Cellular career

From the skin to the intestines

Polina Loseva, "The Attic"

There are high hopes for cell reprogramming, but it still works ineffectively. In addition, it is not completely clear how it happens at all. Scientists have come up with a new way to monitor cells: they have introduced unique DNA tags ("barcodes") into them. This allows them to determine the ancestors of each cell at the end of the experiment and find out at what point they "turned the wrong way".

The history of cell reprogramming began with Shinya Yamanaki, who learned how to transform differentiated adult cells into embryo cells (induced pluripotent stem cells). To do this, he used four proteins that unwound the DNA of cells and made available "silent" germinal genes in adults. Different tissues and organs genetically identical to the patient's cells were grown from the stem cells obtained. This year, the first trials of nerve cells obtained in this way for the treatment of Parkinson's disease have already started.

Later it turned out that it was not necessary to turn the cells into germ cells, but you can try to get the cells of the required tissue right away. This type of reprogramming is called transdifferentiation. To do this, it is enough to unwind the DNA and simultaneously activate the necessary genes characteristic of cells of this type. However, all these are very inefficient procedures: the useful yield, as a rule, does not exceed a few percent. And if we want to understand the reasons for this, we need to learn how to control the state of cells at every stage of the path.

A group of American scientists in an article in Nature (Biddy et al., Single-cell mapping of lineage and identity in direct reprogramming) proposed their own version of cell fate tracking. They took fibroblasts from the skin of mice and tried to turn them into endodermal progenitor cells (from which the intestines and digestive glands develop in the embryo). And in order to monitor their fate, from time to time, a unique DNA marker (the so-called DNA barcode) was embedded in each cell with the help of a virus. This barcode was expressed along with other genes working in the cell. They called this technology cell tagging.

Reprogramming of cells takes about a month. Every three to six days, scientists selected several cells from the total mass and checked which genes were active in them and which barcodes they contained. By the end of the month, a family tree of barcodes turned out: you can see which genes worked in each ancestral cell and whether its descendants turned into an intestinal cell. Based on the results, it is possible to identify genes that obviously interfere with reprogramming. Scientists have already discovered one such gene, Mettl7al. Perhaps later we will learn how to turn off these genes and turn the skin into the intestine more efficiently. And with the help of the same method, it will be possible to build family trees for cancer cells and look for a specific reason for their transformation.

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