Abstract 11664: The Identification and Hierarchy of Bone Marrow-Derived Artery-Resident Mesodermal Progenitor Cells and Their Dynamics in Atherosclerosis

Background: We recently identified bone marrow (BM)-derived artery resident calcifying progenitor cells. Sca-1+PDGFRα- cells may possess bipotent (osteoblastic/osteoclastic) characteristics. However, the nature of progenitor cells remains elusive. Hypothesis: We investigated developmental hierarchy of progenitor cells and in vivo dynamics in atherosclerosis. Methods and Results: We harvested cells from BM and artery of C57 mice. In BM, Lin-CD29+Sca-1+PDGFRα- cells showed hematopoietic potential and differentiated into osteoclasts (OC). They also possessed mesenchymal stem cell property including osteoblastic (OB) differentiation, suggesting that Sca-1+PDGFRα- cells could be mesodermal progenitor cells. Interestingly, BM-derived artery-resident, clonal Sca-1+PDGFRα- cells maintained bipotency but lost hematopoietic nature. In contrast, Sca-1+PDGFRα+ cells in BM and artery only showed unipotency (OB). When we overexpressed or knocked down PDGFRα, there was no alteration in OB or OC differentiation of Sca-1+PDGFRα- cells and no effect on OB differentiation of Sca-1+PDGFRα+ cells, indicating PDGFRα as a surface marker but not a functional player. In hyperlipidemic ApoE-KO mice compared with control, Sca-1+PDGFRα- cells were less mobilized from BM to peripheral circulation and less infiltrated into atherosclerotic plaque, whereas Sca-1+PDGFRα+ cells were not significantly affected. Multiplex cytokine assay of serum and artery revealed that IL-1β was significantly increased and IL-5 was markedly decreased in atherosclerotic mice. IL-1β decreased the migration of Sca-1+PDGFRα- cells by 5 folds compared with TNFα, and IL-5 increased the migration as much as TNFα. But the migration of Sca-1+PDGFRα+ cells was not altered. These data indicate that atherosclerosis-related humoral factors mainly regulated mesodermal progenitor cells’ dynamics. Conclusion: We demonstrate that Sca-1+PDGFRα- cell is a mesodermal progenitor cell that possesses both hematopoietic and mesenchymal potentials. In atherogenesis, the mobilization and infiltration of Sca-1+PDGFRα- progenitor cells were regulated by IL-1β and IL-5. These data provide a novel mechanism regarding the role of bipotent progenitor cells in atherosclerosis.

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Abstract 45: The Identification and Hierarchy of Bone Marrow-derived Artery-resident Mesodermal Progenitor Cells and their Dynamics in Atherosclerosis

Circulation Research ◽

10.1161/res.115.suppl_1.45 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Hyun-Jai Cho ◽

