Corbin E. Meacham | Children’s Research Institute and Department of Pediatrics, Univ. of Texas Southwestern Medical Center, Dallas TX and Sean J. Morrison | Children’s Research Institute and Department of Pediatrics, Univ.. of Texas Southwestern Medical Center, Dallas, Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas TX

Two physiologically important processes occur throughout adult life in the bone marrow: hematopoiesis (the production of blood and immune cells) and osteogenesis (the production of bone cells). Consistent with this, the bone marrow contains two types of stem cells – hematopoietic stem cells (HSCs) and skeletal stem cells (SSCs, often also called mesenchymal stem cells). A major focus of our laboratory has been to identify the cells that create the HSC niche – the specialized microenvironment that maintains HSCs by producing the factors they require. We discovered the Leptin Receptor-expressing (LepR⁺) stromal cells that are a key element of the HSC niche: they are the major source of known factors for the maintenance of hematopoietic stem and progenitor cells in the bone marrow. LepR⁺ cells also include the SSCs that are the major source of osteoblasts and adipocytes in adult bone marrow. Beyond these functions, LepR⁺ cells regulate the bone marrow environment through several other mechanisms, including sensing and mediating the effects of load-bearing exercise on osteogenesis and lymphopoiesis, promoting vascular regeneration after myeloablation, and suppressing bone marrow inflammation. LepR⁺ cells thus sustain HSCs and modulate adult osteogenesis through several different kinds of mechanisms.

The HSC niche: In 2005 we discovered that HSCs reside immediately adjacent to sinusoidal blood vessels in hematopoietic tissues, including in the bone marrow and spleen (Kiel et al., 2005). Sinusoids are a specialized form of venuole that is only present in hematopoietic tissues. Based on that observation, we proposed the existence of a perivascular niche for HSCs around the sinusoids. At the time, this was very controversial as the leading (osteoblastic niche) model was quite different. During the subsequent 10 years we critically tested both models, ultimately proving that HSCs do reside in perisinusoidal niches (Figure 1) and disproving several key elements of the osteoblastic niche model (Morrison and Scadden, 2014).

One important step toward the identification of the HSC niche was identifying the stromal cells that are the critical source of factors for HSC maintenance. We discovered the LepR⁺ mesenchymal stromal cells that surround sinusoids and arterioles throughout the bone marrow and that are the main source of known factors that are required for the maintenance of HSCs, including Stem Cell Factor (SCF) and the chemokine Cxcl12. To test whether LepR⁺ cells were functionally important sources of factors for the maintenance of HSCs, we conditionally deleted Scf (Ding et al., 2012), Cxcl12 (Ding and Morrison, 2013; Greenbaum et al., 2013) and other proposed niche factors (Zhou et al., 2015) from LepR⁺ cells as well as all of the other candidate niche cell populations that had been proposed by other labs. This analysis showed that LepR⁺ cells and endothelial cells (which expressed much lower levels of these factors) were functionally important sources of factors for the maintenance of HSCs. When we deleted Scf from LepR⁺ cells and endothelial cells, all of the quiescent and serially transplantable HSCs disappeared from adult bone marrow, demonstrating that all quiescent bone marrow HSCs rely upon perivascular niches for their maintenance (Oguro et al., 2013). Conversely, other cell populations that had been proposed as potential niche cells, such as osteoblasts, expressed little or none of these niche factors. Conditional deletion of these factors from these candidate niche cells had no effect on HSCs in adult bone marrow.

HSCs are adjacent to sinusoidal blood vessels (blue) throughout the marrow (Acar et al., 2015; Kiel et al., 2005), where LepR⁺ cells and endothelial cells maintain HSCs by producing SCF (Ding et al., 2012), CXCL12 (Ding and Morrison, 2013; Greenbaum et al., 2013), and other factors (Fang et al., 2020; Himburg et al., 2018).

