The Experts below are selected from a list of 822 Experts worldwide ranked by ideXlab platform
Sean J. Morrison - One of the best experts on this subject based on the ideXlab platform.
-
the bone marrow niche for haematopoietic stem cells
Nature, 2014Co-Authors: Sean J. Morrison, David T ScaddenAbstract:Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the Endosteum and functional heterogeneity among perivascular microenvironments.
-
uncertainty in the niches that maintain haematopoietic stem cells
Nature Reviews Immunology, 2008Co-Authors: Mark J. Kiel, Sean J. MorrisonAbstract:Haematopoietic stem cell (HSC) niches are specialized microenvironments that contain stem cells and regulate their maintenance. Cells at the interface of bone and the bone marrow (the Endosteum) contribute to the creation of HSC niches. It remains uncertain whether this interface itself is a niche, or whether endosteal cells secrete factors that diffuse to nearby niches. Vascular and/or perivascular cells may also create niches as many HSCs are observed around sinusoidal blood vessels, and perivascular cells secrete factors that regulate HSC maintenance. Do endosteal and perivascular cells create distinct niches, or do they contribute to a common niche? We discuss a range of niche models consistent with recent evidence.
-
SLAM Family Receptors Distinguish Hematopoietic Stem and Progenitor Cells and Reveal Endothelial Niches for Stem Cells
Cell, 2005Co-Authors: Mark J. Kiel, Omer H Yilmaz, Cox Terhorst, Toshihide Iwashita, Sean J. MorrisonAbstract:Summary To improve our ability to identify hematopoietic stem cells (HSCs) and their localization in vivo, we compared the gene expression profiles of highly purified HSCs and non-self-renewing multipotent hematopoietic progenitors (MPPs). Cell surface receptors of the SLAM family, including CD150, CD244, and CD48, were differentially expressed among functionally distinct progenitors. HSCs were highly purified as CD150 + CD244 − CD48 − cells while MPPs were CD244 + CD150 − CD48 − and most restricted progenitors were CD48 + CD244 + CD150 − . The primitiveness of hematopoietic progenitors could thus be predicted based on the combination of SLAM family members they expressed. This is the first family of receptors whose combinatorial expression precisely distinguishes stem and progenitor cells. The ability to purify HSCs based on a simple combination of SLAM receptors allowed us to identify HSCs in tissue sections. Many HSCs were associated with sinusoidal endothelium in spleen and bone marrow, though some HSCs were associated with Endosteum. HSCs thus occupy multiple niches, including sinusoidal endothelium in diverse tissues.
Wesley E Bolch - One of the best experts on this subject based on the ideXlab platform.
-
Absorbed Fractions for -Particles in Tissues of Trabecular Bone: Considerations of Marrow Cellularity Within the ICRP Reference Male
2015Co-Authors: Christopher J. Watchman, W. Jokisch, Phd Phillip, W. Patton, Phd Didier, A. Rajon, George Sgouros, Wesley E BolchAbstract:-Particles are of current interest in radionuclide therapy due to their short range and high rates of energy transfer to target tissues. Published values of -particle absorbed fraction in the skeletal tissues, as needed for patient-specific dosimetry under the MIRD schema, do not generally account for its vari-ation with particle energy or skeletal site. Furthermore, varia-tions in -particle absorbed fraction with marrow cellularity have yet to be fully considered. Methods: In this study, a 3-dimensional (3D) chord-based radiation transport model (or 3D-CBIST) is pre-sented, which combines (a) chord-based techniques for tracking -particles across bone trabeculae, Endosteum, and marrow cav-ities and (b) a spatial model of the marrow tissues that explicitly considers the presence of marrow adipocytes. Chord-length dis-tributions are taken from a 44-y male subject (ICRP [International Commission on Radiological Protection] Reference Male) and ar
-
SPECIAL CONTRIBUTION A Three-Dimensional Transport Model for Determining Absorbed Fractions of Energy for Electrons Within Trabecular Bone
2015Co-Authors: Lionel G. Bouchet, Derek W. Jokisch, Wesley E BolchAbstract:Bone marrow is generally the dose-limiting organ of concern in radioimmunotherapy and in radionuclide palliation of bone pain. However, skeletal dosimetry is complicated by the intricate nature of its microstructure, which can vary greatly throughout skeletal regions. In this article, a new three-dimensional electron transport model for trabecular bone is introduced, based on Monte Carlo transport and on bone microstructure information for several trabecular bone sites. Methods: Marrow cavity and trabecular chord length distributions originally published by Spiers et al. were randomly sampled to create alternating regions of bone, Endosteum and marrow during the three-dimensional transport of single electrons. For the marrow spaces, explicit consideration of the site-specific elemental composi tion was made in the transport calculations based on the percentage of active and inactive marrow in each region. The electron transport was performed with the EGS4 electron transport code and th
-
su gg i 64 microct based methods of assessing imaging dose to active marrow and Endosteum in ct fluoroscopy and nuclear medicine
