Updates on Old and Weary Haematopoiesis

Abstract

Blood formation, or haematopoiesis, originates from haematopoietic stem cells (HSCs), whose functions and maintenance are regulated in both cell- and cell non-autonomous ways. The surroundings of HSCs in the bone marrow create a specific niche or microenvironment where HSCs nest that allows them to retain their unique characteristics and respond rapidly to external stimuli. Ageing is accompanied by reduced regenerative capacity of the organism affecting all systems, due to the progressive decline of stem cell functions. This includes blood and HSCs, which contributes to age-related haematological disorders, anaemia, and immunosenescence, among others. Furthermore, chronological ageing is characterised by myeloid and platelet HSC skewing, inflammageing, and expanded clonal haematopoiesis, which may be the result of the accumulation of preleukaemic lesions in HSCs. Intriguingly, haematological malignancies such as acute myeloid leukaemia have a high incidence among elderly patients, yet not all individuals with clonal haematopoiesis develop leukaemias. Here, we discuss recent work on these aspects, their potential underlying molecular mechanisms, and the first cues linking age-related changes in the HSC niche to poor HSC maintenance. Future work is needed for a better understanding of haematopoiesis during ageing. This field may open new avenues for HSC rejuvenation and therapeutic strategies in the elderly.

Keywords: ageing; bone marrow; clonal haematopoiesis; haematopoiesis; haematopoietic stem cell niche; inflammageing; leukaemia.

Figure 1

Model of haematopoietic stem cell (HSC) myeloid and platelet skewing with ageing in mice. One of the typical characteristics of HSC ageing is myeloid and platelet HSC skewing, which is accompanied by profound changes in the epigenetic landscape and gene expression profiles. HSC activation in response to external stimuli such as infections and inflammation elicits HSC differentiation and myeloid skewing, aimed at mediating rapid myeloid cell recovery at the expense of their self-renewal capacity. HSCs shift from quiescence to more cycling states, with increased reactive oxygen species (ROS) levels and DNA damage. Prolonged exposure during life may potentially cause the accumulation and aggravation of changes, including telomere shortening, ultimately reducing HSC survival and differentiation potential. The course of lifetime is represented by a dotted arrow.

Figure 2

Major players in bone marrow haematopoietic stem cell (HSC) niches. HSC niches in the bone marrow are complex and closely related to the vasculature. The majority of HSCs localise near sinusoids associated with endothelial cells and leptin receptor (LepR)-expressing mesenchymal stromal cells, which partially overlap with CXC-chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells and Nestin (Nes)-GPF^dim cells. A fraction of HSCs localise adjacent to small-diameter arterioles, adjacent to neural/glial antigen (Ng)2 pericytes that partially overlap with Nes-GFP^bright cells. Other cell subsets that regulate HSC function include sympathetic fibres, non-myelinating Schwann cells, adipocytes, megakaryocytes, neutrophils, macrophages, T regulatory (reg) cells, and osteoclasts, either by direct or indirect mechanisms. Direct mechanisms include cell-to-cell contact and secretion of soluble factors, importantly stem cell factor (SCF) that regulates HSC quiescence and CXCL12 that promotes HSC retention. Other soluble factors that control HSC function are tumor growth factor beta (TGFβ), CXCL4, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and several interleukins (IL), among others.

Figure 3

Model of age-related clonal haematopoiesis. Young (left) versus old (right) haematopoiesis. Long-term haematopoietic stem cells (LT HSC) are present in increased numbers but with reduced self-renewal ability (twisted arrow, red) in the elderly. Somatic mutations arise with ageing in LT HSC, and some of the clones are positively selected and expand, giving rise to age-related clonal haematopoiesis. This status may or not evolve to malignancy by acquisition of additional mutations. It is currently unknown how clonal haematopoiesis relates to inflammageing, why selection of clones originates myeloid skewing, and what is the role of the HSC niche. ST HSC, short-term haematopoietic stem cell; MPP, multipotent progenitor; L, lymphoid; M, myeloid.