Molecular Mechanisms in Hematopoietic Stem Cell Aging

Sammanfattning: The blood is composed of many different cell types that through tightly regulated mechanisms are derived from hematopoietic stem cells (HSCs). In addition, HSCs are able to undergo self-renewing divisions whereby new HSCs are produced. This is an extremely important feature of HSCs in order to ensure the existence of the HSC pool that is paramount to provide life-long hematopoiesis. Aging is in general characterized by reduced ability to sustain tissue homeostasis and return to a homeostatic state after stress or trauma. Several alterations arise in the hematopoietic system with advancing age and several of these have been suggested to originate at the level of HSCs. With advancing age a bias toward myeloid cells arises within the hematopoietic system characterized by a reduced production of lymphoid cells. Despite an accumulation of HSCs in aged mice it has been suggested that aged HSCs display a decreased proliferation that depends on p16Ink4a activity. Although we observed (article I) a decreased replicative activity in physiologically aged HSC we found no evidence for increased p16Ink4a activity in these cells. In article II we demonstrated several hematopoietic defects reminiscent of premature HSC aging including anemia, lymphopenia, and myeloid lineage skewing in mice that rapidly accumulate mitochondrial DNA (mtDNA) mutations. This however, was due to distinct differentiation blocks and/or disappearance of downstream progenitors in the absence of several hallmarks of physiological HSC aging such as epigenetic alterations and accumulation of a myeloid biased subset of HSCs. These findings highlight the necessity of intact mitochondrial function for multilineage hematopoiesis but argue against mtDNA mutations as primary drivers of HSC aging. How growth factors and the relevant signaling pathways dictate HSC lineage specification is not fully understood. Aged mice, deficient in the signal adaptor protein LNK (article III), that acts to dampen several extrinsic signaling pathways, did not display repopulating defects otherwise observed in physiologically aged HSCs. This argues that enhanced cytokine signaling can counteract several key aspects of age-associated HSC decline.