Biomaterials Translational ›› 2022, Vol. 3 ›› Issue (1): 31-54.doi: 10.12336/biomatertransl.2022.01.005
• REVIEW • Previous Articles Next Articles
Received:
2021-12-01
Revised:
2022-03-05
Accepted:
2022-03-10
Online:
2022-03-28
Published:
2022-03-28
Contact:
Suzanne M. Watt
E-mail:suzanne.watt@ndcls.ox.ac.uk;suzanne.watt@adelaide.edu.au
About author:
Suzanne M. Watt., suzanne.watt@ndcls.ox.ac.uk or suzanne.watt@adelaide.edu.au.Watt, S. M. The long and winding road: homeostatic and disordered haematopoietic microenvironmental niches: a narrative review. Biomater Transl. 2022, 3(1), 31-54.
Figure 1. Haematopoietic ontogeny in murine models. (A) The three distinct waves of haematopoiesis that occur in the developing murine embryo. The first primitive wave sees the emergence of haematopoietic cells (nucleated erythroid cells, macrophages and megakaryocytes) at E7 (7 days post-conception) from the blood islands of the yolk sac. The second pro-definitive wave arises from haemogenic endothelium of the vascular plexus of the yolk sac by the process of endothelial-haematopoietic transition (EHT) commencing at E8–8.5 and generates erythro-myeloid progenitors and certain innate immune cells. The para-aortic splanchnopleura (P-Sp) and the aorta-gonad-mesonephros (AGM) region of the embryo proper become the first and principal site of immature hematopoietic stem cell (or pro-haematopoietic stem cell (HSC)) production between E9.5–10.5. These pro-HSCs migrate (between E10.5–11) to the foetal liver, where they mature, proliferate, self-renew and/or differentiate into lymphoid and myeloid cells. The foetal liver then becomes the major haematopoietic organ until E15.5. Foetal liver HSCs migrate to the foetal bone marrow, which becomes the main residence of HSCs in adulthood. (B) A schematic cross-section of the murine embryonic AGM region with pro-HSCs emerging from the ventral floor of the dorsal aorta from haemogenic endothelia by the process of EHT. Here components of the HSC niche include endothelia, mesenchymal stromal cells, macrophages, and sympathetic nerve components. (C) A diagrammatic representation of cells present in the murine foetal liver microenvironment at E14.5 and where HSCs expand, self-renew and differentiate. These include endothelial cells of the portal and sinusoidal vessels, perivascular stromal cells, hepatic stellate cells, hepatocytes and hepatoblasts that produce cytokines, macrophages, proliferating HSCs and various haematopoietic progenitors, both myeloid and lymphoid as well as erythroid cells. Created with Biorender.com.
Figure 2. Architecture of long and flat bones. (A) Diagrammatic representations of an adult long bone showing the epiphyseal, metaphyseal and diaphyseal regions (left) and an adult flat bone (right). Trabeculae and the vasculature (not shown) play key roles in steady state haematopoiesis. In human adults, the epiphyseal or growth plate is replaced by an epiphyseal line. In the adult mouse, the epiphysis and metaphysis remain separated by the growth plate that forms in the foetal bone marrow. (B) A commonly accepted diagrammatic representation of cells that are proposed to have a key role in the haematopoietic stem cells (HSC) niche. Endothelia of the endosteal capillaries, arterioles and sinusoids are associated with mesenchymal stromal cells (MSCs) to varying degrees and form perivascular niches for endosteal and central bone marrow HSC subsets as described. NesbriNG2+ MSCs are associated with endosteal capillaries and arterioles. The endosteum is also lined with osteoblasts and osteoclasts which are derived from MSCs and HSCs respectively and is reported to play a role in maintaining lymphoid biased HSCs and a reserve of multi-potent long term repopulating HSCs. LEPR+/CAR MSCs are associated with sinusoids in the bone marrow, where erythropoiesis and myelopoiesis are regulated. Some recent studies suggest that the sinusoids may lie closer to the endosteum than previously indicated. MSC production of the key HSC-regulator CXCL12 is altered by the action of sympathetic nerve fibres. Adipocytes, which are also derived from MSCs, and megakaryocytes regulate HSCs in these bone marrow niches. Platelet/myeloid biased HSCs are thought to associate with the megakaryocyte-sinusoidal niche. The roles and spatial distribution of these various cells in regulating HSC fate decisions remains a matter of some debate. CXCL12: C-X-C motif chemokine ligand 12; LEPR+/CAR: C-X-C motif chemokine ligand 12-abundant reticular; NESBri: Nestinbright; NG2: neural-glial antigen 2. Created with Biorender.com.
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