Prickly problem of cellular reprogramming solved

USC scientists have overcome a major hurdle in regenerative medicine that previously limited the ability to use recycled cells to treat diseases.

Researchers have discovered how to reprogram cells to change the identity much more reliably than current capabilities allow. The technique uses enzymes to unravel the reprogramming of DNA, a little similar to how a hairdresser treats tangled hair. The technique works with almost perfect efficacy – in mice and humans – for all types of cells tested in the USC stem cell center laboratories.

The results are important because they allow scientists to find treatments for a wide range of diseases, particularly neurological disorders and conditions such as hearing loss.

"It's a strategy that dramatically improves our ability to perform cell reprogramming, which could allow the regeneration of lost tissue and the study of diseases that can not be biopsied by living patients today," said Justin Ichida. , Assistant Professor, Stem Cell Department. Biology and Regenerative Medicine at the USC Keck School of Medicine.

The results appear today in Cell strain cell in a research article entitled "Mitigating the antagonism between transcription and proliferation allows a quasi-deterministic cellular reprogramming". Ichida is the senior author, joined by a team of researchers from the Keck School of Medicine.

How USC researchers have unraveled cell reprogramming

Cell reprogramming has enormous potential as a treatment for the disease, as it allows scientists to study cells and molecular processes at each stage of disease progression under controlled conditions that have been impossible until now.

Reprogramming involves changing a cell to another type of cell, such as a blood cell to a muscle or a nerve cell. This is important for medical research as this technique can be used to recreate tissue lost to disease and to study diseases in tissues that can not be biopsied from living patients.

The technique has been known for decades but has not yet reached its potential. According to the USC team, it's because the DNA does not react well when it's manipulated to change itself. The DNA molecules are twisted by nature, due to the double helix configuration. Reprogramming of DNA requires unwinding, but when scientists begin to unravel the molecules, they tighten up. As a result, nucleotides become much more difficult to use and cells do not replicate properly, Ichida explained. Current disentangling techniques only work 1% of the time.

"Think of it as a phone cord, which is rolled up to begin with, then becomes more coiled and knotted when something is trying to hurt it," Ichida said.

To iron out the problems, the researchers treated the cells with a chemical and genetic cocktail activating enzymes called topoisomerases. The process involves using the enzymes to open the DNA molecules, release the coiled tension and lay it down smoothly. This, in turn, leads to more efficient cell reprogramming, which increases the number of cells capable of simultaneous transcription and proliferation, which is necessary to promote tissue growth. It is the equivalent of a DNA detangler that releases reprogrammed transcriptional tension and facilitates the replication of new cell colonies or new tissues in a laboratory.

This technique has many advantages over current practice. For example, it worked almost 100% of the time. This has been proven in human and animal cells. It can be used today in laboratories to study the development of diseases and drug treatments. It has immediate utility for studying schizophrenia, Parkinson's disease, ALS and other neurological diseases; In these cases, new cells can be created to replace lost cells or acquire cells that can not be extracted from people.

In addition, the technique does not involve stem cells; the reprogrammed cells are not all new, but are the same age as the mother cell, which is advantageous for the study of age-related diseases. The reprogrammed cells may be more apt to create age-appropriate in vitro human disease models, which are useful for studying various degenerative diseases and accelerated aging syndromes.

"The key is to understand the development of the disease at the cellular level and how the disease affects organs," Ichida said. "It's something that you can do with stem cells, but in this case, it goes from one state to another.This is important because stem cells reinitialize epigenetics and produce new young cells. but this method helps to ensure that adult cells of the same age can better study diseases in the elderly, which is important because older people suffer from more diseases. "

This latest breakthrough in regenerative medicine complements other recent technological advances, including gene editing, tissue engineering and stem cell development. It represents a convergence in regenerative medicine that brings scientists closer to treating many diseases. It has practical utility for accelerating targeted medical treatments and precision medicine.

"A modern approach to disease studies and regenerative medicine is to bring cells to change their identity," Ichida said. "This is called reprogramming and makes it possible to obtain inaccessible tissue types from sick patients for examination, as well as to restore lost tissue." However, reprogramming is extremely inefficient, which limits its usefulness. In this study, we identified the dam that prevents cells from changing identities.This turns out to be an entanglement of DNA in the cells that form during the reprogramming process. enzymes that unravel the DNA, we allow a reprogramming efficiency close to 100%. "