Researchers from the Hospital del Mar Medical Research Institute (IMIM) have discovered the key role of an enzyme in the differentiation ability of embryonic stem cells. According to the study published in the journal Molecular Cell, enzyme LOXL2 would be involved in maintaining the balance between the pluripotency and the differentiation in this type of cells that can turn into any cell in the body.
The study was coordinated by the researcher from the Cancer Research Programme Sandra Peiró, and explores in greater depth the knowledge on the specialization mechanism of embryonic stem cells, opening the door to a better manipulation. Researchers from the Experimental and Health Sciences Department at the Universitat Pompeu Fabra also participated in the study.
The capacity of embryonic stem cells to become any cell in the body is one of the most promising processes to treat diseases. Manipulating these pluripotent cells could, for instance be used to generate specialized cells that are missing as a consequence of a disease or that may be faulty.
However, the knowledge on these specialization mechanisms is still very limited In this work, researchers studied in vitro the mechanism by which embryonic stem cells are differentiated, leading to neural progenitor cells. “During differentiation towards neuronal lineage, enzyme LOXL2 plays a key role; through the oxidation of a transcription factor, it blocks the transcription of pluripotency genes. This means these genes become deactivated and lose their pluripotency ability, enabling differentiation towards the neuronal lineage,” explains Sandra Peiró.
This is the first time that the key role of oxidation controlled by enzymes in cell differentiation is proven. “It is a mechanism that regulates the activity and the function of proteins and for which, until now, there was no information”, the researcher highlights. After proving the function of the enzyme in embryonic stem cells in mice, researchers inhibited the function of LOXL2 in zebra fish embryos to check in vivo if the consequences in the balance between pluripotency and cell differentiation. Results showed that blocking LOXL2 prevents normal neural development and causes embryos to have morphological defects in their brain and a very low survival rate.
Turning cells into embryonic stem cells
After identifying this mechanism, researchers will try to advance in the manipulation of the pluripotency of embryonic stem cells. “Our next experiments will focus on trying to see if by blocking LOXL2 in differentiated cells we are able to improve the reprogramming into stem cells; this is, the inverse process” explains Sandra Peiró.
The researcher further adds, “Since LOXL2 is an enzyme, it is easier to manipulate, because we can search for the molecules that inhibit its activity.” Currently, the same team of researchers, in collaboration with the IMIM System Pharmacology group, is testing potential enzyme inhibitors that have shown promising preliminary results.
Article of reference
“LOXL2 Oxidizes Methylated TAF10 and Controls TFIID-Dependent Genes during Neural Progenitor Differentiation” Ane Iturbide, Laura Pascual-Reguant, Laura Fargas, Joan Pau Cebrià, Berta Alsina, Antonio García de Herreros and Sandra Peiró. Molecular Cell 2015