key: cord-0935133-xi572141
authors: Bowers, Emily; Singer, Kanakadurga
title: Obesity-induced inflammation: The impact of the hematopoietic stem cell niche
date: 2021-02-08
journal: JCI insight
DOI: 10.1172/jci.insight.145295
sha: 1b20444249ce1dcf01114e7f1d162be50763dc22
doc_id: 935133
cord_uid: xi572141

Obesity and obesity-related diseases like type 2 diabetes (T2D) are prominent global health issues; therefore, there is a need to better understand the mechanisms underlying these conditions. The onset of obesity is characterized by accumulation of proinflammatory cells, including Ly6c(hi) monocytes (which differentiate into proinflammatory macrophages) and neutrophils, in metabolic tissues. This shift toward chronic, low-grade inflammation is an obese-state hallmark and highly linked to metabolic disorders and other obesity comorbidities. The mechanisms that induce and maintain increased inflammatory myelopoiesis are of great interest, with a recent focus on how obesity affects more primitive hematopoietic cells. The hematopoietic system is constantly replenished by proper regulation of hematopoietic stem and progenitor (HSPC) pools in the BM. While early research suggests that chronic obesity promotes expansion of myeloid-skewed HSPCs, the involvement of the hematopoietic stem cell (HSC) niche in regulating obesity-induced myelopoiesis remains undefined. In this review, we explore the role of the multicellular HSC niche in hematopoiesis and inflammation, and the potential contribution of this niche to the hematopoietic response to obesity. This review further aims to summarize the potential HSC niche involvement as a target of obesity-induced inflammation and a driver of obesity-induced myelopoiesis.

The global prevalence of obesity has risen dramatically over the past decades, leading to an increased incidence of obesity-related diseases -including type 2 diabetes (T2D), cardiovascular disease, liver disease, renal failure, and cancer -and increased mortality (1) (2) (3) (4) (5) . The prevalence of obesity has generated a strong need to better understand mechanisms that lead to obesity-induced disease. While chronic, low-grade inflammation (called metainflammation) is a known contributor to obesity-related diseases (1) (2) (3) (4) (5) (6) (7) , the switch toward proinflammatory myeloid cell production is not well understood and could provide insights into therapeutic targets.

Adipose tissue (AT) expands in response to excess lipids, primarily for nutrient storage, and has a robust immune component. During steady-state, AT maintains metabolic homeostasis through communication between adipocytes and tissue-resident immune cells, the most predominant being AT macrophages (ATMs) (8) . The inflammatory state of ATMs fluctuates depending on nutritional status (9) (10) (11) (12) (13) . Acute AT inflammation following a high-fat meal is believed to contribute to AT remodeling for storage of additional lipids (14) ; however, during obesity, adipocytes expand, and signals drive a sustained inflammation in the AT, leading to generation of persistent inflammatory stimuli that originate from excessive adipocyte hypertrophy and further recruit monocytes to AT, thus exacerbating inflammation. This sustained inflammatory loop ultimately promotes cellular and systemic insulin resistance, as inflammatory cells and signals permeate into other tissues, including liver, pancreas, muscle, and brain (1) (2) (15) (16) (17) .

Expansion and accumulation of ATMs is partially due to proliferation (18) (19) , but it is also due to increases in circulating proinflammatory monocytes (7, 20, 21) , a finding noted in both obese patients (CD14 + monocytes) and mice (Ly6c hi monocytes). Circulating monocytes are produced in the BM and then migrate into tissues, via the MCP-1/CCR2 chemokine axis, where they further differentiate into inflammatory macrophages (1, 22) . Circulating activated neutrophil populations also increase and migrate into and out of expanding AT, where they promote tissue inflammation and metabolic dysfunction (23) (24) (25) (26) . While the role of leukocytes in the promotion and propagation of inflammation in obesity-related dysfunctions continues to be covered, the mechanism driving myeloid progenitor expansion is not well understood.

Here, we will discuss what is known about the factors propagating inflammation intrinsic to hematopoietic Obesity and obesity-related diseases like type 2 diabetes (T2D) are prominent global health issues; therefore, there is a need to better understand the mechanisms underlying these conditions. The onset of obesity is characterized by accumulation of proinflammatory cells, including Ly6c hi monocytes (which differentiate into proinflammatory macrophages) and neutrophils, in metabolic tissues. This shift toward chronic, low-grade inflammation is an obese-state hallmark and highly linked to metabolic disorders and other obesity comorbidities. The mechanisms that induce and maintain increased inflammatory myelopoiesis are of great interest, with a recent focus on how obesity affects more primitive hematopoietic cells. The hematopoietic system is constantly replenished by proper regulation of hematopoietic stem and progenitor (HSPC) pools in the BM. While early research suggests that chronic obesity promotes expansion of myeloid-skewed HSPCs, the involvement of the hematopoietic stem cell (HSC) niche in regulating obesity-induced myelopoiesis remains undefined. In this review, we explore the role of the multicellular HSC niche in hematopoiesis and inflammation, and the potential contribution of this niche to the hematopoietic response to obesity. This review further aims to summarize the potential HSC niche involvement as a target of obesity-induced inflammation and a driver of obesity-induced myelopoiesis.

JCI Insight 2021;6(3):e145295 https://doi.org/10.1172/jci.insight.145295 cells but also within the hematopoietic BM niche (Figure 1 ). Several gaps currently exist, providing an opportunity to further elucidate the mechanism of metainflammation.

Hematopoietic stem and progenitor cell pool fluctuations during obesity. Hematopoiesis is a tightly regulated process that allows for the continued production of the entire hematopoietic system. This process is highly dynamic and responds accordingly when exposed to different environmental stressors before returning to homeostatic hematopoiesis. As the BM is the primary site of active hematopoiesis and home to hematopoietic stem and progenitor cells (HSPCs), BM populations during obesity and chronic inflammation have been a focus of investigation (7, (27) (28) (29) (30) . Similar to AT and peripheral blood, BM exhibits induced expansion of monocytes and neutrophils in response to obesity. Interestingly, this quantitative expansion also extends to more primitive hematopoietic cells (7, (27) (28) (29) (30) . Multiple groups have shown obesity-induced increases of multiple early myeloid progenitor populations, including multipotent progenitors (MPPs), common myeloid progenitors (CMPs), pregranulocyte and macrophage progenitors (Pre-GMs), and granulocyte and macrophage progenitors (GMPs) (7, (27) (28) (29) (30) . Moreover, an increase in circulating CD34 + hematopoietic progenitors has been reported in obese patients (31) .

