RXR Protein Regulates Hematopoietic Stem Cell Maintenance

A new study published in the journal Blood has identified a key protein in maintaining hematopoietic stem cells, which are responsible for the production of all blood cell types. The protein, known as retinoid X receptor (RXR), is essential for maintaining a balanced production of blood cells throughout life.

The findings could have therapeutic implications for conditions with excessive proliferation of myeloid blood cells, such as some blood and cardiovascular diseases. RXR acts as a nutritional sensor of lipids and derivatives of vitamin A, altering gene expression and influencing important biological functions such as immunity, metabolism, and cell differentiation.

Hematopoietic stem cells have a limited lifespan and must be continuously replenished from a small reservoir located in the bone marrow. However, their replicative capacity is limited. Therefore, they must be maintained in a dormant state and divide in a highly controlled way to ensure they do not become prematurely exhausted.

In the study, researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and Cincinnati Children's Hospital demonstrate that the elimination of RXR from hematopoietic stem cells in mice triggers chronic expansion of a subgroup of cells skewed towards megakaryocytes (the progenitors of blood platelets) and the myeloid lineage, resulting in a deficit of the lymphoid lineage and the development of myeloproliferative syndrome as these mice age.

The excessive production of inflammatory myeloid cells in the RXR-deficient mice results in the invasion by these cells of multiple tissues, especially the lung, where they cause severe damage, leading to the premature death of these mice. Collaboration with researchers at the CNIC Bioinformatics Unit and Cincinnati Children's Hospital allowed the use of latest generation massive sequencing techniques and exhaustive analysis of DNA structure and gene expression in hematopoietic stem cells.

"Thanks to this analysis, we were able to demonstrate that deletion of RXR in young mice causes the DNA in their hematopoietic stem cells to adopt an open and active conformation, resulting in the expression of genes typical of old cells and the activation of genes regulated by the oncogene MYC, an important protein in the control of hematopoietic stem cell division," states lead researcher Dr. María Piedad Menéndez-Gutiérrez. "We also generated mice deficient for both MYC and RXR, allowing us to conclude that the activation of MYC is the direct cause of the hyperproliferation of hematopoietic stem cells lacking RXR," she concluded.

The team also emphasize the possibility of modulating RXR activity in hematopoietic stem cells through the use of drugs, some of which are already utilized for treating cutaneous lymphomas. “Our study could have therapeutic implications for conditions characterized by excessive proliferation of myeloid cells, such as some diseases of the blood and cardiovascular systems,” concludes corresponding author Jesús Porcuna. “Moreover, our findings suggest that the modulation of RXR could be exploited to expand hematopoietic stem cells for therapeutic or regenerative purposes.”