Medical Physics, 2010Co-Authors: Wesley E Bolch, C Lee, Perry Johnson, Kwang Pyo KimAbstract:Purpose: To present newly developed microCT‐based methods for assessing radiation dose to radiosensitive tissues of the skeleton within computational patient phantoms for CT,fluoroscopy, and nuclear medicine imaging.Methods and Materials: In this study, 13 skeletal sites were harvested from a 40‐year male and a 45‐year female cadaver from which 32 samples of trabecular spongiosa were cored from each and imaged under microCT. These images were thresholded and coupled to voxelized models of skeletal sites taken from the UF adult hybrid phantoms. EGSnrc‐based Paired ImageRadiationTransport was then performed for a series of monogenetic electrons localized in various spongiosa and cortical source tissues. The resultant electron absorbed fractions were used to assess (1) radionuclide S values for nuclear medicinedosimetry, and (2) bone‐specific fluence‐to‐dose response functions for CT and fluoroscopic x‐ray dosimetry.Results: Radionuclide S values presented in this study uniquely account for the trabecular microstructure of adult bone, account for the finite size and shape of trabecular spongiosa, and allow for electron cross‐fire from particle emissions within the cortical regions of mineral bone. For assessment of bone marrow and Endosteum dose during CTimaging and fluoroscopic procedures, a detailed library of photon fluence‐to‐dose response functions is presented for assessing both regional and skeletal average dose to active marrow and Endosteum. Conclusions: Calculations of secondary electrontransport in the microstructure of trabecular spongiosa of the adult skeleton reveal an enhancement of dose due to secondary electron disequilibrium for x‐rays entering the skeleton at energies below 200 keV. Percent excess dose to active marrow over that predicted under the kerma approximation range from 1–5% in bones such as the pelvis to a high of 25% in the cranium. Percent excess dose to the skeletal Endosteum can approach 100% in some bone sites over that predicted by the kerma approximation.
-
an assessment of bone marrow and bone Endosteum dosimetry methods for photon sources
Physics in Medicine and Biology, 2006Co-Authors: C Lee, Amish P Shah, Wesley E BolchAbstract:The rather complex and microscopic histological structure of the skeletal system generally limits one's ability to accurately model this tissue during dosimetric evaluations. Consequently, various assumptions must be made to evaluate the absorbed dose from external and internal photons to the radiosensitive tissues of the red (or haematopoietically active) bone marrow and the osteogenic tissues of the skeletal Endosteum. These various methods for photon skeletal dosimetry have not been inter-compared, partly due to the lack of a realistic reference model that can provide a high-resolution three-dimensional geometry for secondary electron particle transport. In the present study, the paired-image radiation transport (PIRT) model developed by Shah et al (2005 J. Nucl. Med. 45 344) was utilized to evaluate the absorbed dose per incident photon fluence to these skeletal regions from idealized parallel beams of monoenergetic photons. The PIRT model results were then used as a local reference against which absorbed doses via other methods were compared. For red bone marrow dosimetry, four approximate techniques were considered: (1) the dose response function method (DRF method) presented in ORNL/TM-8381, (2) the mass-energy absorption coefficient ratio method (two-parameter MEAC method), (3) the MEAC method with the additional use of energy-dependent dose enhancement factors from King and Spiers (1985 Br. J. Radiol. 58 345) (three-parameter MEAC method), and (4) the three-parameter MEAC method applied at the voxel level through the use image-specific CT numbers (CTN method). For the bone Endosteum (i.e., bone surfaces), two approximate techniques were compared: (1) the DRF method for bone surfaces and (2) the homogeneous bone approximation (HBA) method. In each case, the local reference standard was assumed to be that of the PIRT model. Four different ex vivo bone specimens with distinctively different internal structures were used in the study: the cranium, the lumbar vertebra, the os coxae and the left middle rib, each excised from a 66 year male cadaver (body mass index, 22.7 kg m(-2)). High-resolution CT images of these skeletal sites were used to construct computational voxel models for Monte Carlo radiation transport. Study results indicated that skeletal sites with thick cortical regions and thick trabeculae such as in the cranium provide considerable beam attenuation at low photon energies, which is not properly accounted for in methods based on a homogeneous skeletal tissue structure (DRF, MEAC, HBA). For bone marrow dose assessment, the CTN method showed the best agreement with PIRT model results over a broad range of photon energies, while the HBA method showed better agreement with the PIRT model in assessing bone Endosteum dose at energies above 100 keV. Bone surface doses were better approximately by the DRF method at energies below 50 keV. Considerable secondary electron escape at photon energies over 1-3 MeV were accounted for in RBM dose assessment only in the PIRT model, as the other methods presume either an infinite expanse of spongiosa (DRF) or the existence of charge-particle equilibrium (MEAC, CTN).