Hematopoietic stem cells (HSCs) in obesity remain controversial, as labs have identified expansion (7, 27) , reduction (28, 30) , and no overall change (29) in HSC pool size in obese mouse models. BM transplant (BMT) studies conducted to functionally test the repopulating ability of the HSC pool in obesity have also produced conflicting data. Some groups have observed an enhanced production of inflammatory myeloid cells from high-fat diet-derived (HFD-derived) BM in both competitive and serial transplantation assays (7, 27) , while others have identified impairments in HSC repopulation potential linked to altered quiescence, self-renewal, and impaired differentiation (28) (29) (30) . However, a further look at these studies indicates that variability in experimental design contributes to these differences. These variations include use of genetic models of obesity (e.g., ob/ob and db/db mice) versus diet-induced obesity, models of which may also differ in the percent of calories from fat, length of diet exposure, and BMT design. It should also be noted that leptin, whose signaling is modified in ob/ob and db/db strains and elevated in obesity, has been researched as a possible regulator of the hematopoietic system. Studies going back to the 1990s have implicated leptin signaling as a positive regulator of HSC proliferation and differentiation (32) (33) (34) , thus raising the question of the developmental impacts on hematopoiesis prior to the onset of obesity in an environment devoid of functional leptin or leptin receptors, as in the ob/ob and db/db mice, respectively.

Obesity, regardless of model, is marked by increased levels of a wide array of proinflammatory cytokines, like IL-6, TNF-α, and IL-1β, in the expanding tissues and circulation. These proinflammatory signals further promote inflammation through signaling pathways like TLR4 (35) (36) (37) (38) . While there is consensus that inflammation is a major contributor of the obesity phenotype, the exact mechanisms driving increased myelopoiesis in obese models is unclear, with both dietary components and inflammatory pathways implicated. The impact of inflammation itself on the hematopoietic system has been studied for decades, but the role of metainflammation on HSPC populations has only recently been explored (39) (40) (41) (42) . HSCs remain predominantly quiescent during steady state, with more committed downstream progenitors taking on the majority of the hematopoietic production (43) . However, in response to inflammatory stressors, the HSC compartment becomes active, leading to increased proliferation and altered production of mature blood cells (44) . Inflammatory signals, like IL-1β, TNF-α, IL-6, and TLR ligands, have all been shown to impact the HSC pool during acute and chronic inflammation and, interestingly, are also all elevated during obesity.

Inflammatory cytokines and hematopoiesis. Early research using in vitro cultures of primitive HSPCs, including human CD34 + cells and murine Lineage -Sca-1 + cKit + (LSK) cells, suggested a role for proinflammatory cytokines, like IL-1β, TNF-α, and TLR ligands, in the induction of hematopoiesis (45) (46) (47) . In vitro studies have implicated IL-1β (48), TNF-α (49) (50) (51) (52) , and TLR (53-57) signaling in accelerated proliferation and myeloid differentiation of human and murine HSPCs. This enhanced HSPC proliferation and differentiation has been linked to increased expression of cell cycle activators (cyclin C, cyclin E1, cyclin-dependent kinase 4, and Myc) and myeloid lineage genes (GM-CSF receptor, PU.1, GATA-1, and C/EBPα), along with reduced expression of proliferation inhibitors like p57 (48, 55) . TNF-α signaling has also been linked to increased HSC repopulation potential following BMT (52) . While elevated IL-6 levels promote myelopoiesis and inhibit lymphopoiesis, its role during an inflammatory state is not well studied (58, 59) . However, in vitro cultures and BMT studies from other groups have suggested that TNF-α inhibits HSPC function due to increased apoptosis and impaired self-renewal (49, 51, 60, 61) . Recent work has suggested that TNF-α JCI Insight 2021;6(3):e145295 https://doi.org/10.1172/jci.insight.145295 effects may be concentration dependent, as increasing TNF-α levels proportionally increases negative effects on HSCs (62) . This dosage effect varies between different HSPC populations, as GMPs respond differently than HSCs. These data suggest that HSPC populations are differentially regulated by not just the presence or absence of TNF-α, but also higher or lower TNF-α (and possibly other cytokines), within the environment.

Mechanisms of direct obesity-induced hematopoiesis. While many gaps remain in the study of inflammation in hematopoiesis, current literature suggests that activation of inflammatory pathways in HSPCs significantly influences their function, specifically in decisions concerning proliferation versus quiescence and differentiation versus self-renewal. There is also a large overlap in hematopoietic phenotypes, including enhanced myelopoiesis and HSPC expansion, observed in obesity and inflammation. Genetic loss of TLR4 signaling (via deletion of Tlr4 or downstream regulators Myd88 or Ticam1) in obese mice through whole-body KOs (36, 37) and BM chimeras (35, 38) leads to decreased levels of TNF-α and IL-6 (35), improved insulin sensitivity (35, 38) , decreased activation of proinflammatory ATMs (36, 38) , and decreased AT fibrosis (37) . Loss of TLR4 signaling also alters the HSPC phenotype in the BM of obese mice. Tlr4 -/-, Myd88 -/-, and Ticam1 -/mice placed on HFD for 16 weeks had decreases in GMPs and decreased production of myeloid colonies Hematopoiesis is tightly regulated by cytokines produced through the HSC niche, and research has begun to identify the individual contribution of each of these populations in the regulation and maintenance of the HSC pool (top panel). During obesity (bottom panel), the BM landscape changes dramatically. Increased production of leptin from expanding adipose tissue leads to biased differentiation of LepR + perivascular cells toward adipogenesis at the expense of osteogenesis, leading to a significant loss of bone density. While the impact of this physical expansion of the BMAT on the rest of the HSC niche and hematopoiesis is not yet known, this increase would bring many more hematopoietic and stromal cells into direct and/or closer contact with BMAT. Additionally, the expanding AT leads to increased production of proinflammatory monocytes, macrophages, and neutrophils, which in turn leads to an increase in the basal levels of inflammatory cytokines. Chronic exposure to HFD also leads to increased levels of circulating free fatty acids, which could act on both stromal and hematopoietic cells to drive and sustain production of inflammatory myelopoiesis. Illustrated by Rachel Davidowitz. via CFU assay (38) . Hematopoietic-specific deletion of Tlr4 has been achieved with chimeric transplant systems generating recipient mice that contain BM either entirely (7, 28, 32) or partially (27, 28, 38) devoid of TLR4 in hematopoietic cells. Exposure of these mice to HFD decreased HSC, CMP, and GMP populations compared with the WT HFD controls. HSCs isolated from TLR4-deficient HFD-fed mice for BMT showed normal reconstitution compared with the myeloid-biased reconstitution noted from WT HFD HSCs.