We went on to show that restricted progenitors reside in cellularly and spatially distinct niches as compared to HSCs. For example, a subset of common lymphoid progenitors reside in osteoblastic niches, at the endosteum (the interface of bone and bone marrow) where they derive factors for their maintenance from osteoblasts (Ding and Morrison, 2013; Greenbaum et al., 2013). LepR⁺ cells also synthesize SCF for the maintenance of many restricted hematopoietic progenitors, including early myeloid, lymphoid, and erythroid progenitors (Comazzetto et al., 2019; Cordeiro Gomes et al., 2016). At least some of these restricted progenitors localize adjacent to sinusoidal blood vessels, like HSCs (Comazzetto et al., 2019). Daniel Lucas’ laboratory extended these results by showing that there are likely to be distinct domains along the sinusoids in which different kinds of myeloid progenitors reside within distinct perisinusoidal neighborhoods that are specialized for cells at different stages of myeloid differentiation (Zhang et al., 2021). This suggests there are different kinds of LepR⁺ cells that are specialized to create different kinds of niches in distinct locations within the bone marrow (Comazzetto et al., 2021).

While HSCs and erythroid progenitors are sustained in peri-sinusoidal niches (blue) by factors from LepR⁺ cells and endothelial cells (Comazzetto et al., 2019; Ding and Morrison, 2013; Ding et al., 2012) (colored dots), early lymphoid progenitors (CLPs) are sustained in peri-arteriolar niches (red blood vessel) by SCF from Osteolectin⁺LepR⁺ cells that proliferate in response to mechanical activation of Piezo1 (Shen et al., 2021). Other CLPs are sustained in endosteal niches by CXCL12 from osteoblasts (Ding and Morrison, 2013; Greenbaum et al., 2013). Adipocytes promote HSC regeneration by producing SCF and other factors (Zhou et al., 2017).

Consistent with these conclusions, recent single cell RNA sequencing studies of bone marrow stromal cells have confirmed that LepR⁺ cells express the highest levels of niche factors within the bone marrow but that these cells are quite heterogeneous (Baccin et al., 2020; Baryawno et al., 2019; Tikhonova et al., 2019).

Skeletal stem cells (SSCs) in adult bone marrow: LepR⁺ cells include the SSCs that give rise to all of the adipocytes and osteoblasts that form in adult bone marrow (Zhou et al., 2014). When bone marrow cells are cultured adherently to form mesenchymal stem cells, these mesenchymal stem cells arise from the LepR⁺ cells (Zhou et al., 2014). The physiological function of the LepR⁺ SSCs in the bone marrow is to give rise to the osteoblasts that contribute to the maintenance and repair of the adult skeleton (Zhou et al., 2014) and to form the adipocytes that accumulate during aging or after myeloablation (Zhou et al., 2017). LepR⁺ cells, therefore, not only regulate HSC maintenance and hematopoiesis but are also a critical source of osteoblasts and adipocytes in adult bone marrow.

Peri-sinusoidal LepR⁺ cells create niches for HSCs and certain restricted progenitors, including erythroid progenitors (Comazzetto et al., 2019). The adipocytes formed by adipocyte progenitors promote HSC maintenance and hematopoietic regeneration by synthesizing SCF (Zhou et al., 2017). The LepR⁺Osteolectin⁺ progenitors create a peri-arteriolar niche for early lymphoid progenitors as well as giving rise to osteoblasts that maintain the adult skeleton (Shen et al., 2021). Osteoblasts create a distinct endosteal niche for early lymphoid progenitors at the interface of bone and bone marrow (Ding and Morrison, 2013; Greenbaum et al., 2013).

LepR⁺ cells are also a critical source of growth factors that regulate osteogenesis. In an effort to identify new growth factors, we performed RNA sequencing on bone marrow LepR⁺ cells. We looked for transcripts that are preferentially expressed by these cells and predicted to encode growth factor-like secreted proteins whose function had not been studied in vivo. This led to the identification of a new bone-forming growth factor that we named Osteolectin. Osteolectin promotes the maintenance of adult skeletal bone mass by acting on LepR⁺ cells to promote their differentiation into osteoblasts (Yue et al., 2016).