Hyun-Ju Cho ◽

Yoo-Wook Kwon ◽

Young-Bae Park ◽

Hyo-Soo Kim

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Peripheral Circulation ◽

Humoral Factors ◽

Cell Property ◽

Apoe Ko Mice ◽

Multiplex Cytokine ◽

Developmental Hierarchy

Background: We recently identified bone marrow (BM)-derived artery resident calcifying progenitor cells. Sca-1+PDGFRα- cells may possess bipotent (osteoblastic/osteoclastic) characteristics. However, the nature of progenitor cells remains elusive. Therefore, we investigated developmental hierarchy of progenitor cells and in vivo dynamics in atherosclerosis. Methods and Results: We harvested cells from BM and artery of C57 mice. In BM, Lin-CD29+Sca-1+PDGFRα- cells showed hematopoietic potential and differentiated into osteoclasts OC). They also possessed mesenchymal stem cell property including osteoblastic (OB) differentiation, suggesting that Sca-1+PDGFRα- cells could be mesodermal progenitor cells. Interestingly, BM-derived artery-resident, clonal Sca-1+PDGFRα- cells maintained bipotency (OB/OC) but lost hematopoietic nature. In contrast, Sca-1+PDGFRα+ cells in BM and artery only showed unipotency (OB). When we overexpressed or knocked down PDGFRα, there was no alteration in OB or OC differentiation of Sca-1+PDGFRα- cells and no effect on OB differentiation of Sca-1+PDGFRα+ cells, indicating PDGFRα as a surface marker but not a functional player. In hyperlipidemic ApoE-KO mice compared with control, Sca-1+PDGFRα- cells were less mobilized from BM to peripheral circulation and less infiltrated into atherosclerotic plaque, whereas Sca-1+PDGFRα+ cells were not significantly affected. Multiplex cytokine assay of serum and artery revealed that IL-1β was significantly increased and IL-5 was markedly decreased in atherosclerotic mice. IL-1β decreased the migration of Sca-1+PDGFRα- cells by 5 folds compared with TNFα, and IL-5 increased the migration as much as TNFα. But the migration of Sca-1+PDGFRα+ cells was not altered. These data indicate that atherosclerosis-related humoral factors mainly regulated mesodermal progenitor cells’ dynamics. Conclusion: We demonstrate that Sca-1+PDGFRα- cell is a mesodermal progenitor cell that possesses both hematopoietic and mesenchymal potentials. In atherogenesis, the mobilization and infiltration of Sca-1+PDGFRα- progenitor cells were regulated by IL-1β and IL-5. These data provide a novel mechanism regarding the role of bipotent progenitor cells in atherosclerosis.

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Abstract 272: Chronic Hyperlipidemia Alters the Population of Endothelial Progenitor Cells in Bone Marrow and Peripheral Circulation via Both ROS-dependent and Independent Mechanisms

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.272 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Dylan Z Liu ◽

Yuqi Cui ◽

Jason Z Liu ◽

Lingjuan Liu ◽

Xin Li ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Ldl Receptor ◽

Peripheral Circulation ◽

Cell Number ◽

Ros Production ◽

Endothelial Progenitor ◽

Ros Formation

Background/Aims: Bone marrow (BM)-derived endothelial progenitor cells (EPCs) make significant contribution to the function and integrity of vasculature. The number of EPCs is significantly decreased in hyperlipidemic patients. Reactive oxygen species (ROS) and oxidative stress were considered an important mechanism for the development of atherosclerosis in hyperlipidemia. The present study was to determine the role of ROS production in the changes of EPC population in chronic hyperlipidemia. Methods and Results: EPC numbers and ROS formation in BM and blood were determined in wild-type (WT) male C57BL/6 mice and hyperlipidemic LDL receptor knockout (LDLR-/-) mice with high fat diet for 4 months. Intracellular blood, extracellular BM and blood ROS production was significantly increased in hyperlipidemic LDLR-/- mice that was effectively blocked with N-acetylcysteine treatment. Hyperlipidemia produced complex changes in EPC populations in BM and blood. The c-Kit+/CD31+ cell number was significantly decreased in BM and blood, and the numbers of CD34+/CD133+ cells and Sca-1+/Flk-1+ cells were significantly decreased in blood without change in BM, which were not affected by inhibition of ROS production. Interestingly, blood CD34+/Flk-1+ cell number was significantly increased in hyperlipidemic mice that was prevented when ROS formation was inhibited. Conclusions: Chronic hyperlipidemia produced significant and complex changes in EPC populations in both BM and circulation through both ROS-dependent and ROS-independent mechanisms in mice.

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Activation of heme oxygenase-1 by Ginkgo biloba extract differentially modulates endothelial and smooth muscle-like progenitor cells for vascular repair

Scientific Reports ◽

10.1038/s41598-019-53818-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Tao-Cheng Wu ◽

Jia-Shiong Chen ◽

Chao-Hung Wang ◽

Po-Hsun Huang ◽

Feng-Yen Lin ◽

...

