Stem cells exist in order to minimize the number of cells capable of unrestricted replication; most cells in the body are limited in the number of times that they can divide. This limit serves to reduce the risk of cancer - and other severe disruptions that could result from unlimited replication of a malfunctioning cell - to an acceptably low level to enable evolutionary success. Stem cells provide a supply of daughter somatic cells to replace those that are lost over time, due to limited somatic cell replication. In actuality, stem cells spend much of their time in a state of quiescence, without replicating. This is necessary to preserve their function and minimize damage over the course of a lifetime. When forced into excessive activity, stem cells risk a state of exhaustion, becoming dysfunctional and displaying harmful alterations in behavior.
Hematopoietic stem cells reside in the bone marrow and are responsible for generating immune cells and red blood cells. The dysfunctions that arise with aging in this cell population, such as a growing bias towards the production of myeloid cells at the expense of lymphoid cells, appear similar to the dysfunctions that arise when hematopoietic stem cells are forced into exhaustion by excessive replication. In today's open access paper, researchers explore the relevance to hematopoietic stem cell aging of IL-10 signaling intended to bring an end to an acute episode of inflammation, such as in response to an infection that is now defeated. Hematopoietic stem cells must be ever ready to produce large numbers of immune cells to help defend the body, but at the same time they must also return to quiescence when that danger is passed. The chronic inflammation of aging may well sabotage this balance, driving ever greater dysfunction in the production of immune cells.
Hematopoietic stem cells (HSCs) are maintained in quiescence, which protects this pool from the damaging effects of excessive proliferation. Quiescence is tightly regulated by intrinsic programs, including FoxO3a, p53, and cyclin-dependent kinase inhibitors, and by extrinsic cues such as TGF-beta and Notch. Under homeostatic conditions, HSCs remain largely dormant but can rapidly activate in response to inflammatory stimuli, such as infection, to support emergency hematopoiesis. A timely return to quiescence after activation is essential to prevent stem cell exhaustion, which occurs if cycling persists.
Many hallmarks of stem cell exhaustion, including impaired regenerative capacity, expansion of phenotypic HSCs with reduced function, increased inflammatory signaling, and a shift toward myeloid-biased differentiation, mirror features of aged hematopoiesis. Aging is associated with chronic, low-grade inflammation that stresses the HSC pool, driving both functional decline and selective pressure for clones that resist inflammation-induced exhaustion.
Although much is known about maintaining HSC quiescence under steady-state conditions, the signals that govern the return to quiescence after inflammatory activation remain poorly defined. In other cell types IL-10 is an anti-inflammatory cytokine that restrains excessive immune activation by suppressing responses downstream of Toll-like receptor (TLR) stimulation. We identify IL-10 receptor (IL-10R) signaling as critical for returning HSCs to quiescence. IL-10R blockade prolongs HSC cycling and sustains activated transcriptional programs after acute inflammation. With chronic exposure, blockade increases cumulative divisions and accelerates aging hallmarks, including myeloid bias, loss of polarity, and functional defects, under conditions that do not otherwise exhaust HSCs when IL-10R signaling is intact. Our findings identify IL-10R signaling as a key coordinator of post inflammatory return to quiescence and suggest that modulating this axis could preserve HSCs and shape clonal hematopoiesis.
View the full article at FightAging
