Niches that regulate stem cells and hematopoiesis in adult bone marrow

Abstract

In mammals, hematopoietic stem cells (HSCs) engage in hematopoiesis throughout adult life within the bone marrow, where they produce the mature cells necessary to maintain blood cell counts and immune function. In the bone marrow and spleen, HSCs are sustained in perivascular niches (microenvironments) associated with sinusoidal blood vessels-specialized veins found only in hematopoietic tissues. Endothelial cells and perivascular leptin receptor⁺ stromal cells produce the known factors required to maintain HSCs and many restricted progenitors in the bone marrow. Various other cells synthesize factors that maintain other restricted progenitors or modulate HSC or niche function. Recent studies identified new markers that resolve some of the heterogeneity among stromal cells and refine the localization of restricted progenitor niches. Other recent studies identified ways in which niches regulate HSC function and hematopoiesis beyond growth factors. We summarize the current understanding of hematopoietic niches, review recent progress, and identify important unresolved questions.

Keywords: bone marrow; endothelial cell; hematopoietic stem cell; niche; restricted hematopoietic progenitor.

Figure 1.. Schematic representation of adult hematopoiesis.

Rare HSCs give rise to multipotent progenitors and restricted hematopoietic progenitors that differentiate into several different types of blood cells. The approximate frequencies of each cell population in the bone marrow and thymus are shown. It is uncertain if HSCs undergo progressive lineage restriction in a stereotypical manner, as diagrammed, or whether lineage restriction occurs in a more flexible and variable way (Yamamoto et al., 2013; Paul et al., 2015; Notta et al., 2016; Velten et al., 2017; Carrelha et al., 2018; Hofer and Rodewald, 2018; Rodriguez-Fraticelli et al., 2018).

Figure 2.. Bone marrow anatomy and HSC localization.

A) A bisected mouse femur. B) A schematic of landmarks in the bone marrow and HSC and lymphoid progenitor localization. Arterioles carry blood into the bone marrow while sinusoids carry it out. HSCs reside in perisinusoidal niches. LepR⁺ stromal cells and endothelial cells synthesize factors required for HSC maintenance (SCF, Cxcl12, and Pleiotrophin). There are many additional stromal cells and hematopoietic cells in the bone marrow that directly or indirectly regulate aspects of HSC and niche function. There are also factors critical for HSC maintenance that are not synthesized in the bone marrow, such as Thrombopoietin, which is made by the liver and transported by the blood into the bone marrow (Decker et al., 2018). There are multiple niches for early lymphoid progenitors in the bone marrow. One subset resides near the endosteum where they depend upon Cxcl12 from osteoblasts (Ding and Morrison, 2013; Greenbaum et al., 2013). Another subset resides near arterioles where they depend upon SCF from LepR⁺Osteolectin⁺ stromal cells (Pinho et al., 2018; Shen et al., 2021). Some early lymphoid progenitors depend upon IL-7 from LepR⁺ cells and it is unclear whether they reside in periarteriolar or perisinusoidal niches (Cordeiro Gomes et al., 2016). It is uncertain to what extent these subsets of lymphoid progenitors overlap with each other or if they represent distinct stages of lymphoid development.

Figure 3.. HSCs and different kinds of myeloid restricted progenitors reside in distinct perisinusoidal niches.

Granulocyte progenitors and monocyte dendritic progenitors reside in spatially distinct niches along sinusoidal blood vessels that do not colocalize with HSCs (Zhang et al., 2021). There may be distinct domains along sinusoidal blood vessels that are specialized for the maintenance of different kinds of stem and progenitor cells.

Figure 4.. Multiple waves of mesenchymal stem/progenitor cells give rise to the skeleton and to bone marrow stromal cells during development.

These mesenchymal stem/progenitor cells give rise to LepR⁺ bone marrow stromal cells postnatally (Mizoguchi et al., 2014; Ono et al., 2014b; Pineault et al., 2019). LepR⁺ cells include the fibroblast-colony forming skeletal stem cells in adult bone marrow (Zhou et al., 2014) and give rise to both osteogenic (Shen et al., 2021) and adipogenic progenitors (Zhou et al., 2017)(Baryawno et al., 2019; Tikhonova et al., 2019; Baccin et al., 2020; Matsushita et al., 2020; Zhong et al., 2020). They are the main source of new osteoblasts and adipocytes that form in adult bone marrow (Mizoguchi et al., 2014; Zhou et al., 2014). There may be multiple distinct lineages of mesenchymal stem/progenitor cells that co-exist in and around the bone marrow during the early postnatal period.