ASYMMETRIC HEMATOPOIETIC STEM CELL DIVISION AND AGEING

Ageing is characterized by a gradual loss of organ and tissue fitness caused by a decline in the numbers and/or functional capability of somatic stem cells, which are able to self-renew and to differentiate in multiple lineages, thus replacing damaged cells and maintaining tissue homeostasis. The production of new blood cells throughout life (hematopoiesis) crucially depends on the function of hematopoietic stem cells (HSC). HSC replenish erythrocytes, platelets and immunocompetent cells, thereby preserving the energetic balance of the organism and ensuring the proper functioning of the coagulation system and an efficient immune response. To maintain the HSC compartment while ensuring output of differentiated cells, HSCs must undergo asymmetric cell division, a process that generates two daughter cells with different fates: one which will proliferate and give rise to the differentiated cells progeny, and one which will return to quiescence to maintain the HSC compartment. Ageing HSCs have lower regenerative capacity than young HSC, and this has been correlated with a propensity toward self- renewing rather than asymmetric divisions. We plan to investigate the process by which ageing affects HSC fate decision. The results of these experiments are expected to be highly significant considering that very little is known about the events involved in this process. In addition, it is hoped that the knowledge generated by this project will be useful in the design of rejuvenation strategies aimed at restoring the function of residual HSCs in aging organisms.