Targeting Rhoa to Restore Function in Hematopoietic Stem Cells

Aging is defined as the deterioration of function overtime, and it is one of the main risk factors for numerous chronic diseases. Although aging is a complex phenomenon affecting the whole organism, it is proved that the solely manifestation of aging in the hematopoietic system affects the whole organism.

Last September, Dr. M. Carolina Florian and her team revealed the significancy of using blood stem cells to pharmacologically target aging of the whole body, thereby suggesting rejuvenating strategies that could extend healthspan and lifespan. Now, in a Nature aging publication, they propose rejuvenating aged blood stem cells by treating them with the drug Rhosin, a small molecule that inhibits RhoA, a protein that is highly activated in aged hematopoietic stem cells. This study combined in vivo and in vitro assays at IDIBELL together with innovative machine learning techniques by the Barcelona Institute for Global Health (ISGlobal), a centre supported by the "la Caixa" Foundation, and the Barcelona Supercomputing Center.

Acting on the Heart of the Aging Process: The Nucleus of Blood Stem Cells

Blood stem cells, or hematopoietic stem cells, are located in the bone marrow, a highly dynamic and specialised tissue within the cavity of long bones. They are responsible for the vital function of continuously producing all types of blood cells: red blood cells (oxygen transporters), megakaryocytes (future platelets) and white blood cells (immune cells, lymphocytes and macrophages). Over time, however, stem cells also do age, they lose their regenerative capacity and generate fewer and lower quality immune cells. This has been linked to immunosenescence, chronic low grade inflammation and certain chronic diseases.

In their nucleus, as they replicate, blood stem cells can accumulate mutations and lose epigenetic marks that used to keep DNA well-arranged, ultimately increasing mechanical tension on the nuclear envelope. This study figured out RhoA is a mechanosensor activated by such tension and conducts a key role in the stem cell aging process. Researchers subsequently proved its rejuvenating potential: after ex vivo treatment of blood stem cells with the drug Rhosin, a RhoA inhibitor, they observed an improvement in aged-related markers.

Overall, our experiments show that Rhosin did rejuvenate blood stem cells, increased the regenerative capacity of the immune system and improved the production of blood cells once transplanted in the bone marrow."

Dr. Eva Mejía-Ramírez, IDIBELL researcher and study co-author 

The in vitro and in vitro assays took place in IDIBELL, while Dr Paula Petrone and Pablo Iañez Picazo from ISGlobal and the Barcelona Supercomputing Centre discovered the chromatin remodelling induced by Rhosin using an innovative machine learning approach. This project also relies on a long-term collaboration with Prof. Yi Zheng at CCHMC, who had previously developed the Rhosin molecule.

The Aging of Society: A Not-So-Far Future Health Problem

In 2050 the population over 60 in Western countries will have doubled compared to 2015. This will lead to a higher incidence of many chronic diseases such as cancer, dementia and cardiovascular conditions, placing a major burden on all countries health and social systems. Quality biomedical research becomes indispensable to design treatments that relieve the negative effects of aging on health, regardless of aesthetic or cosmetic aspects. There is positive scientific evidence on lifestyle changes and some pharmacological treatments that may qualify as anti-aging, together with some promising research lines that explore the aging phenomena on a molecular level. However, according to Dr. Florian, "These measures cannot be qualified as rejuvenation because they combat the effects of aging rather than acting on the process itself. In contrast, we target the core of the aging process: by reverting blood stem cells to a younger state, we make them more capable of regenerating and producing new healthy blood cells, which improves the health of the whole organism. This is why we talk about cell rejuvenation".

Results are promising and researchers feel very optimistic about how this new strategy might improve the quality of life of the elderly. Now, clinical research must verify whether the results in animal models can be safely and effectively translated to humans. In this line, Dr Florian counted on the IDIBELL Innovation Unit to submit the results for a European patent, an essential legal instrument to enable the potential commercialization of this innovative drug and prevent unappropriate use by third parties.