Other labs have also investigated the involvement of IL-1β and the NLRP3 inflammasome in the propagation of myelopoiesis in obesity (7, 39) . Il1r -/mice placed on HFD for 6 months have less expansion of HSCs, CMPs, and GMPs compared with the Il1r +/+ HFD controls and decreased production of inflammatory cytokines from BM-derived macrophages (7) . Reciprocal transplants of WT or Nlrp3 -/-BM into irradiated ob/ob recipients also suggest a role for the inflammasome in the obesity-induced BM phenotype. Five weeks after transplant, recipient mice that received Nlrp3 -/-BM had less expansion of GMPs, and circulating monocytes and neutrophils, compared with WT BM recipients (7).

Ki67 staining has shown increased cellular proliferation of the HSC, MPP, CMP, and GMP populations of obese mice (7, 28, 63) . Obese HSPCs also exhibit consistent increases in expression of genes associated with myeloid differentiation (Csfr1, Spi1, and Runx1), myeloid activity (Stat3 and Stat6), and cell cycle activators (Cdk1 and Ccna2) (28) . Increased cMyc expression, which promotes the cell cycle, and decreased expression of cell cycle inhibitors p21 and p57 have also been reported in purified obese HSCs. This gene expression profile is believed to be the result of lipid raft loss on the HSC cellular membrane, resulting in inhibited TGF-β signaling, which has been shown to nudge HSCs out of quiescence and into proliferation (63) . However, other groups have identified increased quiescence at the expense of differentiation and impaired long-term reconstitution capability in HSCs from mice exposed to chronic HFD. Increased quiescence is associated with increased Gfi1 and Cdkn1 expression of HSCs isolated from obese animals (29) . The majority of these studies used different models, which could heavily impact the results. However, these studies shed light on the complexity of obesity and inflammation, and the dynamic changes that can occur within the hematopoietic system in response to the environment (both locally and systemically).

The HSC niche is a multicellular structure within the BM composed of nonhematopoietic stromal cells (adipocytes, osteoblasts [OBs], endothelial cells, perivascular mesenchymal stem cells [MSCs] , and sympathetic nerves) and hematopoietic cells (megakaryocytes [Mks], macrophages, and neutrophils) that provide instructional signaling to associated HSCs. HSC niche-derived signals are important in the maintenance and proper functioning of the HSC pool during steady-state and stressed conditions, as these signals balance HSC proliferation, quiescence, differentiation, self-renewal, extravasation into circulation, and homing into the BM (64) (65) (66) (67) (68) . While emphasis has been placed on interactions between the niche and HSCs, there is growing evidence that HSPCs residing within BM niches may also rely on these signaling pathways for proper regulation and function (65) . As these populations are critical for hematopoiesis, understanding how obesity-driven inflammation impacts niche population function and the contributions of the niche to obesity-associated hematopoiesis alterations is important.

The role of BM adipocytes in hematopoiesis. Bone marrow AT (BMAT) has been an enigma in the hematopoietic and HSC niche fields. BMAT is heterogenous and can be divided into 2 populations: constitutive BMAT (cBMAT), which is densely packed and is present from birth, and regulated BMAT (rBMAT), which is more dispersed within the BM and capable of both expansion and contraction throughout life (6, 69) . Studies initially linked BM adiposity with inhibited hematopoiesis based on observations that bones containing higher amounts of BMAT had less active hematopoiesis (70, 71) . However, newer data point to a possible positive regulatory role for BMAT on hematopoiesis. Coculture of adipocytes and primary hematopoietic cells supports increased HSPC differentiation into mature blood cells (72, 73) , and recent work suggests that BMAT is a source of hematopoietic and HSC regulatory cytokines. A study of human BMAT implicated this niche as a source of CXCL12 and G-CSF (74) , while studies of murine BMAT suggest it is a source of SCF during hematopoietic regeneration following lethal irradiation and transplantation (75) . The specific role of BMAT in the regulation of hematopoiesis is still under investigation; however, adipocyte-derived adipokines have been shown to regulate HSCs (6, 32-34, 69, 74, 76-78) . Adipose-derived adiponectin promotes HSC proliferation and BMT, reconstituting potential through p38 MAPK activation (77) and mTORC signaling (78) . Leptin, another adipokine, has also been shown to promote HSC expansion and differentiation (32-34), though the intracellular mechanism inducing proliferation is not known. During obesity, circulating leptin increases while adiponectin decreases. While both adipokines have been shown to promote HSC proliferation, their specific role during obesity is not known. However, expanding BMAT could provide a local source of leptin to promote HSC expansion. While scarce, some data suggest that AT-derived fatty acids could have regulatory roles in myelopoiesis (79, 80) and HSC pool maintenance (81) . Additionally, prostaglandin E 2 (PGE2), which is also elevated during obesity and derived from the fatty acid arachidonic acid, has been shown to inhibit B lymphopoiesis, suggesting another possible mechanism for increased myelopoiesis or skewing in obese BM (82) .

As expanding white AT (WAT) increases production of inflammatory cytokines and receptors (83) (84) (85) , BMAT also increases production of inflammatory cytokines like IL-6, TNF-α, and serum amyloid A3 (SAA3) (76, (86) (87) (88) . In humans, BMAT expresses higher basal levels of IL-6 and TNF-α compared with WAT (87) . Interestingly, recent data have suggested that a switch occurs during obesity wherein secretion of these factors is significantly lower in BMAT compared with expanding WAT (89) . This discovery emphasizes the complexity and heterogeneity of the different AT depots, their response to obesity, and their impact on hematopoietic system regulation.