-
tu e i 611 04 bone marrow and bone Endosteum dosimetry methods comparison for external photons
Medical Physics, 2005Co-Authors: C Lee, Wesley E BolchAbstract:Purpose: To compare and verify different bone Endosteum and bone marrow photondosimetry methods through the use of a high‐resolution micro CT‐based radiation transport model. Method and Materials: Two different Monte Carlodosimetry algorithms for bone Endosteum and bone marrow were compared to a high‐resolution microCT image‐based radiation transport model developed in our laboratory. Bone marrow dosimetry methods are (1) the dose response function method by Eckerman (DRF), and (2) the mass energy absorption coefficient ratio method (MEAC). Bone Endosteum dosimetry methods include (1) DRF method and (2) homogeneous bone dose approximation (HGB). Each method was compared to results obtained from the microCT‐based paired‐image radiation transport (PIRT) model. Two ex‐vivo bone samples of a 66‐year male (lumbar vertebrae and cranium) were chosen for the comparison because of their distinctively different microstructures. Simple mono‐energetic parallel photon beams were simulated from 0.01 to 4.0 MeV. Results: For the bone marrow dose, the DRF method shows good agreement with PIRT result in the lumbar vertebra, but showed over estimates of bone marrow dose in the cranium, while the MEAC method shows good agreement with PIRT in both bone sites. For the bone Endosteum dose, the DRF method shows closer results to the PIRT model at lower energies, but shows significant over‐ estimates of Endosteum dose in higher photon energies. This can be explained by the fact the Eckerman model assumes that secondary electrons are followed through an infinite expanse of trabecular spongiosa, with no loss of energy to the bone cortex at high energy. Conclusion: For the bone marrow dose assessment, the MEAC method seems to be the best choice among the methods considered, while for the bone Endosteum dose, the HGB method shows better agreement with PIRT than is seen with the DRF method, especially at higher photon energies.
Julie Nigro - One of the best experts on this subject based on the ideXlab platform.
-
the effect of bovine Endosteum derived particles on the proliferation of human mesenchymal stem cells
Biomaterials, 2010Co-Authors: Susan K. Nilsson, David N. Haylock, Julie Nigro, Jacinta F White, J A Ramshaw, Jerome A WerkmeisterAbstract:There is a large biomanufacturing and clinical need for cost-effective and simple techniques to expand mesenchymal stem cells whilst retaining their multipotency. Endosteum-derived particles were prepared, characterised and examined as a biomaterial to facilitate the in vitro expansion of human mesenchymal stem cells. Bovine Endosteum-derived particles are composed of chondroitin sulphate glycosaminoglycans with 4- and 6-sulphation and N-sulphated heparan sulphate glycosaminoglycans. The particles were positive for perlecan, laminin and fibronectin by immunohistochemistry and alpha-mannose, alpha-glucose, terminal N-acetyl-alpha-D-glucosamine, N-acetyl-alpha-galactosamine and alpha-fucose, using lectin binding. Human mesenchymal stem cells showed greater than 96% attachment to the particles after one day in spinner culture. After 7 days, the stem cells on decalcified particles were viable and had a 5-fold higher growth than the stem cells grown on Cytodex-2 beads. Significantly more stem cells were recovered from decalcified particles compared with mineralised particles (P < 0.05). Differentiation to chondrogenic, osteogenic and adipogenic lineages was maintained after culturing stem cells on the demineralised particles. We conclude that bovine Endosteum-derived particles can be extracted from bone marrow to retain sulphated proteoglycans and glycosylated proteins. These particles are a suitable biomaterial for supporting the growth and retaining the multipotency of human mesenchymal stem cells.
