Fight Aging!

Hematopoiesis is the generation of blood and immune cells that takes place in the bone marrow, conducted by an array of stem cell and progenitor cell populations that are differentiated from hematopoietic stem cells, a tree of subpopulations with differing tasks that together contribute to the overall outcome. Nothing in biology is simple, and hematopoiesis is a complex, dynamic process governed by many interacting regulatory mechanisms. Hematopoietic cells respond to signals from other tissues, and particularly to the activities of the immune system, such as the inflammatory signals that arise when immune activity is needed. This complexity of feedback mechanisms is well known, but far from completely mapped. For example, it is thought that the thymus, the organ in which thymocytes created in the bone marrow mature into T cells of the adaptive immune system, can influence hematopoiesis, but it is unclear as to how exactly this cross-talk occurs.

Hematopoiesis becomes altered with age, both faltering in the output of immune cells, and becoming biased to the production of myeloid rather than lympoid cells. This progressive deterioration is an important contribution to the age-related decline of the immune system. As today's open access paper notes, the age-related dysfunction of the immune system is in fact a contributing cause of these problems in hematopoiesis. With age, the immune system falls into a state of chronic inflammation, constantly roused to inappropriate activation and generation of inflammatory signals. The causes of this inflammatory state include persistent infections, metabolic waste, excess visceral fat, and rising numbers of senescent cells. Chronic inflammation is disruptive of tissue function throughout the body, and bone marrow and its hematopoietic cell populations are among those negatively affected.

Immuno-Modulation of Hematopoietic Stem and Progenitor Cells in Inflammation

Lifelong blood production is maintained by bone marrow (BM)-residing hematopoietic stem cells (HSCs) that are defined by two special properties: multipotency and self-renewal. Since dysregulation of either may lead to a differentiation block or extensive proliferation causing dysplasia or neoplasia, the genomic integrity and cellular function of HSCs must be tightly controlled and preserved by cell-intrinsic programs and cell-extrinsic environmental factors of the BM.

Since the initial establishment of the hematopoietic differentiation tree, our understanding of the hematopoietic system, and of the HSC population situated at its apex undergoes continuous refinement. Formerly presumed unresponsive to tissue insult, HSCs in fact show high adaptability under various scenarios and actively cooperate with downstream hematopoietic progenitors, mature cells, and environmental stromal cells as frontline responders to preserve blood homeostasis. However, their ability to respond deftly through self-renewal and differentiation at times brings about detrimental consequences.

It is now clear that the BM is not immune-ignorant but a prominent lymphoid organ that receives a large spectrum of hemato-immunological insults. Likewise, BM-residing HSCs are not just quiescent sleeping cells but directly respond to insults not limited to infection and inflammation but also the regeneration of the BM after toxic agents or irradiation. Depending on the type of DAMPs, PAMPs, cytokines, and growth factors involved and the strength and duration of the stimulation, HSCs will alter their fate toward myelopoiesis, granulopoiesis, or even bypass progenitors altogether to directly orchestrate on-demand hematopoiesis. HSCs positioned at the interface of perturbed hematopoiesis will execute distinct emergency programs to integrate and fine-tune responses to maintain hematopoietic integrity.

However, such beneficial effects of HSC activation can be counteracted by chronic inflammatory conditions. HSC dysfunction upon chronic inflammation or aging as the cause of clonal hematopoiesis and in certain cases leukemic transformation are all readily imaginable scenarios, although direct causality remains to be demonstrated.