BMAT is considered a hybrid of white and brown adipocytes; however, during HFD, BMAT appears to undergo a shift toward a more WAT-like phenotype (90) . Comparison of BMAT and WAT during homeostasis identified differential lipid metabolism, with decreased lipolytic activity and a shift toward cholesterol-oriented metabolism in BMAT compared with WAT (91). However, how BMAT lipid metabolism is impacted during obesity is still unknown. As WAT is typically associated with energy storage and BAT with energy expenditure, the observed metabolic shift in BMAT during HFD-induced obesity could be the result of an increased lipid storage demand. Additionally, it is not clear how this shift in metabolic signature in BMAT impacts hematopoiesis. Extensive research has gone into the identification and characterization of WAT and BAT depots during both homeostasis and metabolic dysfunction, while much less is known about the metabolic contributions of the BMAT -let alone the alterations that occur in this depot during conditions like obesity. This emphasizes the need to better understand the role of BMAT in both systemic metabolism and hematopoiesis.

The role of endothelial cells in hematopoiesis. The close proximity of HSCs to the BM vasculature was an initial clue that BM endothelial cells (BMECs) play a role in the regulation of HSCs (92) (93) (94) (95) (96) (97) (98) . BMECs induce HSC proliferation and differentiation through activation of AKT (94) and the Notch signaling pathway (95, 96) , while in vitro MAPK activation in BMECs induces significantly less expansion of hematopoietic cells (94) , suggesting that various activation states within the BMEC population could have differing effects on the associated HSCs. BMECs are a major source of SCF, CXCL12 (93, 98-100), BMEC-derived EGF, and pleiotrophin (101-103), which are critical for homeostasis and hematopoietic system regeneration following BMT (97) . BMECs make up a heterogenous population composed of arteriolar ECs (AECs) and sinusoidal ECs (SECs). While differences in production of all known HSC regulatory genes are not fully elucidated, AEC-derived SCF has been observed to be more critical for HSCs than SEC-derived SCF (99) . HSCs also exist in different proliferative states depending on the BMEC niche. HSCs associated with AECs are found in a more quiescent state than those associated with SECs (104, 105); however, whether this is strictly due to the BMECs themselves or influenced by additional niche populations is not known.

BMECs express a range of TLRs (TLR1-7, TLR9) and inflammatory receptors, such as those for TNF-α, IL-1, and IL-6 (106-108), suggesting a role in stress-induced hematopoiesis. Early in vitro assays of human EC lines identified increased expression of the myeloid differentiation cytokine GM-CSF upon IL-1 or TNF-α stimulation, suggesting that BMECs contribute to demand-dependent hematopoiesis (109, 110) . In recent years, it has become apparent that G-CSF-mediated emergency granulopoiesis is heavily dependent on inflammatory signaling through BMECs, in part through TLR4 (111) (112) (113) (114) . Additionally, LPS and TNF-α induce expression of Jagged-2 on BMECs and Notch-1 and -2 on hematopoietic cells, suggesting that these pathways may work together to promote Notch signaling in the BM during inflammation (115) . Chronic activation of the inflammatory stress-associated MAPK pathway in BMECs (116, 117) promotes aberrant NF-κB signaling, which is believed to drive myeloid bias in HSCs ex vivo at the expense of self-renewal (118) . While the majority of this research has been within the context of acute infection and the associated immune response, several cytokine and signaling pathways (IL-1β, TNF-α, and TLR4) and the skewing toward myelopoiesis are also implicated in obesity, making these pathways prime targets for further analysis. While not studied during infection, expression of Del-1 by BMECs has also been shown to regulate homeostatic production of myeloid cells, suggesting a possible signaling pathway that is disrupted during obesity (119). Significant impairments in BMECs of the HSC niche have been observed in the context of diabetes (120) (121) (122) . While some studies focus on type 1 diabetes (T1D), which addresses the impact of hyperglycemia and differs from the obese conditions associated with T2D, they still provide insight into the effect of metabolic dysfunction on the BM. When mice are exposed to streptozotocin to induce β cell failure, the BM undergoes significant loss of hematopoietic cells, a dramatic decrease in vascular density, and increased vascular permeability (120, 122) . BMECs from streptozotocin-treated mice also have increased levels of ROS and decreased migration toward chemokines CXCL12 and VEGF-A (120, 121) . BMECs from these mice also exhibit decreased AKT pathway activation, which is associated with impaired BMEC migration, leukocyte extravasation, and vascular permeability (122) .

The role of BMECs in metainflammation are limited, but recent work described BMEC-specific EGFR signaling in mediating the BM phenotype observed in obesity (123) . The authors noted a significant reduction in CXCL12 in BMECs from obese mice; however, increased HSC localization at the BM vasculature was observed in obese mice compared with controls. These results are conflicting, as CXCL12 is considered the prominent cytokine for HSC retention in the BM, and a reduction in CXCL12 would not typically associate with increased HSC recruitment. BMEC-specific EGFR deletion in Cdh5-Cre;EGFR fl/fl mice had no effect on CXCL12 expression in response to HFD, and EGFR-deficient mice underwent increased expansion of HSCs, along with notably more myelopoiesis compared with the WT HFD group. The authors of this study conclude that BMEC EGFR signaling is protective and aids in maintenance of normal hematopoiesis. One possible caveat of this study arises from the use of Cdh5-Cre mice, as constitutive deletion in BMECs could result in deletion in the hematopoietic system (86) . Overall, these data suggest that obesity and hyperglycemia influence the HSC niche by both promoting enhanced myelopoiesis and affecting mechanisms that keep hematopoiesis in check (124) .

The role of perivascular stromal cells in hematopoiesis. Perivascular stromal cells are found throughout the BM space, although they are most frequently found in close association with BM vasculature (93, 104) . Recent work has further characterized this population into, roughly, 2 distinct subtypes: leptin receptor + (LepR + ) cells (98) , which are relevant to obesity, and the Ng2 + population (104) . Perivascular stromal cells not only show characteristics of MSCs, but also express high levels of critical HSC regulatory proteins, including SCF, CXCL12, VCAM1, and Ptn (67, 98, 104, 125, 126) . BM stromal cell-derived TNF-α has also been shown to regulate HSC biasing toward myelopoiesis via activation of angiotensin II (127) . Mice lacking the angiotensin II receptor in their BM stroma have decreased production of granulocytes and macrophages and reduced GMPs (127), pointing to an involvement of the BM niche in promoting HSC skewing. Recent data have also suggested that these CXCL12 sources are important for maintenance of the MPP population (128) . Thus, it is possible that the niche is not specific to HSCs but regulates hematopoiesis through multiple stages of differentiation.