Keyword(s):

Bone Marrow ◽

Smooth Muscle ◽

Progenitor Cells ◽

Heme Oxygenase ◽

Neointimal Hyperplasia ◽

Vascular Repair ◽

Vascular Progenitor Cells

AbstractVascular progenitors such as endothelial progenitor cells (EPCs) and smooth muscle-like progenitor cells (SMPCs) may play different roles in vascular repair. Ginkgo biloba extract (GBE) is an exogenous activator of heme oxygenase (HO)-1, which has been suggested to improve vascular repair; however, the detailed mechanisms have yet to be elucidated. This study aimed to investigate whether GBE can modulate different vascular progenitor cells by activating HO-1 for vascular repair. A bone marrow transplantation mouse model was used to evaluate the in vivo effects of GBE treatment on wire-injury induced neointimal hyperplasia, which is representative of impaired vascular repair. On day 14 of GBE treatment, the mice were subjected to wire injury of the femoral artery to identify vascular reendothelialization. Compared to the mice without treatment, neointimal hyperplasia was reduced in the mice that received GBE treatment for 28 days in a dose-dependent manner. Furthermore, GBE treatment increased bone marrow-derived EPCs, accelerated endothelial recovery, and reduced the number of SMPCs attached to vascular injury sites. The effects of GBE treatment on neointimal hyperplasia could be abolished by co-treatment with zinc protoporphyrin IX, an HO-1 inhibitor, suggesting the in vivo role of HO-1. In this in vitro study, treatment with GBE activated human early and late EPCs and suppressed SMPC migration. These effects were abolished by HO-1 siRNA and an HO-1 inhibitor. Furthermore, GBE induced the expression of HO-1 by activating PI3K/Akt/eNOS signaling in human late EPCs and via p38 pathways in SMPCs, suggesting that GBE can induce HO-1 in vitro through different molecular mechanisms in different vascular progenitor cells. Accordingly, GBE could activate early and late EPCs, suppress the migration of SMPCs, and improve in vivo vascular repair after mechanical injury by activating HO-1, suggesting the potential role of pharmacological HO-1 activators, such as GBE, for vascular protection in atherosclerotic diseases.

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HIF-1α Is Not Essential For The Establishment Of MLL-Leukaemic Stem Cells

Blood ◽

10.1182/blood.v122.21.3767.3767 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3767-3767

Author(s):

Deniz Gezer ◽

Amelie V Guitart ◽

Milica Vukovic ◽

Chithra Subramani ◽

Karen Dunn ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Myeloid Leukaemia ◽

Progenitor Cells ◽

Board Of Directors ◽

Advisory Committees ◽

Hypoxic Conditions ◽

Significant Difference

Abstract Haematopoietic stem cells (HSCs) reside in hypoxic niches in the bone marrow (BM) and sustain long-life haematopoiesis. HSCs are largely quiescent, self-renew, undergo apoptosis and generate progenitor cells, which differentiate to multiple blood lineages. The strict regulation of the balance between these fate decisions is essential for haematopoiesis and their dysregulation in HSCs and progenitor cells can result in leukaemic transformation. HSCs and leukemic stem cells (LSCs) are suggested to share the same niche and are in need to adapt to hypoxic conditions. Hypoxia-inducible-factor-1α (HIF-1α) is a key mediator of cellular responses to hypoxia and is important for the maintenance of HSC functions under stressful conditions. Furthermore, in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) HIF-1α is essential for LSC maintenance and ablation or knockdown of HIF-1α leads to exhaustion of established LSCs. The aim of this study was to investigate the requirement for HIF-1α in the generation of pre-LSCs and the establishment of LSCs. To investigate the role of HIF-1α in the generation of pre-LSCs we retrovirally transduced haematopoietic stem and progenitor cells (HSPCs) from either WT or HIF1-αfl/fl Vav-iCre with MLL-ENL retroviruses. Next we performed serial re-plating assays under normoxic and hypoxic conditions to generate pre-LSCs. Surprisingly, WT and HIF-1α deficient HSPCs generated comparable numbers of colonies in normoxia and hypoxia (Fig. 1a). In addition no significant difference was found in the immunophenotypic profile of colonies (Figure 1b). Furthermore, microscopic examination indicated that colonies of all genotypes were dense consistent with their transformed shape (Fig. 1c). WT and HIF-1α-deficient pre-LSCs cultured under normoxia and hypoxia had similar cloning efficiency, which is known to directly correlate with the numbers of LSCs in vivo (Fig. 2). These results indicate that HIF-1α is dispensable for the generation of pre-LSCs. To test the role of HIF-1α in establishment of LSCs from pre-LSCs we transplanted pre-LSCs into lethally irradiated mice together with support BM and monitored the mice for disease development. No significant difference was found in disease latency (Fig. 3a) or frequency of LSCs in peripheral blood, bone marrow or spleens (Fig. 3b) indicating that pre-LSCs lacking HIF-1α can efficiently generate LSCs that cause aggressive AML. In conclusion, we provide genetic evidence that HIF-1α is dispensable for the generation of pre-LSCs and the establishment of LSCs from pre-LSCs. These surprising findings, together with published results indicating that HIF-1α is essential for maintenance of LSCs, imply that HIF-1α has different roles at different stages of leukaemic transformation. Further studies are required to explain the distinct roles of HIF-1α in different stages of leukaemogenesis. Disclosures: Ratcliffe: RedOx: Founder Other. Holyoake:Novartis: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees.

