Inflammation Regulates Haematopoietic Stem Cells and Their Niche

Abstract

Haematopoietic stem cells (HSCs) reside in the bone marrow and are supported by the specialised microenvironment, a niche to maintain HSC quiescence. To deal with haematopoietic equilibrium disrupted during inflammation, HSCs are activated from quiescence directly and indirectly to generate more mature immune cells, especially the myeloid lineage cells. In the process of proliferation and differentiation, HSCs gradually lose their self-renewal potential. The extensive inflammation might cause HSC exhaustion/senescence and malignant transformation. Here, we summarise the current understanding of how HSC functions are maintained, damaged, or exhausted during acute, prolonged, and pathological inflammatory conditions. We also highlight the inflammation-altered HSC niche and its impact on escalating the insults on HSCs.

Keywords: bone marrow niche; haematopoietic stem cells; inflammation.

Figure 1

Emergency myelopoiesis triggered by inflammatory signals. Upon infection or tissue damage, the release of PAMPs and DAMPs (green dots) at inflammatory site are recognised by PRRs expressed on immune cells such as macrophages and dendritic cells, as well as the primitive HSCs (direct activation). The activated antigen-presenting cells massively produce inflammatory molecules (red dots) to recruit neutrophils and macrophages to eradicate the pathogens or dead cells. The secreted inflammatory cytokines and growth factors also indirectly activate BM and peripheral HSPCs through respective receptors to increase their mobilisation and myelopoiesis. The stimulated HSC niche under inflammation also contributes to accumulation of inflammatory molecules in BM and increases inflammatory stress on BM HSPCs.

Figure 2

Pathogenic BM remodelling increases inflammatory stress on HSCs. In homeostasis, primitive HSCs prefer to reside in close proximity to sinusoids (sinusoidal niche) where the HSCs are supported by the HSC maintenance factors, such as CXCL12 and VCAM-1, secreted by various HSC niche cells. Inflammation suppresses the functions of HSC niche cells to produce the HSC maintenance factors, making the microenvironment unstable to support the HSC quiescence and contributing to HSC mobilisation. The HSC niche cells also participate in the secretion of inflammatory cytokines and impair the self-renewal potential of HSCs. The enriched pro-inflammatory cytokines and growth factors finally damage the primitive HSCs by promoting their cell cycling and apoptosis.