Defining epigenetic reprogramming, cellular reprogramming & rejuvenation

Epigenetic reprogramming is a term used in cell biology that is increasingly ending up in news stories too.

Unfortunately, some folks, especially in the cellular rejuvenation and anti-aging space, are getting this term and other things confused.

Just to start off, epigenetic reprogramming does not specifically mean cellular rejuvenation.

The goal of today’s post is to clearly define epigenetic reprogramming. I also differentiate it from the terms “cellular reprogramming” and “rejuvenation.”

epigenetic reprogramming
Artist’s rendition of epigenetic reprogramming. Knoepfler image.

So how do we define and differentiate these terms? How do they relate to rejuvenation?

What is epigenetic reprogramming?

Let’s start with epigenetic reprogramming, which can manifest in different contexts. It’s a broad term.

Simply put, it means making a major change in the epigenetic state of a cell. Such changes are sometimes so powerful that they transform aspects of the cell’s identity, leading to cellular reprogramming. However, that doesn’t always happen.

Notably, some developmental biologists use the term epigenetic reprogramming only to refer to early developmental events. That feels too limited to me, but there are different ideas about this.

Examples of epigenetic reprogramming

In one case it’s how you achieve the end goal of cellular reprogramming to change somatic cell identity back to become iPS cells.

Different versions of this reprogramming also can be attempted just to achieve the different goal of “cellular rejuvenation”.  For instance, keeping a blood cell a blood cell, but making it physically younger (change the clock, not the identity). This is difficult to achieve in a tissue without producing at least some stem cells like iPS cells too, which can potentially grow into teratoma tumors or even cancers.

Another example is during somatic cell nuclear transfer or SCNT. The nucleus of a somatic cell is epigenetically reprogrammed by its new home within the oocyte cytoplasm.

To further complicate things, epigenetic reprogramming happens in other ways too including outside the scope of a lab. As noted earlier, it also occurs during normal human development. When egg and sperm fuse during fertilization and in the early embryo after that, the genomes must have their epigenetic states reset. There’s a shift from maternal to zygotic gene expression, which depends on major epigenetic changes.

Cancer cells can also exhibit reprogramming of their epigenomes.

One take-home here is that epigenetic reprogramming is a very broad term. It does not just mean rejuvenation.

What is cellular reprogramming?

How do we define cellular reprogramming? It’s also not entirely simple.

Cellular reprogramming means a cell’s identity has been fundamentally changed. This can be accomplished in different ways in the lab. For instance, there is the reprogramming we talked about to make iPS cells. However, there’s also direct reprogramming (sometimes called transdifferentiation) where one cell type like a neuron is changed into a different one like a kidney cell. Swap in any two of your favorite at least somewhat differentiated cell types into that direct reprogramming equation. Fibroblast to neuron is another example.

Cellular reprogramming also occurs in vivo. It can manifest in diseases such as during the genesis of some types of cancer. In that case, we can see that cells can be reprogrammed in harmful ways. For instance, in a brain cancer’s early days, some cells can take on an abnormal “younger” identity and grow too much leading to a tumor when the brain shouldn’t be growing at all.

There is some sense that cellular reprogramming could happen normally in the body too but that is less clear.

Often cellular reprogramming results from epigenetic reprogramming, but they aren’t equivalent terms.

How should scientists rigorously define cellular rejuvenation?

What about rejuvenation? Some are using the terms “rejuvenation” or “cellular rejuvenation” in too loose a manner. On one level cellular rejuvenation can simply mean to make something like a cell or organism appear and function in a younger manner.

As I’ve written before, there are tough questions here on rejuvenation.

At a rigorous scientific level, how is rejuvenation measured and statistically evaluated? Is evidence of epigenetic reprogramming such as changes in DNA methylation to a state associated with younger cells or organisms sufficient to say, boom, we’ve got rejuvenation? Should researchers also look at the transcriptome for potential signatures of “young RNAs”? How well-defined are “young transcriptomes”?

What about cell and tissue and organism metabolism? Telomere length?

All these things wrapped up into one? There are no standards at this point, but they are needed to help boost rigor in this research space.

Overall, we need to be precise with the language and terms we use related to reprogramming of various types. One of the challenges though is that there are different opinions on how to define things. Some researchers even define stem cells in different ways. Even with some flexibility in mind, within the research community the term epigenetic reprogramming just does not mean cellular rejuvenation.


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