Critical protein to keep blood stem cells young and trained

A certain cellular protein is essential for keeping our hematopoietic stem cells (the most immature blood-forming cells) young and trained, thereby reducing the risk of developing myeloproliferative syndromes associated with aging.

This has been seen in research carried out at the National Center for Cardiovascular Research (CNIC) in Spain, in collaboration with researchers from the Cincinnati Pediatric Hospital (United States).

The protein in question is called the Retinoid X Receptor (RXR) and the new study shows that the control exerted by RXR on hematopoietic stem cells is essential in maintaining a balanced production of the different cellular components of the blood throughout the life cycle. of the life.

The results of the new study could have therapeutic repercussions in pathologies in which an excessive proliferation of myeloid cells can contribute to the development of the disease, such as some hematological or cardiovascular diseases.

RXR is a cellular protein that acts as a nutritional sensor for lipids and vitamin A derivatives, altering genetic expression and influencing such important biological functions as immunity, metabolism, or cell differentiation. Alterations in the expression or activation of RXR are related to the development of metabolic and inflammatory diseases that affect, among others, the cardiovascular system.

“Because the half-life of blood cells is very limited, our body needs to continuously replenish them from a small reserve of hematopoietic stem cells that reside in the bone marrow,” explains Dr. Mercedes Ricote, head of the Nuclear Receptor Signaling Group of the CNIC. “However, the replicative potential of hematopoietic stem cells is not infinite and therefore it is essential that they remain in a ‘sleeping’ state and divide in a highly controlled manner to avoid premature exhaustion.”

In the research, the team led by Dr. Ricote and Dr. Jose Cancelas from Cincinnati Children’s Hospital, has shown that knockout of RXR in mouse hematopoietic stem cells causes chronic expansion of a subset of cells with megakaryocytic bias ( platelet-producing) and myeloid, causing a deficit of the lymphoid lineage and the development of a myeloproliferative syndrome in aged mice.

The research, whose main authors are Dr. María Piedad Menéndez-Gutiérrez and Jesús Porcuna (CNIC), indicates that the excess of inflammatory myeloid cells in RXR-deficient mice leads to the invasion of various tissues, especially the lung, where cause severe damage and premature death of these mice.

The collaboration of the bioinformatics teams of Dr. Sánchez-Cabo (CNIC) and Dr. Salomonis (Cincinnati) has allowed the use of state-of-the-art massive sequencing techniques and exhaustive analyzes of the structure and gene expression of stem cell DNA. hematopoietic.

Mercedes Ricote, María Piedad Menéndez-Gutiérrez, Jesús Porcuna, Ana Paredes, Vanessa Núñez and Irene Calero. (Photo: CNIC)

“Thanks to these analyzes we have shown that the deletion of RXR in young mice causes the DNA of their hematopoietic stem cells to open and activate excessively, giving rise to the expression of genes specific to aged cells and the activation of genes regulated by a very important protein for controlling the division capacity of these cells: the MYC oncoprotein”, comments Dr. Menéndez-Gutiérrez. “In addition, we have developed a mouse model deficient in MYC and RXR that has allowed us to conclude that MYC activation is a direct cause of the hyperproliferation of RXR-deficient hematopoietic stem cells”, concludes the researcher.

The scientists highlight the possibility of modulating RXR activity in hematopoietic stem cells through the use of drugs, some of which are currently used for the treatment of cutaneous lymphomas. “Our research could have therapeutic implications in pathologies in which an excessive proliferation of myeloid cells can contribute to the development of the disease, such as some hematological or cardiovascular diseases. In addition, our studies suggest that RXR modulation could serve for the expansion of hematopoietic stem cells for therapeutic and regenerative purposes,” they conclude.

The study is titled “Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homeostasis”. And it has been published in the academic journal Blood. (Source: CNIC)