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Further Evidence That HO-1 Regulates SDF-1 Expression in the Bone Marrow Microenvironment and That HO-1-Deficient Mice Show a Defect in the SDF-1–CXCR4 Retention Axis of Hematopoietic Stem/Progenitor Cells in Bone Marrow and Thus Are Easy Mobilizers - Studies in HO-1 Mutant Mice, Irradiation Chimeras, and the Effect of in Vivo Pharmacological Inhibition of HO-1

Blood ◽

10.1182/blood.v120.21.344.344 ◽

2012 ◽

Vol 120 (21) ◽

pp. 344-344

Author(s):

Marcin Wysoczynski ◽

Janina Ratajczak ◽

Gregg Rokosh ◽

Roberto Bolli ◽

Mariusz Z Ratajczak

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Crucial Role ◽

Conflicts Of Interest ◽

Wild Type ◽

Hematopoietic Stem ◽

Cell Counts ◽

Deficient Mice

Abstract Abstract 344 Background: Stromal derived factor-1 (SDF-1), which binds to the CXCR4 receptor expressed on the surface of hematopoietic stem/progenitor cells (HSPCs), plays an important role in the retention of HSPCs in BM niches. Heme oxygenase (HO-1) is a stress-responsive enzyme that catalyzes the degradation of heme and plays an important function in various physiological and pathophysiological states associated with cellular stress, such as ischemic/reperfusion injury, atherosclerosis, and cancer. Interestingly, it has also been reported that HO-1 regulates the expression of SDF-1 in myocardium (J Mol Cell Cardiol. 2008;45:44–55). Aim of study: Since SDF-1 plays a crucial role in retention and survival of HSPCs in BM, we become interested in whether HO-1 is expressed by BM stromal cells and whether deficiency of HO-1 affects normal hematopoiesis and retention of HSPCs in BM. Experimental approach: To address this issue, we employed several complementary strategies to investigate HO-1–/–, HO-1+/–, and wild type (wt) mouse littermates for i) the expression level of SDF-1 in BM, ii) the number of clonogenic progenitors from major hematopoietic lineages in BM, iii) peripheral blood (PB) cell counts, iv) the chemotactic responsiveness of HSPCs to an SDF-1 gradient as well as to other chemoattractants, including sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and extracellular nucleotiodes (ATP, UTP), iv) the adhesiveness of clonogenic progenitors to immobilized SDF-1 and stroma, v) the number of circulating HSPCs in PB, and vi) the degree of mobilization in response to granulocyte-colony stimulating factor (G-CSF) or AMD3100, assessed by enumerating the number of CD34–SKL cells and clonogeneic progenitors (CFU-GM) circulating in PB. We also exposed mice to the small HO-1 molecular inhibitor tin protoporphyrin IX (SnPP) and studied the effect of this treatment on G-CSF- or AMD3100-induced mobilization of HSPCs. Finally, to prove an environmental HSPC retention defect in HO-1-deficient mice, we created radiation chimeras, wild type mice transplanted with HO-1-deficient BM cells, and, vice versa, HO-1-deficient mice reconstituted with wild type BM cells. Results: Our data indicate that under normal, steady-state conditions, HO-1–/– and HO+/– mice have normal PB cell counts and numbers of circulating CFU-GM, while a lack of HO-1 leads to an increase in the number of erythroid (BFU-E) and megakaryocytic (CFU-GM) progenitors in BM. However, while BMMNCs from HO-1–/– have normal expression of the SDF-1-binding receptor, CXCR4, we observed that the mRNA level for SDF-1 in BM-derived fibroblasts was ∼4 times lower. This corresponded with the observation in vitro that HSPCs from HO-1–/– animals respond more robustly to an SDF-1 gradient, and HO-1–/– animals mobilized a higher number of CD34–SKL cells and CFU-GM progenitors into PB in response to G-CSF and AMD3100. Both G-CSF and AMD3100 mobilization were also significantly enhanced in normal wild type mice after in vivo administration of HO-1 inhibitor. Finally, mobilization studies in irradiation chimeras confirmed the crucial role of the microenvironmental SDF-1-based retention mechanism of HSPCs in BM niches. Conclusions: Our data demonstrate for the first time that HO-1 plays an important and underappreciated role in modulating the SDF-1 level in the BM microenvironment and thus plays a role in retention of HSPCs in BM niches. Furthermore, our recent data showing a mobilization effect by a small non-toxic molecular inhibitor of HO-1 (SnPP), suggest that blockage of HO-1 could be a promising strategy to facilitate mobilization of HSPCs. Further studies are also needed to evaluate the role of HO-1 in homing of HSPCs after transplantation to BM stem cell niches. Disclosures: No relevant conflicts of interest to declare.

