The cellular protein "RXR" is the secret to keeping blood stem cells young and healthy

The cellular protein vitamin A X receptor (RXR) is a key factor in the maintenance of hematopoietic stem cells, which are immature stem cells
that produce all blood cell lineages.
RXR ensures that these cells remain young and healthy, thereby reducing the risk of
developing myeloproliferative syndrome as the body ages.
The National Center for Cardiovascular Research (CNIC) collaborated
with researchers at Cincinnati Children's Hospital.
The results suggest that the regulatory effect of RXR on hematopoietic stem cells is essential
for maintaining balanced production of blood cell type profiles throughout life.

The findings, published in Blood, may have therapeutic implications for diseases in which myeloid blood cells proliferate, as are some diseases of the blood and cardiovascular system
.

RXR acts as a nutritional sensor for lipids and vitamin A derivatives, altering gene expression and influencing important biological functions such as immunity, metabolism, and cell differentiation
.
Alterations in RXR expression or activation are associated
with the development of metabolic and inflammatory diseases that affect a variety of bodily functions, including the cardiovascular system.

Blood cells have a short lifespan, and because of this, "they have to be constantly replenished from a small pool of hematopoietic stem cells located in the bone marrow," explains
Dr.
Mercedes Ricote, head of the CNIC nuclear receptor signaling group.
However, hematopoietic stem cells have a limited ability to replicate, so they must remain dormant and divide in a highly controlled manner to ensure they do not deplete
prematurely.

In one study, Dr.
Ricote's team and a team led by Dr.
Jose Cancelas of Cincinnati Children's Hospital demonstrated that the elimination of RXR in mouse hematopoietic stem cells triggered a chronic expansion of a subset of cells tilted toward megakaryocytes (progenitor cells of platelets) and myeloid, leading to defects in the lymphatic line and developing myeloproliferative syndrome
as these mice aged.

The study's first authors, Dr.
MaPiedad Menéndez-Gutiérrez and Jesús Porcuna (CNIC), showed that in RXR-deficient mice, the overproduction of inflammatory bone marrow cells caused these cells to invade multiple tissues, particularly the lungs, where they caused serious damage that led to the premature death
of these mice.

The collaboration with Dr.
Sánchez-Cabo and Dr.
Salomonis (Children's Hospital of Cincinnati) in the Department of Bioinformatics of CNIC allowed the use of the latest generation of large-scale sequencing technology and detailed analysis
of DNA structure and gene expression in hematopoietic stem cells.

"Thanks to this analysis, we were able to show that deletion of RXR in young mice causes the DNA in their hematopoietic stem cells to adopt an open and active conformation, leading to the expression of genes typical of old cells and the activation of genes regulated by the oncogene MYC, an important protein that controls hematopoietic stem cell division," commented
Dr.
Menéndez-Gutiérrez.
"We also made mice deficient in MYC and RXR, leading us to conclude that activation of MYC is the direct cause
of excessive proliferation of RXR-deficient hematopoietic stem cells," she concluded.

The researchers highlighted the possibility of modulating RXR activity in hematopoietic stem cells through the use of drugs, some of which have been used to treat cutaneous lymphoma
.
Jesús Porcuna concludes: "Our study may have therapeutic implications for conditions characterized by excessive proliferation of myeloid cells, such as some diseases of the blood and cardiovascular system
.
Furthermore, our results suggest that modulation of RXR can be used for therapeutic or regenerative purposes to expand hematopoietic stem cells
.
”

Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homeostasis