External Versus Intrinsic Causes of Hematopoietic Stem Cell Aging

Today I'll point out a pair of open access review papers in which the authors discuss mechanisms involved in the age-related declines and detrimental altered behaviors of hematopoietic stem cells. These stem cells are responsible for generating blood and immune cells, and so are of vital importance to the function of the immune system throughout life. One paper focuses on external contributions, those arising from the surrounding environment, while the other looks at damage and change arising from the stem cells themselves.

This encapsulates the divide in thinking about stem cell aging in general. At least some stem cell populations, such as those supporting skeletal muscle, appear to remain capable of function well into late life. That their output of daughter somatic cells to support tissue function declines is a matter of the cells lapsing into quiescence for ever longer periods, rather than there being too few competent cells remaining. This is probably more a matter of signals from the surrounding environment rather than inherent damage to the stem cells.

In the case of hematopoietic stem cells, evidence suggests more of a role for damage and declining numbers of competent cells than is the case for muscle stem cells, however. In this situation, rejuvenation therapies will almost certainly have to involve the delivery of new patient-matched stem cells capable of engrafting into tissue and continuing the work of their damaged predecessors. This aspect of stem cell therapy has proven to be challenging. It remains the case that most cell therapies, certainly those presently available in clinics, struggle to achieve lasting cell survival. Whatever benefits they produce result from signals released by the transplanted cells in the short time they remain viable. Still, progress has been made, and organizations like AgeX Therapeutics are working towards reliable approaches to the replacement of stem cell populations.

Microenvironmental contributions to hematopoietic stem cell aging

Hematopoietic stem cell (HSC) aging was originally thought to be essentially an HSC-autonomous process. However, studies on the microenvironment that maintains and regulates HSCs (the HSC niche) over the past 20 years have suggested that microenvironmental aging contributes to declined HSC function over time. The HSC niches comprise a complex and dynamic molecular network of interactions across multiple cell types, including endothelial cells, mesenchymal stromal cells (BMSCs), osteoblasts, adipocytes, neuro-glial cells and mature hematopoietic cells.

Upon aging, functional changes in the HSC niches, such as microenvironmental senescence, imbalanced BMSC differentiation, vascular remodeling, changes in adrenergic signaling, and inflammation, coordinately and dynamically influence the fate of HSCs and their downstream progeny. The end result is lymphoid deficiency and myeloid skewing. During this process, aged HSCs and their derivatives remodel the niche to favor myeloid expansion. Therefore, the crosstalk between HSC and the microenvironment is indispensable for the aging of the hematopoietic system and might represent a therapeutic target in age-related pathological disorders.

Understanding intrinsic hematopoietic stem cells aging

Hematopoietic stem cells (HSCs) are sustaining blood production during the whole life of an organism. It is of extreme importance that these cells maintain self-renewal and differentiation potential over time, in order to preserve homeostasis of the hematopoietic system. Many HSC intrinsic aspects are affected by the aging process, leading to the deterioration of the potential of these cells independently of their microenvironment. Here we review recent findings characterizing most of the intrinsic aspects of aged HSCs, ranging from phenotypic to molecular alterations.

Historically, DNA damage was thought to be the main responsible for HSC aging. However, in the last years, many new findings have defined an increasing number of biological processes that are intrinsically changing with age in HSCs. Epigenetics and chromatin architecture together with autophagy, proteostasis, and metabolic changes and how they are interconnected to each other are acquiring growing importance for understanding the intrinsic aging of stem cells. Considering that aging is the primary risk factors for most diseases, understanding HSC aging becomes particularly relevant as well in the context of hematological disorders, such as myelodysplastic syndrome and acute myeloid leukemia. Research on intrinsic mechanisms responsible of HSC aging is and will continue to provide new potential molecular targets to possibly ameliorate or delay aging of the hematopoietic system and consequently improve the outcome of hematological disorders in the elderly.