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Anti-Obese Hormone Adiponectin Regulates Emergency Hematopoiesis and Antibacterial Response Through Downregulation Of Socs3 In Hematopoietic Progenitor Cells

Blood ◽

10.1182/blood.v122.21.221.221 ◽

2013 ◽

Vol 122 (21) ◽

pp. 221-221

Author(s):

Yosuke Masamoto ◽

Shunya Arai ◽

Tomohiko Sato ◽

Akihide Yoshimi ◽

Iseki Takamoto ◽

...

Keyword(s):

Bone Marrow ◽

Steady State ◽

Listeria Monocytogenes ◽

Progenitor Cells ◽

Myeloid Cells ◽

Bacterial Clearance ◽

High Fat ◽

Hematopoietic Response

Abstract Anti-obesity countermeasures attract rising attention because obesity induces multiple health complications such as metabolic syndrome, predisposition to cancer, heart diseases, stroke, infections, etc. One of the key features of obesity is decreased adiponectin, a critical anti-diabetic hormone secreted by adipocytes to modulate a number of metabolic processes including glucose regulation and fatty acid oxidation. Hematopoietic stem and progenitor cells (HSPCs) expand in size against infections, especially bacterial infections through immune response. In spite of the emerging clinical and basic reports of adiponectin, precise mechanisms of adiponectin for infectious control, especially for hematopoietic response, are largely unknown. As adipocytes are one of the major cellular components of bone marrow microenvironment which is critical for the proliferation and maintenance of hematopoietic cells, we hypothesized that obesity-related dysfunction of adipocytes in bone marrow might cause compromised hematopoietic response leading to increased susceptibility to infection. With the use of high-fat-fed mice, a well-known obesity model, we revealed that obesity had no apparent impact on steady-state hematopoiesis except for a slightly hypercellular bone marrow. Upon G-CSF administration to mimic harmful infection in vivo, high-fat-fed mice showed impaired expansion of HSPCs and myeloid cells in the bone marrow, along with the reduction of myeloid cells in peripheral circulation, i.e. diminished “emergency hematopoiesis”. In a Listeria monocytogenes peritonitis model, high-fat-fed mice also confirmed reduced expansion of HSPCs and myeloid cells in the bone marrow, attenuated leukocytosis and infiltration of leucocytes into the peritoneal cavity, resulting in a delayed bacterial clearance in vivo. Interestingly, the concentration of adiponectin was significantly reduced in the bone marrow of high-fat-fed mice compared to control mice, possibly reflecting a high relevance of adiponectin to hematopoietic response. To assess the exact role of adiponectin in emergency hematopoiesis, we utilized adiponectin-deficient (adipo-/-) mice. Genetic ablation of adiponectin caused no change in steady-state hematopoiesis, whereas G-CSF administration in adipo-/- mice showed attenuated HSPC expansion in the bone marrow, consistent with a series of high-fat-fed mice. Reciprocal transplants with adipo+/+ and adipo -/- mice demonstrated that adiponectin from bone marrow environment of the recipient, not from the donor hematopoietic cells, is essential for the efficient expansion of HSPCs in response to G-CSF. Furthermore, adipo-/- mice showed reduced hematopoietic response against Listeria monocytogenes infection, similar to the phenotype of high-fat-fed mice. Importantly, we confirmed that intravenous administration of recombinant adiponectin restored the responsiveness to G-CSF and the bacterial clearance on Listeria infection, both in adipo-/- and high-fat-fed mice, which affirm