25 results found
Singh A, Veeriah V, Xi P, et al., 2019, Angiocrine signals regulate quiescence and therapy resistance in bone metastasis., JCI Insight, Vol: 4, ISSN: 2379-3708
Bone provides supportive microenvironments for hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) and is a frequent site of metastasis. While incidences of bone metastases increase with age, the properties of the bone marrow microenvironment that regulate dormancy and reactivation of disseminated tumor cells (DTCs) remain poorly understood. Here, we elucidate the age-associated changes in the bone secretome that trigger proliferation of HSCs, MSCs, and DTCs in the aging bone marrow microenvironment. Remarkably, a bone-specific mechanism involving expansion of pericytes and induction of quiescence-promoting secretome rendered this proliferative microenvironment resistant to radiation and chemotherapy. This bone-specific expansion of pericytes was triggered by an increase in PDGF signaling via remodeling of specialized type H blood vessels in response to therapy. The decline in bone marrow pericytes upon aging provides an explanation for loss of quiescence and expansion of cancer cells in the aged bone marrow microenvironment. Manipulation of blood flow - specifically, reduced blood flow - inhibited pericyte expansion, regulated endothelial PDGF-B expression, and rendered bone metastatic cancer cells susceptible to radiation and chemotherapy. Thus, our study provides a framework to recognize bone marrow vascular niches in age-associated increases in metastasis and to target angiocrine signals in therapeutic strategies to manage bone metastasis.
Romeo SG, Alawi KM, Rodrigues J, et al., 2019, Endothelial proteolytic activity and interaction with non-resorbing osteoclasts mediate bone elongation, Nature Cell Biology, Vol: 21, Pages: 430-441, ISSN: 1465-7392
Growth plate cartilage contributes to the generation of a large variety of shapes and sizes of skeletal elements in the mammalian system. The removal of cartilage and how this process regulates bone shape are not well understood. Here we identify a non-bone-resorbing osteoclast subtype termed vessel-associated osteoclast (VAO). Endothelial cells at the bone/cartilage interface support VAOs through a RANKL–RANK signalling mechanism. In contrast to classical bone-associated osteoclasts, VAOs are dispensable for cartilage resorption and regulate anastomoses of type H vessels. Remarkably, proteinases including matrix metalloproteinase-9 (Mmp9) released from endothelial cells, not osteoclasts, are essential for resorbing cartilage to lead directional bone growth. Importantly, disrupting the orientation of angiogenic blood vessels by misdirecting them results in contorted bone shape. This study identifies proteolytic functions of endothelial cells in cartilage and provides a framework to explore tissue-lytic features of blood vessels in fracture healing, arthritis and cancer.
Lo Celso C, Hawkins ED, Akinduro O, et al., 2017, Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML, Cell Stem Cell, Vol: 22, Pages: 64-77.e6, ISSN: 1875-9777
Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand. Remodeled endosteal regions have reduced capacity to support non-leukemic HSCs, correlating with loss of normal hematopoiesis. Preserving endosteal endothelium with the small molecule deferoxamine or a genetic approach rescues HSCs loss, promotes chemotherapeutic efficacy, and enhances survival. These findings suggest that preventing degradation of the endosteal vasculature may improve current paradigms for treating AML.
Ramasamy SK, 2017, Structure and functions of blood vessels and vascular niches in bone, Stem Cells International, Vol: 2017, ISSN: 1687-9678
Bone provides nurturing microenvironments for an array of cell types that coordinate important physiological functions of the skeleton, such as energy metabolism, mineral homeostasis, osteogenesis, and haematopoiesis. Endothelial cells form an intricate network of blood vessels that organises and sustains various microenvironments in bone. The recent identification of heterogeneity in the bone vasculature supports the existence of multiple vascular niches within the bone marrow compartment. A unique combination of cells and factors defining a particular microenvironment, supply regulatory signals to mediate a specific function. This review discusses recent developments in our understanding of vascular niches in bone that play a critical role in regulating the behaviour of multipotent haematopoietic and mesenchymal stem cells during development and homeostasis.
