Description:
Advancing age frequently associates with the onset of a variety of hematological conditions characterized by diminished clonal heterogeneity and homeostatic control of blood cell production. Upstream hematopoietic stem and progenitor cells are obligate mediators of homeostatic control of all blood lineages. Hematopoietic stem cell and progenitor clonality is frequently associated with specific epigenetic changes and mutations resulting in inflammation, impaired adaptive immune system and elevated incidence of myeloproliferative diseases. The cell-autonomous and non-autonomous causative of clonal-dependent and clonal-independent hematopoietic aging represent a major area of interest in hematology and vascular biology.

Dr. Danica Chen will highlight a mitochondrial metabolic checkpoint that is critical for the maintenance of hematopoietic stem cells (HSCs) and discuss how dysregulation of that mitochondrial metabolic checkpoint leads to HSC aging. Evidence is provided to support the role of the NLRP3 inflammasome in the mitochondrial metabolic checkpoint of HSC aging and, more broadly, how HSC aging impacts the distance tissues and organismal aging. Therapeutic implications will also be discussed.

Dr. Carolina Florian will discuss the aging of the stem cell niche. With aging, intrinsic HSC activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation, and increased susceptibility to diseases. However, whether aging also affects the HSC niche impairing its capacity to support HSC function is still largely debated. Recently by using in vivo long-term label retention assays, we demonstrated that aged labeling (LR) HSCs, which are in old mice, reside predominantly in perisinusoidal niches. These cells are also the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity. Furthermore, studies in her lab have revealed that sinusoidal niches are uniquely preserved in shape, morphology, and number upon aging, and that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches long term. This is linked to the lack of recovery of endothelial Jag2 at sinusoids and to decreased survival of aged mice to chemotherapy. Overall, Dr. Florian’s research has characterized the functional alterations of the aged HSC niche and unveiled that perisinusoidal niches are uniquely preserved and protect HSCs from aging.

Dr. Hartmut Geiger will describe the implications of hematopoietic aging on HSC activity. Aging of HSCs is linked to age-associated remodeling of the immune system, age-associated leukemia as well as a large number of other age-associated diseases. Besides changes intrinsic to HSCs that are causatively linked to the aging of HSCs (aka cause the changes in the function of HSCs that are found in HSCs from old animals for example), more recent research supports that changes in the local bone marrow niche microenvironment are also very potent influencers of the aging- associated decline in HSCs function. Dr. Geiger’s talk will present novel data and concepts on causes and consequences of aging of hematopoietic stem cells, and implications for the clinic.