Inflammation: a key regulator of hematopoietic stem cell fate in health and disease

Abstract

Hematopoietic stem cells (HSCs) are responsible for lifelong production of blood cells. At the same time, they must respond rapidly to acute needs such as infection or injury. Significant interest has emerged in how inflammation regulates HSC fate and how it affects the long-term functionality of HSCs and the blood system as a whole. Here we detail recent advances and unanswered questions at the intersection between inflammation and HSC biology in the contexts of development, aging, and hematological malignancy.

Figure 1.

Inflammatory signals regulate HSC fate. (A) Adult hematopoiesis. Under homeostatic conditions, hematopoietic output is dominated by lineage-biased MPP subsets, particularly the numerically most abundant MPP4 compartment, which generates primarily myeloid and lymphoid output, resulting in balanced blood production. On the other hand, the megakaryocyte/erythroid (Meg/E)-biased MPP2 and myeloid-biased MPP3 are less numerous and may contribute little to normal homeostasis. The phenotypic HSC compartment also includes a subset of metabolically active HSCs, termed MPP1, which likely serves as a “ready” compartment for rapid activation during acute need. Under homeostatic conditions, this system is regulated by BM niche signals and basal levels of proinflammatory cytokines, which maintains a balance between HSC dormancy and lineage priming. In response to proinflammatory signals or during hematopoietic regeneration, the HSC compartment undergoes distinct fate changes, including transient proliferation, expansion of MPP1, and the activation of instructive lineage-specific programs in subsets of HSCs. These include Meg priming in CD41⁺ cells following IFN, TNF, and IL-1 exposure, as well as activation of C/EBPβ and PU.1 in response to IFN-γ and IL-1, respectively. These lineage-primed HSCs in turn lead to expansion of Meg/E-biased MPP2 and myeloid-biased MPP3, likely resulting in rapid production of platelets and myeloid populations. Meanwhile, lymphoid output is suppressed via inflammatory reprogramming of MPP4, resulting in additional myeloid production. (B) Embryonic development. Proinflammatory factors produced in the AGM by myeloid cells from the primitive hematopoietic wave, as well as from other sources, directly activate NF-κB and STAT3 in hemogenic endothelial cells, leading to increased expression of Notch ligands, hence promoting HSC specification. Thus, inflammatory signals have emerged as central players in controlling developmental pathways required for HSC emergence. These findings suggest a close evolutionary and functional relationship between inflammation and tissue development. G-CSF, granulocyte colony-stimulating factor.

Figure 2.

Chronic inflammation in hematological malignancy. Unlike homeostatic blood production, in which HSCs generate a balanced lineage output, chronic inflammation related to disease and/or physiological aging is characterized by continuous production of proinflammatory signals that can lead to significant alteration in HSC function and output. In particular, chronic overproduction of myeloid cells and platelets occurs, often accompanied by loss of lymphoid output (immunosenescence) and impaired erythroid production (anemia of chronic disease). Moreover, chronic inflammation, or even serial inflammatory episodes, may create a maladaptive context in which continued exposure to stress conditions brought about by continued proliferation, BM niche dysfunction, and exposure to stressors such as reactive oxygen species (ROS) promotes genomic instability and potentially the acquisition of somatic mutations, including those characteristic of clonal hematopoiesis of indeterminate potential. In the context of chronic inflammation, normal hematopoiesis may also be impaired in a manner such that preexisting HSC clones carrying leukemogenic mutations may have increased potential to expand and evolve. Hence, chronic inflammation may function as an initiator, as well as a driver, of hematological malignancy. Further investigation is required to identify the source(s) of inflammatory signals, particularly in the bone marrow niche, and whether the effects of chronic inflammation on HSCs play a causative role in the development of hematological malignancies.