells, making them via transdifferentiation could yield better results. We’ll see.

Cautionary note

The team used a combination of transcription factors to make the iOPCs: OLIG2, SOX10, ASCL1, NKX2.2 (NKX2-2) and NKX6.1. This efficiently produced the desired cells from fibroblasts. The iOPCS could then be differentiated into mature, functional oligodendrocytes. Very cool.

However, one thing that caught my eye here is the use of ASCL1 in the transdifferentiation protocol. Some of the other factors rang a bell too.

My lab has found that high-grade childhood gliomas overexpress ASCL1. Further, ASCL1 seems to play a central role in these tumors downstream of histone H3.3 mutations like K27M. We also observed elevation of OLIG2 in some of these tumors and changes in some SOX proteins.

So some caution is in order here with this reprogramming cocktail.

The encouraging news is that the iOPC paper team found no evidence of tumors in eight mice that received the cells. Transient expression of the reprogramming factors lowers risk.

I found 15 listings on in this space, but few seem to be using reprogrammed cells for clinical interventions.

Overall, I remain am hopeful for transdifferentiation to have clinical impact. It’s just a long road ahead.

1 thought on “Paper sparks renewed interest in transdifferentiation & clinical potential”

  1. I continue to be wary of transdifferentiation. I see it as being more complex, not simpler, than generating cell types from pluripotent cells. Using transcription factors to make one cell type take on characteristics as another has a long history, considerably predating the dramatic reprogramming of somatic cells into iPSCs. The same transcription factors are used over and over again in different combinations and levels to direct differentiation of many types of cells, so there can be surprises, and it’s important to ask hard questions of the cells- about how similar they are to the real thing. I’m afraid I’m an embryologist – we’re sticklers for that kind of thing.

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