BM MSCs have been implicated in regulating both the innate and adaptive immune response through the production of cytokines and inflammatory factors, such as TNF-α, IL-10, IL-6, PGE-2, NO, and CXCL12 (129, 130) . The effect of these cells on the immune system is quite varied, as BM MSCs can both inhibit (131) (132) (133) (134) (135) and promote (136) (137) (138) (139) (140) immune responses. MSCs can inhibit T cell responses (via IFN-γ, TNF-α, or IL-1β) (141) (142) (143) and promote antiinflammatory signaling in macrophages (via PGE-2 and TLR2) (134, 135) . Activation of MSC TLRs promotes the increased production and secretion of proinflammatory cytokines (IL-1β, IL-6, TNF-α, CCL5, and type 1 IFNs; refs. 136, 137) , which could increase inflammation in the BM environment. MSC-derived IL-6 promotes expansion of myeloid progenitors and mature myeloid cells (138, 139) , and TLR4 signaling on MSCs directly leads to secretion of the monocyte chemokine MCP-1 (also known as CCL2) to promote the extravasation of inflammatory Ly6c hi monocytes into circulation (140) , another mechanism that could be exacerbated during obesity.

We have a limited understanding of the role of perivascular MSCs during obesity-induced hematopoiesis. In T1D, BM MSCs become nonresponsive to G-CSF signaling, leading to a maintained CXCL12 expression and impaired mobilization of HSPCs (144) . BM MSCs are capable of differentiating down the osteogenic or adipogenic pathways, and data taken from obese mice heavily suggest that differentiation is altered during obesity. LepR + perivascular cells are targeted by elevated leptin and differentiate into adipocytes at the expense of OBs, leading to BMAT accumulation and decreased bone density (6, 145) . However, it is not clear if differentiation of these MSCs would lead to HSC niche loss or if this would contribute to obesity-associated hematopoietic phenotypes.

The role of the sympathetic nervous system (SNS) in hematopoiesis. The SNS innervates the BM by traveling along the arteriolar vasculature (146) . The SNS helps prevent HSC exhaustion through production of JCI Insight 2021;6(3):e145295 https://doi.org/10.1172/jci.insight.145295 TGF-β, which pushes HSCs into a quiescent state (146) . Catecholamines produced by the SNS can directly act on HSCs or aid in the BM response to G-CSF-mediated mobilization by altering CXCL12 expression (147) (148) (149) (150) (151) . Treatment of human CD34 + HSPCs with a dopamine agonist in the presence of G-CSF prior to BMT increased hematopoietic colonies and increased engraftment into NOD-SCID recipient mice (150) .

While the use of adrenergic receptor agonists on both human and murine immune cells leads to decreased production of cytokines (TNF-α, IL-6, IL-12, and IFN-γ) and increased migration (149, 152) , there is limited information on how SNS signals affect either BM immune cells or HSPCs during inflammatory stress and obesity. Some data suggest that T1D impairs SNS-induced mobilization of HSCs following G-CSF treatment by preventing CXCL12 downregulation in BM MSCs (144) . A recent model of SNS-driven atherosclerosis (a comorbidity of obesity) led to a reduction in HSC niches -like sinusoidal endothelial cells -and extravasation of HSPCs out of the BM and into the spleen, suggesting severe BM dysfunction (153) . This correlated with increased production of neutrophil-derived proteases capable of targeting a critical HSPC chemokine receptor, CXCR4 (153) . Treatment of these mice with an adrenergic receptor blocker prevented CXCR4 cleavage, suggesting a possible mechanism by which SNS targets neutrophils to regulate HSPC trafficking into and out of the BM. However, the impact of chronic low-grade inflammation and obesity on the SNS and its role in regulating hematopoiesis is still largely unknown and clinically important to investigate.

The role of OBs in hematopoiesis. OBs are responsible for bone synthesis and mineralization, and they are capable of positively regulating hematopoiesis and HSC function (154, 155) . In vivo murine models have suggested that OBs can modulate the size of the HSC pool through increased expression of Jagged-1 (156) and activation of BMP signaling (157) . OB-derived angiogenin -another factor elevated in obesity -can promote HSC quiescence, as loss of angiogenin from osteolineage BM cells leads to increased proliferation of the HSC pool (158) . However, recent studies have contradicted these data and suggest OB signaling is dispensable for proper HSC maintenance and function (159) . Interestingly, CXCL12 deletion from OBs has no effect on the HSC pool but does lead to depletion of early lymphoid progenitors (93, 98) , further supporting the existence of niches for hematopoietic progenitors. While the data might still be unclear as to the specific role of OBs in regulation of hematopoiesis, plenty of data support their role during inflammation. Following bacterial infection, OBs are a source of several inflammatory factors (e.g., IL-6, IL-8, CXCL10, and MCP-1) (160) (161) (162) (163) . Additionally, OBs express several TLRs (TLR2, TLR4, TLR5) and increase IL-6 expression when cultured in the presence of TNF-α or IL-1β, suggesting an active contribution to the immune response (161, (163) (164) (165) .

Obese patients and mice undergo significant bone loss. Studies suggest that obesity-induced bone loss is due to skewed differentiation of LepR + cells toward adipogenesis instead of osteogenesis (145) ; however, several cytokines produced both by AT and immune cells can negatively impact maintenance of the OB population and bone remodeling. Leptin and adiponectin have also been implicated as regulators of bone homeostasis. Leptin has been shown to positively and negatively influence the OB pool size. Early in life, leptin is believed to stimulate bone growth; however, later in development and during obesity, it may promote bone loss through induction of RANKL expression, thereby promoting osteoclast production and bone reabsorption (166) . Adiponectin is significantly reduced in obesity and appears to have a more protective role on OBs. In vitro and in vivo assays have suggested that adiponectin promotes OB production and inhibits osteoclast formation (167) . Moreover, IL-6 and TNF-α, which are elevated during obesity, have been shown to promote osteoclast differentiation (168) (169) (170) , thereby prompting bone loss. While OBs may not directly impact the HSC pool, loss of this population could negatively impact the production of lymphoid cells in obese mice and humans.