Osteolectin is a C-type lectin domain protein, originally named CLEC11a (Bannwarth et al., 1998; Mio et al., 1998) that is expressed by a subset of LepR⁺ cells as well as by osteoblasts, osteocytes, and chondrocytes (Yue et al., 2016). Others had detected Osteolectin/CLEC11a expression in the bone marrow and presumed it to be a hematopoietic growth factor (Hiraoka et al., 1997). We generated Osteolectin-deficient mice and found they are developmentally normal, with normal hematopoiesis (Yue et al., 2016); however, they exhibit accelerated bone loss throughout adulthood and delayed fracture healing. Osteolectin-deficient bone marrow stromal cells show impaired osteogenic differentiation, but normal adipogenic and chondrogenic differentiation. Recombinant Osteolectin promotes osteogenesis by LepR⁺ cells in culture and injection of the recombinant protein into mice systemically increases bone formation.

Osteolectin thus maintains the adult skeleton by promoting the differentiation of LepR⁺ cells and other mesenchymal progenitors into mature osteoblasts.

We identified α11β1 integrin as the Osteolectin receptor (Shen et al., 2019). α11 integrin is highly restricted in its expression to osteogenic cells, including LepR⁺ cells and osteoblasts. α11β1 binds Osteolectin with nanomolar affinity and is required for the osteogenic response to Osteolectin (Shen et al., 2019). Like Osteolectin-deficient mice, Lepr-cre; α11^fl/fl mice are grossly normal but exhibit reduced osteogenesis and accelerated bone loss during adulthood (Shen et al., 2019). Osteolectin binding to α11β1 promotes Wnt pathway activation, which is necessary for the osteogenic response to Osteolectin.

Osteolectin appears to mediate much of the osteogenic effect of parathyroid hormone (PTH), an agent widely used to treat osteoporosis (Zhang et al., 2021). PTH promotes Osteolectin expression by bone marrow stromal cells and increases serum Osteolectin levels in mice and humans. Osteolectin deficiency attenuates Wnt pathway activation by PTH in bone marrow stromal cells and substantially reduces the osteogenic response to PTH in vitro and in vivo. The identification of Osteolectin, and its receptor α11β1, thus revealed a new mechanism that is necessary for the maintenance of adult skeletal bone mass, fracture repair, and the response to an anabolic factor that is used to treat osteoporosis.

LepR+ cells mediate the effects of the bone marrow mechanical environment on osteogenesis and lymphopoiesis: One of the primary recommendations to people with osteoporosis is to engage in load-bearing exercise, because this increases the production of bone cells, thickening and strengthening of bones. However, the mechanism by which load-bearing exercise increases bone formation has been unclear.

We generated Osteolectin reporter mice to identify the LepR⁺ cells in the bone marrow that synthesize Osteolectin. We found that Osteolectin expression distinguishes peri-arteriolar LepR⁺ cells poised to undergo osteogenesis from peri-sinusoidal LepR⁺ cells poised to undergo adipogenesis (Shen et al., 2021). We found that peri-arteriolar LepR⁺Osteolectin⁺ cells are rapidly-dividing, short-lived, osteogenic progenitors that increase in number after fracture and are depleted during aging (Figure 3). Scf deletion from peri-arteriolar Osteolectin⁺ cells does not affect the maintenance of HSCs or most restricted hematopoietic progenitors but it depletes common lymphoid progenitors, demonstrating the existence of a periarteriolar niche for lymphoid progenitors created by Osteolectin⁺ cells. Deletion of Scf from these Osteolectin⁺ cells broadly depletes lymphoid progenitors, impairing lymphopoiesis and survival after acute bacterial infection (Shen et al., 2021).

Remarkably, voluntary running increases, and hindlimb unloading decreases, the frequencies of peri-arteriolar Osteolectin⁺ cells and lymphoid progenitors in the bone marrow, demonstrating mechanical regulation of periarteriolar niches. Our results suggest that mechanical forces are transmitted along arterioles, from bone surfaces into the marrow, where they are sensed by LepR⁺Osteolectin⁺ cells, increasing the division of these cells and expanding the numbers of osteogenic and lymphoid progenitors in the periarteriolar niche. The mechanism by which Osteolectin⁺ cells sense these mechanical signals involves opening of the Piezo1 mechanically-regulated ion channel. Deletion of Piezo1 from Osteolectin⁺ cells depletes Osteolectin⁺ cells and lymphoid progenitors around arterioles. This identified a new mechanism by which load-bearing exercise promotes osteogenesis and immune function. LepR⁺ cells thus sense the mechanical environment in the bone marrow and transduce mechanical signals into niche factor expression in a manner that regulates both osteogenesis and lymphopoiesis.

