Young Endothelial Cells can be Used to Restore Some Degree of Youthful Behavior in Aged Hematopoietic Stem Cells
Stem cells reside in a niche composed of other cell types that provide necessary support. Age-related changes in that niche, the accumulation of damage and reactions to that damage, contribute to stem cell decline in later life. Stem cells become less active, and this and other alterations in behavior produce downstream consequences of various sorts. An example is the tendency of old hematopoietic stem cells, responsible for generating blood and immune cells, to create more myeloid and fewer lymphoid daughter cells. This leads to subtle imbalance and dysfunction in the immune system, an additional burden atop the problems caused by the declining rate at which new immune cells are created.
Finding ways to restore the youthful behavior of hematopoietic stem cells is thus an area of interest for the research community. Scientists here show that engineering a less damaged stem cell niche for these hematopoietic stem cells can reverse declining activity, but not the myleoid bias, suggesting that signals of age-related change arriving from beyond the niche are also influential. Other lines of research suggest that chronic inflammation is an important part of the problem, for example, and inflammatory signals can spread widely through the bloodstream. Nonetheless, the results here suggest that delivery of young niche cells as a therapy could restore some degree of lost immune cell production in aged individuals, strengthening the immune system.
Aging of the hematopoietic system is associated with a decline in adaptive immunity, an increased incidence of anemia, and a predisposition to myeloid neoplasms. Hematopoietic stem cells (HSCs) show an increase in immunophenotypically defined cells with age, a decrease in their long-term reconstitution abilities, and a significant increase in myeloid-biased cell output at the expense of lymphopoiesis. These studies clearly describe the cell-intrinsic HSC alterations that lead to aging-related hematopoietic deficiencies. While the cell-autonomous changes in the HSC that promote aging-related changes in hematopoiesis are more well defined, the contribution of the aged bone marrow (BM) microenvironment in promoting aged hematopoietic phenotypes is poorly understood.
The adult BM microenvironment is a highly specialized cellular niche composed of vascular endothelial cells (ECs) and perivascular stromal constituents that support HSC maintenance and hematopoietic homeostasis. Within the BM hematopoietic microenvironment, the vascular endothelium is indispensable for supporting HSC quiescence, self-renewal, and differentiation into lineage-committed progeny. The aged BM microenvironment has also been shown to influence hematopoietic aging in young HSCs. While ECs are a critical component of the HSC niche, the individual role of aged ECs in the process of hematopoietic aging has not been examined. Here, we explore the idea that aged ECs are sufficient to promote aging of young HSCs and that the infusion of young ECs can be exploited to improve age-related hematopoietic deficiencies.
In this study, we used cultured BM-derived endothelium from young and aged mice to evaluate whether an age-dependent dysregulation of the BM endothelial niche is sufficient to disrupt the homeostatic HSC-supportive microenvironment and drive aging-associated hematopoietic phenotypes. Using an established ex vivo cell culture system, we demonstrated that culturing of young hematopoietic stem and progenitor cells (HSPCs) on aged endothelium inhibited long-term HSC repopulating activity in a competitive transplantation setting and promoted a myeloid bias at the expense of B cell and T cell lymphopoiesis. Moreover, aged HSPCs cultured on young endothelium showed a marked increase in hematopoietic reconstitution.
These results extended to endothelial infusions in young and aged mice, in which aged BM-derived ECs failed to support endogenous hematopoietic recovery following myelosuppressive irradiation and imparted a myeloid bias in young mice; conversely, infusions of young ECs enhanced HSC activity and increased B and T cell output in young and aged animals. Moreover, young EC infusions enhanced aged HSC transplantation (HSCT) and overall survival through protection of the endogenous BM vascular niche. This lays the groundwork for the development of cellular therapies that can serve to enhance hematopoietic recovery in the elderly population following myelosuppressive treatments to ultimately protect patients from severe morbidities and mortality associated with the treatment of hematological disorders.