The role of Mks in hematopoiesis. Mks are large, multinucleated cells that reside in close proximity to the vasculature, where they shed platelets into circulation. As with other identified niche populations, Mks became of interest due to their close association with HSCs (171) (172) (173) . Data suggest that Mks induce HSC quiescence through CXCL4, CLEC2, and TGF-β signaling (171) (172) (173) . More recently, coculture of Mk-derived microparticles with human CD34 + HSPCs appears to induce Mk lineage differentiation (174) . This work on Mks was among the first to implicate a mature hematopoietic cell as a component of the HSC niche.

Mks are targeted in response to inflammation (175) (176) (177) . In mice, IL-1β administration increases not only the size of Mks, but also circulating platelets and granulocytes (178, 179) . IL-6 has also been shown to influence the output of platelets (179, 180) through increasing levels of thrombopoietin (TPO), a critical cytokine for Mk differentiation and maturation (178, 179) . Mks and platelets also express TLRs (TLR1-4, TL6, and TLR9), and treatment with LPS in humans leads to an eventual increase in TPO and platelets (181) (182) (183) (184) (185) (186) . Platelets may produce additional inflammatory cytokines, and levels of these transcripts have JCI Insight 2021;6(3):e145295 https://doi.org/10.1172/jci.insight.145295 been directly correlated to BMI. Humans with a higher BMI have elevated transcripts encoding IL-1R1, IL-6, TNF-α, TLR2, and TLR4 (187) . While platelets have been linked to inflammatory states in systemic lupus (188) and inflammatory arthritis (189) , the role of platelets and Mks in the HSC niche, metainflammation, and the increased myelopoiesis seen in obesity still remains unclear.

The role of macrophages and neutrophils in hematopoiesis. Surprisingly, Mks are not the only mature hematopoietic population with HSC regulatory function. BM macrophages, and more recently neutrophils, have been implicated as indirect regulators of the HSC pool. Macrophages regulate CXCL12 expression in BM perivascular cells, which may facilitate G-CSF-induced mobilization of HSPCs into circulation (190) (191) (192) . Additionally, radio-resistant BM macrophages locate in perivascular niches following myeloablation, where they produce PGE2 to promote HSC reconstitution and induce CXCL12 expression in BM stromal cells (193, 194) . The clearance of neutrophils by BM macrophages has also been linked to altered expression of CXCL12 in the BM and extravasation of HSPCs (195) . Neutrophil-derived TNF-α promotes regeneration of damaged BM vasculature following myeloablation, leading to increased hematopoietic reconstitution (196) . While these data suggest that BM macrophages and neutrophils indirectly regulate HSCs, some data indicate that these mature immune cells directly regulate the HSC pool through histamine production (197) . These studies suggest that direct mechanisms of HSC regulation by myeloid cells in hematopoiesis have yet to be identified.

BM myeloid cells are important niche components that regulate hematopoiesis. Obesity-induced inflammation is well known to induce expansion of proinflammatory monocytes and neutrophils; however, the impact of this expansion specifically in the BM has yet to be determined. Tissue-resident macrophages, and infiltrating monocytes and neutrophils, are major drivers of inflammation through production of cytokines; however, whether or not BM myeloid cells produce similar levels is not known. Therefore, these cells may promote the transition into an inflammatory BM environment through similar mechanisms. These signals could target both HSPCs and the BM niche to promote production of more inflammatory myeloid cells. While studies suggest defective acute inflammatory responses, they also raise the question as to how functional impairments of these mature myeloid cells could alter HSC regulation in the BM.

Metainflammation is a driver for lifetime mortality and morbidity; hence, it is critical to understand the mechanisms contributing to alterations of hematopoiesis. While the majority of studies conducted have focused on the changes occurring within metabolic tissues such as the AT, the impact of obesity on hematopoiesis is still a new area of research. Several groups have begun identifying alterations to hematopoietic production during the onset of obesity in mice. More specifically, obesity promotes increased production of myeloid cells through biased expansion of myeloid-specific progenitors and skewing of the HSC pool toward myelopoiesis. However, there are gaps in understanding the mechanisms underlying these processes and the impact of obesity on hematopoiesis and the HSC pool ( Figure 1 ).

Going forward, it will be important to further determine if there is a dependence on specific dietary factors, such as saturated fats, or if genetic obesity itself can mimic what is observed in dietary obesity. In addition, the age of mice used in studies is another confounding factor; therefore, understanding the immune changes in both young and aged animals is clinically relevant and necessary, as seen with regard to age-related influence of metainflammation observed in recent pandemic infections (198) . The use of either HSPC frequency or cell number are also important to consider in study design and data analysis. Given that cellularity itself might significantly shift in the BM space with obesity and HFD exposure, the use of frequency could be misleading. For example, expansion of a population like neutrophils (one of the most abundant blood cells in the BM) could drastically alter BM cellularity, which would significantly affect the frequency of HSCs, even if the total number of HSCs was unchanged. While this review has focused on the phenotypes attributed to obesity, it is critical to mention that all of these studies utilize male mice, as female mice do not present the same inflammatory signatures (199) or metabolic impairment. A very similar phenotype is also observed in humans, suggesting a possible effect of sex hormones. The study of the HSC niche in female BM could provide critical insight into the regulatory roles of these populations in the chronic inflammatory response.

The HSC niche in obesity has yet to be heavily interrogated. While some studies suggest that obesity impairs BMEC function, increases BM adiposity, and decreases bone density, the impact of these changes on the ability of the niche to properly regulate hematopoiesis remains to be determined. Recent work demonstrates that adipocytes and ECs can communicate through extracellular vesicles (200) . Such com-JCI Insight 2021;6(3):e145295 https://doi.org/10.1172/jci.insight.145295 munication would have large implications into the role of BMAT as a signaling hub in the BM space that could influence hematopoietic decisions.

Given that inflammation is so heavily linked to the pathogenesis of obesity, understanding the cell types within the hematopoietic niche that support or impair hematopoiesis is critical. Focused research into the signals and the role of inflammation in the regulation of hematopoiesis through the HSC niche is essential to understand the therapeutic potential of altering the BM niche to regulate immune responses and improve metabolic health in obesity.

MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity

Minireview: emerging concepts in islet macrophage biology in type 2 diabetes

Obesity and cancer metabolism: a perspective on interacting tumor-intrinsic and extrinsic factors

The dual roles of obesity in chronic kidney disease: a review of the current literature

Adipose tissue, inflammation, and cardiovascular disease

Bone marrow adipose cells -cellular interactions and changes with obesity

Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity

Circulating classical monocytes are associated with CD11c + macrophages in human visceral adipose tissue

Obesity induces a phenotypic switch in adipose tissue macrophage polarization

Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity

Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue

M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet--induced obesity in mice

Newly identified adipose tissue macrophage populations in obesity with distinct chemokine and chemokine receptor expression

Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling

Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance

Skeletal muscle inflammation and insulin resistance in obesity

Obesity-induced neuroinflammation: beyond the hypothalamus

Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation

Local proliferation initiates macrophage accumulation in adipose tissue during obesity

Comparison of numbers of circulating blood monocytes in men grouped by body mass index (<25, 25 to <30, > or =30)

Perturbation of the monocyte compartment in human obesity

Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance

Elevated white blood cell count in subjects with impaired glucose tolerance

Neutrophil functions in morbidly obese subjects

Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase

Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding

Diet-induced obesity promotes myelopoiesis in hematopoietic stem cells

Bone marrow lympho-myeloid malfunction in obesity requires precursor cell-autonomous TLR4

Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression

Diet-induced obesity in mice diminishes hematopoietic stem and progenitor cells in the bone marrow

Influence of BMI on level of circulating progenitor cells

A synthetic fragment of leptin increase hematopoietic stem cell population and improve its engraftment ability

Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells

A role for leptin in sustaining lymphopoiesis and myelopoiesis

Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice

Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages

Immune cell Toll-like receptor 4 mediates the development of obesity-and endotoxemia-associated adipose tissue fibrosis

TRIF, and MyD88 are essential for myelopoiesis and CD11c + adipose tissue macrophage production in obese mice

Inflammation: a key regulator of hematopoietic stem cell fate in health and disease

Regulation of inflammation-and infection-driven hematopoiesis

Pro-inflammatory cytokines: emerging players regulating HSC function in normal and diseased hematopoiesis

Stress and non-stress roles of inflammatory signals during HSC emergence and maintenance

Clonal dynamics of native haematopoiesis

Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair

The in vitro response of phenotypically defined mouse stem cells and myeloerythroid progenitors to single or multiple growth factors

Proliferation of myeloid progenitor cells in human long-term bone marrow cultures is stimulated by interleukin-1 beta

Ex vivo expansion of enriched peripheral blood CD34+ progenitor cells by stem cell factor, interleukin-1 beta (IL-1 beta), IL-6, IL-3, interferon-gamma, and erythropoietin

Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal

Tumor necrosis factor (TNF)-mediated activation of the p55 TNF receptor negatively regulates maintenance of cycling reconstituting human hematopoietic stem cells

Tumor necrosis factor-alpha strongly potentiates interleukin-3 and granulocyte-macrophage colony-stimulating factor-induced proliferation of human CD34+ hematopoietic progenitor cells

Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors

Tumor necrosis factor receptors support murine hematopoietic progenitor function in the early stages of engraftment

Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment

Signaling through toll-like receptor 7/8 induces the differentiation of human bone marrow CD34+ progenitor cells along the myeloid lineage

The TLR1/2 agonist PAM(3)CSK(4) instructs commitment of human hematopoietic stem cells to a myeloid cell fate

Cutting edge: hematopoietic stem cell expansion and common lymphoid progenitor depletion require hematopoieticderived, cell-autonomous TLR4 in a model of chronic endotoxin

Pathogen-induced TLR4-TRIF innate immune signaling in hematopoietic stem cells promotes proliferation but reduces competitive fitness

IL-6 blocks a discrete early step in lymphopoiesis

IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development

Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death

The suppressive influences of human tumor necrosis factors on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: synergism of tumor necrosis factor and interferon-gamma

TNF-α coordinates hematopoietic stem cell survival and myeloid regeneration

High-fat diet disturbs lipid raft/TGF-beta signaling-mediated maintenance of hematopoietic stem cells in mouse bone marrow

Haematopoietic stem cell activity and interactions with the niche

Niches for hematopoietic stem cells and their progeny

The hematopoietic stem cell niche: from embryo to adult. Development

Differential cytokine contributions of perivascular haematopoietic stem cell niches

Deciphering hematopoietic stem cells in their niches: a critical appraisal of genetic models, lineage tracing, and imaging strategies

Marrow adipose tissue: trimming the fat

Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment

Hematopoietic recovery following chemotherapy is improved by BADGE-induced inhibition of adipogenesis

Adipocytic cells augment the support of primitive hematopoietic cells in vitro but have no effect in the bone marrow niche under homeostatic conditions

Human bone marrow adipocytes support complete myeloid and lymphoid differentiation from human CD34 cells

Bone marrow adipocytes support hematopoietic stem cell survival

Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF

Characterization of age-related gene expression profiling in bone marrow and epididymal adipocytes

Identification of adiponectin as a novel hemopoietic stem cell growth factor

Adiponectin enhances quiescence exit of murine hematopoietic stem cells and hematopoietic recovery through mTORC1 potentiation

Hematopoietic cell-restricted deletion of CD36 reduces high-fat diet-induced macrophage infiltration and improves insulin signaling in adipose tissue

Identification of CD13+CD36+ cells as a common progenitor for erythroid and myeloid lineages in human bone marrow

A PML-PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance

Prostaglandin E2 and stem cell factor can deliver opposing signals to B lymphocyte precursors

Adipocyte differentiation induces dynamic changes in NF-kappaB expression and activity

The lipopolysaccharide-activated toll-like receptor (TLR)-4 induces synthesis of the closely related receptor TLR-2 in adipocytes

Minireview: the adipocyte--at the crossroads of energy homeostasis, inflammation, and atherosclerosis