the importance of adiponectin treatment against infection. In HSPCs and myeloid cells from adipo-/- mice or high-fat-fed mice, phosphorylation of Stat3, a key component for emergency hematopoiesis, was suppressed, underscoring a role of adiponectin in emergency hematopoiesis at the molecular level. We revealed that those cells aberrantly expressed Socs3, a major inhibitory factor of Stat3, and that was reverted by intravenous administration of adiponectin, indicating that adiponectin potentiated G-CSF-dependent Stat3 phosphorylation in vitro and in vivo. These data revealed that adiponectin regulates hematopoietic response against infections, highlighting adiponectin as a legitimate target against infectious diseases in obese patients. From our findings breakthrough drugs to increase adiponectin are highly warranted. Disclosures: No relevant conflicts of interest to declare.

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Bone Marrow Niches for Skeletal Progenitor Cells and their Inhabitants in Health and Disease

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190123161447 ◽

2019 ◽

Vol 14 (4) ◽

pp. 305-319 ◽

Cited By ~ 4

Author(s):

Marietta Herrmann ◽

Franz Jakob

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Progenitor Cell ◽

Adult Stem Cells ◽

Current Knowledge ◽

Cell Populations ◽

Surface Markers ◽

Bone Marrow Niches

The bone marrow hosts skeletal progenitor cells which have most widely been referred to as Mesenchymal Stem or Stromal Cells (MSCs), a heterogeneous population of adult stem cells possessing the potential for self-renewal and multilineage differentiation. A consensus agreement on minimal criteria has been suggested to define MSCs in vitro, including adhesion to plastic, expression of typical surface markers and the ability to differentiate towards the adipogenic, osteogenic and chondrogenic lineages but they are critically discussed since the differentiation capability of cells could not always be confirmed by stringent assays in vivo. However, these in vitro characteristics have led to the notion that progenitor cell populations, similar to MSCs in bone marrow, reside in various tissues. MSCs are in the focus of numerous (pre)clinical studies on tissue regeneration and repair.Recent advances in terms of genetic animal models enabled a couple of studies targeting skeletal progenitor cells in vivo. Accordingly, different skeletal progenitor cell populations could be identified by the expression of surface markers including nestin and leptin receptor. While there are still issues with the identity of, and the overlap between different cell populations, these studies suggested that specific microenvironments, referred to as niches, host and maintain skeletal progenitor cells in the bone marrow. Dynamic mutual interactions through biological and physical cues between niche constituting cells and niche inhabitants control dormancy, symmetric and asymmetric cell division and lineage commitment. Niche constituting cells, inhabitant cells and their extracellular matrix are subject to influences of aging and disease e.g. via cellular modulators. Protective niches can be hijacked and abused by metastasizing tumor cells, and may even be adapted via mutual education. Here, we summarize the current knowledge on bone marrow skeletal progenitor cell niches in physiology and pathophysiology. We discuss the plasticity and dynamics of bone marrow niches as well as future perspectives of targeting niches for therapeutic strategies.

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