LepR⁺ cells regulate vascular regeneration in the bone marrow: Irradiation and chemotherapy not only deplete HSCs but also disrupt their niche in the bone marrow, particularly damaging the sinusoids (Hooper et al., 2009; Knospe et al., 1966; Kopp et al., 2005; Li et al., 2008).

Regeneration of the perivascular niche after injury, including endothelial and LepR⁺ cells, is necessary for the regeneration of HSCs and hematopoiesis after myeloablation (Hooper et al., 2009; Kopp et al., 2005). After 5-fluorouracil treatment, Tie2 signaling (which is regulated by its ligands Angpt1, Angpt2, and possibly Angpt3 (also known as Angptl1) (Augustin et al., 2009; Eklund and Saharinen, 2013; Fagiani and Christofori, 2013; Thomson et al., 2014)) regulates the remodeling of blood vessels in the bone marrow (Kopp et al., 2005).

We systematically assessed the expression and function of Angiopoietin-1 (Angpt1) in bone marrow (Zhou et al., 2015). Angpt1 was not expressed by osteoblasts. Angpt1 was most highly expressed by HSCs, and at lower levels by c-kit⁺ hematopoietic progenitors, megakaryocytes, and LepR⁺ stromal cells. Global conditional deletion of Angpt1, or deletion from osteoblasts, LepR⁺ cells, Nestin-cre-expressing cells, megakaryocytes, endothelial cells or hematopoietic cells in normal mice did not affect hematopoiesis, HSC maintenance, or HSC quiescence.

Deletion of Angpt1 from hematopoietic cells and LepR⁺ cells had little effect on vasculature or HSC frequency under steady-state conditions but accelerated vascular and hematopoietic recovery after irradiation while increasing vascular leakiness. Hematopoietic stem/progenitor cells and LepR⁺ stromal cells thus regulate vascular and niche regeneration by secreting Angpt1, reducing vascular leakiness but slowing niche recovery. LepR+ cells and endothelial cells also promote the regeneration of sinusoids after myeloablation by synthesizing VEGF-C (Fang et al., 2020).

LepR⁺ cells and adipocytes maintain quiescent HSCs by suppressing inflammation: Adiponectin is a circulating factor that suppresses inflammation (Berg et al., 2001; Fruebis et al., 2001; Yamauchi et al., 2001). It is synthesized by adipocytes throughout the body (Hu et al., 1996; Maeda et al., 1996; Nakano et al., 1996; Scherer et al., 1995) as well as by LepR⁺ cells and adipocytes in the bone marrow (Baccin et al., 2020; Baryawno et al., 2019; Tikhonova et al., 2019. Adiponectin suppresses the activation of macrophages (Ohashi et al., 2010; Yamaguchi et al., 2005), NK cells (Wilk et al., 2013), and T cells (Surendar et al., 2019) through multiple mechanisms, reducing their production of inflammatory factors, including IFNy (Surendar et al., 2019) and TNF (Maeda et al., 2002; Masamoto et al., 2016; Ohashi et al., 2010). Adiponectin deficiency has been reported to have no effect on HSCs or hematopoiesis in the bone marrow of specific pathogen free mice but after bacterial infection, adiponectin promotes hematopoietic progenitor proliferation by suppressing TNF expression (Masamoto et al., 2016).

The bone marrow becomes more inflammatory during aging (Chambers et al., 2007; Ergen et al., 2012; Henry et al., 2015; Valletta et al., 2020; Yamashita and Passegue, 2019; Young et al., 2021). Inflammatory factors promote HSC activation and chronic inflammation promotes HSC depletion (Baldridge et al., 2010; Essers et al., 2009; Matatall et al., 2016; Pietras et al., 2016). However, HSCs remain mainly quiescent (Pietras et al., 2011) and increase in number with age in most mouse strains (Morrison et al., 1996). This suggests the existence of mechanisms to protect HSCs from chronic inflammation in adult bone marrow. Regulatory T cells protect HSCs from immune cells after allogeneic transplantation (Fujisaki et al., 2011; Hirata et al., 2018), raising the question of whether there are factors that protect HSCs from immune cells and sustain HSC quiescence in normal adult bone marrow.