Hyperglycemia-induced production of acute phase reactants in adipose tissue

Human bone marrow adipocytes display distinct immune regulatory properties

The unique metabolic characteristics of bone marrow adipose tissue

High-fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice

Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes

Human bone marrow is comprised of adipocytes with specific lipid metabolism

SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells

Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches

Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells

Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells

Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis

Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells

Endothelial and perivascular cells maintain haematopoietic stem cells

Stem cell factor is selectively secreted by arterial endothelial cells in bone marrow

Regulation of the hematopoietic stem cell lifecycle by the endothelial niche

Epidermal growth factor regulates hematopoietic regeneration after radiation injury

Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells

Distinct bone marrow sources of pleiotrophin control hematopoietic stem cell maintenance and regeneration

Arteriolar niches maintain haematopoietic stem cell quiescence

Distinct bone marrow blood vessels differentially regulate haematopoiesis

Vascular endothelial cell Toll-like receptor pathways in sepsis

Evolving functions of endothelial cells in inflammation

Bone marrow dysfunction in mice lacking the cytokine receptor gp130 in endothelial cells

Interleukin 1 induces cultured human endothelial cell production of granulocyte-macrophage colony-stimulating factor

Tumor necrosis factor type alpha stimulates human endothelial cells to produce granulocyte/macrophage colony-stimulating factor

Cutting edge: LPS-induced emergency myelopoiesis depends on TLR4-expressing nonhematopoietic cells

Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis

Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection

Endothelium-derived Toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs

Tumor necrosis factor-alpha and endothelial cells modulate Notch signaling in the bone marrow microenvironment during inflammation

Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis

Map3k8 controls granulocyte colony-stimulating factor production and neutrophil precursor proliferation in lipopolysaccharide-induced emergency granulopoiesis

Chronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Diabetes mellitus induces bone marrow microangiopathy

Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model

Diabetes causes bone marrow endothelial barrier dysfunction by activation of the RhoA-Rho-associated kinase signaling pathway

Bone marrow endothelial cells regulate myelopoiesis in diabetes mellitus

Transient intermittent hyperglycemia accelerates atherosclerosis by promoting myelopoiesis

Mesenchymal and haematopoietic stem cells form a unique bone marrow niche

PDGFRα and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion

Bone marrow angiotensin AT1 receptor regulates differentiation of monocyte lineage progenitors from hematopoietic stem cells

Hematopoietic stem cell niches produce lineage-instructive signals to control multipotent progenitor differentiation

Mesenchymal stromal cells: new directions

New concepts on the immune modulation mediated by mesenchymal stem cells

Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide

Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R

Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression

Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages

Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production

Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses

Cytokine modulation of TLR expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype

Stromal-derived IL-6 alters the balance of myeloerythroid progenitors during Toxoplasma gondii infection

Cytotoxic CD8+ T cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells

Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating tolllike receptor ligands

Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation

Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli

Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide

Diabetes impairs hematopoietic stem cell mobilization by altering niche function

Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow

Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche

Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow

Haematopoietic stem cell release is regulated by circadian oscillations

Adrenergic nerves govern circadian leukocyte recruitment to tissues

Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling

Blood-forming stem cells are nervous: direct and indirect regulation of immature human CD34+ cells by the nervous system

Neural regulation of hematopoiesis, inflammation, and cancer

Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis

Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor

Human osteoblasts support human hematopoietic progenitor cells in vitro bone marrow cultures

Osteoblastic cells regulate the haematopoietic stem cell niche

Identification of the haematopoietic stem cell niche and control of the niche size

Proximity-based differential single-cell analysis of the Niche to identify stem/progenitor cell regulators

Strontium can increase some osteoblasts without increasing hematopoietic stem cells

Osteoblasts express the inflammatory cytokine interleukin-6 in a murine model of Staphylococcus aureus osteomyelitis and infected human bone tissue

The modulation of the expression of IL-6 and its receptor in human osteoblasts in vitro

Osteoblasts produce monocyte chemoattractant protein-1 in a murine model of Staphylococcus aureus osteomyelitis and infected human bone tissue

Bacterium-induced CXCL10 secretion by osteoblasts can be mediated in part through toll-like receptor 4

Induction of Nod1 and Nod2 intracellular pattern recognition receptors in murine osteoblasts following bacterial challenge

Signaling via Toll-like receptor 5 can initiate inflammatory mediator production by murine osteoblasts

The complex effects of leptin on bone metabolism through multiple pathways

Adiponectin is associated with bone mineral density in perimenopausal women

IL-1 mediates TNF-induced osteoclastogenesis

Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha

Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways

Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion

Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells

CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow

Shear enhances thrombopoiesis and formation of microparticles that induce megakaryocytic differentiation of stem cells

The role of inflammation in regulating platelet production and function: Toll-like receptors in platelets and megakaryocytes

Modulation of megakaryopoiesis and platelet production during inflammation

Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors

Interleukin-1 beta (IL-1 beta) induces thrombocytosis in mice: possible implication of IL-6

Interleukin-1 potentiates granulopoiesis and thrombopoiesis by producing hematopoietic factors in vivo

Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis

Expression of Toll-like receptors on human platelets

Expression and functionality of Toll-like receptor 3 in the megakaryocytic lineage

T granules in human platelets function in TLR9 organization and signaling

Regulatory effects of TLR2 on megakaryocytic cell function

Toll-like receptor 4 ligand can differentially modulate the release of cytokines by human platelets

Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo

Relation of platelet and leukocyte inflammatory transcripts to body mass index in the Framingham heart

The non-haemostatic role of platelets in systemic lupus erythematosus

Platelets amplify inflammation in arthritis via collagen-dependent microparticle production

Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche

Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs

Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice

Monocytes-macrophages that express ɑ-smooth muscle actin preserve hematopoietic cells in the bone marrow

Self-repopulating recipient bone marrow resident macrophages promote long-term hematopoietic stem cell engraftment

Rhythmic modulation of the hematopoietic niche through neutrophil clearance

Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow

Bone marrow myeloid cells regulate myeloid-biased hematopoietic stem cells via a histamine-dependent feedback loop

The collision of meta-inflammation and SARS-CoV-2 pandemic infection

Sexually dimorphic myeloid inflammatory metabolic responses to diet-induced obesity

An endothelial-to-adipocyte extracellular vesicle axis governed by metabolic state

We would like to thank members of the Singer lab that participated in review of this manuscript. EB is supported by the AHA Postdoctoral Fellowship 20POST35120473, and KS is supported by NIH/NIDDK R01DK11583.