Gamrekelashvili J, Giagnorio R, Jussofie J, et al., 2017, Corrigendum: Regulation of monocyte cell fate by blood vessels mediated by Notch signalling, Nature Communications, Vol: 8, ISSN: 2041-1723
Bixel MG, Kusumbe AP, Ramasamy SK, et al., 2017, Flow dynamics and HSPC homing in bone marrow microvessels., Cell Reports, Vol: 18, Pages: 1804-1816, ISSN: 2211-1247
Measurements of flow velocities at the level of individual arterial vessels and sinusoidal capillaries are crucial for understanding the dynamics of hematopoietic stem and progenitor cell homing in the bone marrow vasculature. We have developed two complementary intravital two-photon imaging approaches to determine blood flow dynamics and velocities in multiple vessel segments by capturing the motion of red blood cells. High-resolution spatiotemporal measurements through a cranial window to determine short-time dynamics of flowing blood cells and repetitive centerline scans were used to obtain a detailed flow-profile map with hemodynamic parameters. In addition, we observed the homing of individual hematopoietic stem and progenitor cells and obtained detailed information on their homing behavior. With our imaging setup, we determined flow patterns at cellular resolution, blood flow velocities and wall shear stress in small arterial vessels and highly branched sinusoidal capillaries, and the cellular dynamics of hematopoietic stem and progenitor cell homing.
Allocca G, Kusumbe AP, Ramasamy SK, et al., 2016, Confocal/two-photon microscopy in studying colonisation of cancer cells in bone using xenograft mouse models, BoneKEy Reports, Vol: 5, ISSN: 2047-6396
Confocal and two-photon microscopy has been widely used in bone research to not only produce high quality, three-dimensional images but also to provide valuable structural and quantitative information. In this article, we describe step-by-step protocols for confocal and two-photon microscopy to investigate earlier cellular events during colonisation of cancer cells in bone using xenograft mouse models. This includes confocal/two-photon microscopy imaging of paraformaldehyde fixed thick bone sections and frozen bone samples.
Ramasamy SK, Kusumbe AP, Schiller M, et al., 2016, Blood flow controls bone vascular function and osteogenesis, Nature Communications, Vol: 7, ISSN: 2041-1723
While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood. Here we show that the long bone vasculature generates a peculiar flow pattern, which is important for proper angiogenesis. Intravital imaging reveals that vessel growth in murine long bone involves the extension and anastomotic fusion of endothelial buds. Impaired blood flow leads to defective angiogenesis and osteogenesis, and downregulation of Notch signalling in endothelial cells. In aged mice, skeletal blood flow and endothelial Notch activity are also reduced leading to decreased angiogenesis and osteogenesis, which is reverted by genetic reactivation of Notch. Blood flow and angiogenesis in aged mice are also enhanced on administration of bisphosphonate, a class of drugs frequently used for the treatment of osteoporosis. We propose that blood flow and endothelial Notch signalling are key factors controlling ageing processes in the skeletal system.
Gur-Cohen S, Avemaria F, Kollet O, et al., 2016, EPCR Guides Hematopoietic Stem Cells Homing to the Bone Marrow Independently of Niche Clearance, 58th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Ramasamy SK, Kusumbe AP, Adams RH, 2016, Regulation of angiogenesis in long bone, Joint Autumn Meeting of the British-Society-for-Matrix-Biology (BSMB) and Bone-Research-Society (BRS), Publisher: WILEY-BLACKWELL, Pages: A8-A9, ISSN: 0959-9673
Gamrekelashvili J, Giagnorio R, Jussofie J, et al., 2016, Regulation of monocyte cell fate by blood vessels mediated by Notch signalling, Nature Communications, Vol: 7, ISSN: 2041-1723
A population of monocytes, known as Ly6C(lo) monocytes, patrol blood vessels by crawling along the vascular endothelium. Here we show that endothelial cells control their origin through Notch signalling. Using combinations of conditional genetic deletion strategies and cell-fate tracking experiments we show that Notch2 regulates conversion of Ly6C(hi) monocytes into Ly6C(lo) monocytes in vivo and in vitro, thereby regulating monocyte cell fate under steady-state conditions. This process is controlled by Notch ligand delta-like 1 (Dll1) expressed by a population of endothelial cells that constitute distinct vascular niches in the bone marrow and spleen in vivo, while culture on recombinant DLL1 induces monocyte conversion in vitro. Thus, blood vessels regulate monocyte conversion, a form of committed myeloid cell fate regulation.