Adiponectin binds two receptors, AdipoR1 and AdipoR2, which have ceramidase activity that increases upon adiponectin binding. We found adiponectin receptors are non-cell-autonomously required in hematopoietic cells to promote HSC quiescence and self-renewal (Meacham et al., 2022). Adiponectin receptor signaling suppresses inflammatory cytokine expression by myeloid cells and T cells, including interferon gamma (IFNy) and tumor necrosis factor (TNF). Without adiponectin receptors, the levels of these factors increase, chronically activating HSCs, reducing their self-renewal potential, and depleting them during aging. Pathogen infection accelerates this loss of HSC self-renewal potential. Blocking IFNy or TNF signaling partially rescues these effects. Adiponectin receptors are thus required in immune cells to sustain HSC quiescence and to prevent premature HSC depletion by reducing inflammation.

In adiponectin or adiponectin receptor deficient mice, myeloid cells and T cells secrete inflammatory cytokines, chronically activating HSCs, reducing their self-renewal potential, and depleting them during aging. Niche cells thus sustain adult HSCs by suppressing inflammation by immune effector cells.

Conclusions

LepR⁺ stromal cells regulate hematopoiesis and osteogenesis in the bone marrow through several different kinds of mechanisms:

1. They are the main source of factors required for the maintenance of HSCs and several early restricted progenitors, including SCF and Cxcl12 (Ding and Morrison, 2013; Ding et al., 2012).
2. They regulate vascular regeneration after myeloablation by synthesizing Angpt1 (Zhou et al., 2015) and VEGF-C (Fang et al., 2020).
3. A subset of LepR⁺ cells are the SSCs that give rise to the osteoblasts and adipocytes that form in adult bone marrow (Zhou et al., 2014). LepR⁺ cells are the bone marrow cells that give rise to mesenchymal stem cells in culture. The osteoblasts formed by LepR⁺ cells contribute the maintenance of adult skeletal bone mass and the repair of certain kinds of bone injuries. The adipocytes formed by LepR⁺ cells promote the regeneration of HSCs and hematopoiesis after myeloablation (Zhou et al., 2017).
4. LepR⁺ cells secrete bone-forming growth factors that are necessary for the maintenance of adult skeletal bone mass, including Osteolectin (Shen et al., 2019; Yue et al., 2016).
5. LepR⁺ cells mediate the effects of load-bearing exercise on osteogenesis and lymphopoiesis by sensing mechanical forces transmitted along arterioles in the bone marrow as a result of opening of the Piezo1 mechanically activated cation channel (Shen et al., 2021).
6. LepR⁺ cells and adipocytes suppress inflammation in adult bone marrow by secreting adiponectin, which suppresses the expression of inflammatory cytokines by immune effector cells (Meacham et al., 2022). This is necessary for the maintenance of quiescent HSCs throughout adult life.

Acknowledgements

This review summarizes a lecture given at a Pontifical Academy of Sciences Workshop on “Stem Cells and Their Promise for Regenerative Medicine” in Vatican City in May 2022. S.J.M. is a Howard Hughes Medical Institute (HHMI) Investigator, the Mary McDermott Cook Chair in Pediatric Genetics, the Kathryn and Gene Bishop Distinguished Chair in Pediatric Research, the director of the Hamon Laboratory for Stem Cells and Cancer, and a Cancer Prevention and Research Institute of Texas Scholar. This work was supported by the National Institutes of Health (DK118745), the Moody Medical Research Institute, the Josephine Hughes Sterling Foundation, and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (all to S.J.M).

C.E.M. performed some of the work described in this review and helped to write the review. Her work was supported by a Postdoctoral Fellowship from the American Cancer Society (PF-13-245-01-LIB).

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