Ramasamy SK, Kusumbe AP, Itkin T, et al., 2016, Regulation of Hematopoiesis and Osteogenesis by Blood Vessel-Derived Signals, ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, VOL 32, Vol: 32, Pages: 649-675, ISSN: 1081-0706
Itkin T, Gur-Cohen S, Spencer JA, et al., 2016, Distinct bone marrow blood vessels differentially regulate haematopoiesis, Nature, Vol: 532, Pages: 323-328
Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols.
Kusumbe AP, Ramasamy SK, Itkin T, et al., 2016, Age-dependent modulation of vascular niches for haematopoietic stem cells, Nature, Vol: 532, Pages: 380-384, ISSN: 0028-0836
Blood vessels define local microenvironments in the skeletal system, play crucial roles in osteogenesis and provide niches for haematopoietic stem cells. The properties of niche-forming vessels and their changes in the ageing organism remain incompletely understood. Here we show that Notch signalling in endothelial cells leads to the expansion of haematopoietic stem cell niches in bone, which involves increases in CD31-positive capillaries and platelet-derived growth factor receptor-β (PDGFRβ)-positive perivascular cells, arteriole formation and elevated levels of cellular stem cell factor. Although endothelial hypoxia-inducible factor signalling promotes some of these changes, it fails to enhance vascular niche function because of a lack of arterialization and expansion of PDGFRβ-positive cells. In ageing mice, niche-forming vessels in the skeletal system are strongly reduced but can be restored by activation of endothelial Notch signalling. These findings indicate that vascular niches for haematopoietic stem cells are part of complex, age-dependent microenvironments involving multiple cell populations and vessel subtypes.
Ramasamy SK, Kusumbe AP, Adams RH, 2016, REGULATION OF ENDOTHELIAL NOTCH SIGNALLING IN AGE-RELATED BONE LOSS, WCO-IOF-ESCEO World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, Publisher: SPRINGER LONDON LTD, Pages: S347-S347, ISSN: 0937-941X
Kusumbe AP, Ramasamy SK, Adams RH, 2016, CELLULAR COUPLING OF ANGIOGENESIS AND OSTEOGENESIS IN BONE, WCO-IOF-ESCEO World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, Publisher: SPRINGER LONDON LTD, Pages: S259-S260, ISSN: 0937-941X
Itkin T, Cohen SG, Spencer JA, et al., 2015, Distinct Bone Marrow Blood Vessels Differentially Regulate Normal and Malignant Hematopoietic Stem and Progenitor Cells, 57th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Kusumbe AP, Ramasamy SK, Starsichova A, et al., 2015, Sample preparation for high-resolution 3D confocal imaging of mouse skeletal tissue, NATURE PROTOCOLS, Vol: 10, Pages: 1904-1914, ISSN: 1754-2189
Ramasamy SK, Kusumbe AP, Adams RH, 2015, Regulation of tissue morphogenesis by endothelial cell-derived signals, TRENDS IN CELL BIOLOGY, Vol: 25, Pages: 148-157, ISSN: 0962-8924
Kusumbe AP, Ramasamy SK, Adams RH, 2014, Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone (vol 507, pg 323, 2014), NATURE, Vol: 513, ISSN: 0028-0836
Ramasamy SK, Kusumbe AP, Adams RH, 2014, Endothelial Notch activity promotes angiogenesis and osteogenesis in bone, FEBS EMBO 2014 Conference, Publisher: WILEY-BLACKWELL, Pages: 323-323, ISSN: 1742-464X
Kusumbe AP, Ramasamy SK, Adams RH, 2014, Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone, NATURE, Vol: 507, Pages: 323-+, ISSN: 0028-0836
Ramasamy SK, Kusumbe AP, Wang L, et al., 2014, Endothelial Notch activity promotes angiogenesis and osteogenesis in bone, NATURE, Vol: 507, Pages: 376-+, ISSN: 0028-0836
Ramasamy SK, Lenka N, 2010, Notch Exhibits Ligand Bias and Maneuvers Stage-Specific Steering of Neural Differentiation in Embryonic Stem Cells, MOLECULAR AND CELLULAR BIOLOGY, Vol: 30, Pages: 1946-1957, ISSN: 0270-7306
Lenka N, Ramasamy SK, 2007, Neural Induction from ES Cells Portrays Default Commitment but Instructive Maturation, PLOS ONE, Vol: 2, ISSN: 1932-6203
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