David T Scadden - One of the best experts on this subject based on the ideXlab platform.
-
the microanatomy of the leukemic stem cell niche in murine chronic myelogenous leukemia
Blood, 2014Co-Authors: Melanie Meister, David T Scadden, Joel A Spencer, Cher Zhao, Lymperi Stefania, Francesca Ferraro, Cristina Lo Celso, Richard A Van Etten, Charles P Lin, Daniela S KrauseAbstract:Objectives and background: Constituents of the bone marrow microenvironment (BMM) influence the proliferation, differentiation and location of hematopoietic stem and progenitor cells (HSPC). Dependent on their maturation stage, different subsets of HSPC are localized at distinct sites in the BMM. This location depends on HSPC-intrinsic, as well as HSPC-extrinsic factors. The BMM protects leukemic stem cells (LSC) from treatment with tyrosine kinase inhibitors or chemotherapy. We, therefore, investigated the microanantomy of the LSC niche hypothesizing that it may differ from the normal HSPC niche. Methods: We used a combination of confocal and 2-photon intravital microscopy (IVM) of the murine calvarium and well-described retroviral models of BCR-ABL1 + chronic myelogenous leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). Results: We show here that BCR-ABL1 + Lin – c-Kit + Sca-1 + (LKS) CD150 + CD48 – (LKS SLAM) cells, which harbor the LSC fraction in the CML model, homed to locations further away from the Endosteum than their normal counterparts. Prior in-vitro treatment of BCR-ABL1 + LKS with imatinib mesylate, considered standard of care in CML, reversed this phenotype and the cells were found closer to the Endosteum. Native BCR-ABL1, as well as the imatinib-resistant BCR-ABL1 point mutants BCR-ABL1 Y253F , BCR-ABL1 E255K , BCR-ABL1 T315I and BCR-ABL1 M351T had similar intrinsic catalytic activity, but the BCR-ABL1 Y253F , BCR-ABL1 E255K , and BCR-ABL1 T315I mutants increased the IL-3-independent proliferative capacity of 32D cells relative to native BCR-ABL1 . BCR-ABL1 Y253F and BCR-ABL1 M351T caused increased transformation of primary BM B-lymphoid progenitors in vitro and led to accelerated induction of B-ALL in mice. In the CML model, BCR-ABL1 Y253F and BCR-ABL1 T315I induced myeloproliferative neoplasia with shortened survival and features of accelerated phase disease compared to native BCR-ABL1, whereas BCR-ABL1 T315I LKS cells homed closer to osteoblastic cells than LKS cells expressing native BCR-ABL1 . Sequential in vivo tracking of leukemic progenitor growth by IVM showed a similar nadir in the number of cells per leukemic cell ‘nest’ 11 days after irradiation and IV transplantation in recipients of DsRed + BCR-ABL1 + or empty vector control-transduced bone marrow. However, between days 18-25 after transplantation there was a significant increase in the number of cells per leukemic cell ‘nest’ compared to the empty vector control group. Sequential immunohistochemistry and TUNEL assays of leukemic bone sections in imatinib- or vehicle-treated recipient mice with CML showed that initial BCR-ABL1 + growth tends to occur at locations further away from the Endosteum, whereas erythroid islands were found closer to the Endosteum and trabeculae. Apoptosis in response to imatinib appeared most prominent in the metaphysis. Lastly, we could demonstrate by IVM in the CML model that treatment of mice with a combination of imatinib plus granulocyte colony-stimulating factor led to ‘emptying’ of the LSC niche and superior eradication of BCR-ABL1 + leukemic cells compared to treatment with imatinib alone. Conclusions: In summary, these data suggest that the microanatomy of the LSC niche in CML differs from the normal hematopoietic niche. BCR-ABL1 mutation status may affect the positioning of CML LSC in the microenvironment, and location in the niche may be altered pharmacologically, suggesting that niche location may influence clinical outcome. Disclosures Krause: Glycomimetics. Inc.: Research Funding.
-
the bone marrow niche for haematopoietic stem cells
Nature, 2014Co-Authors: Sean J. Morrison, David T ScaddenAbstract:Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the Endosteum and functional heterogeneity among perivascular microenvironments.
Tsvee Lapidot - One of the best experts on this subject based on the ideXlab platform.
-
The Endosteum
2015Co-Authors: Human Leukemi, Tsvee Lapidot, Polina GoichbergAbstract:Only a subset of hierarchically arranged, primitive humanAMLprogenitor cells can initiate the disease in transplanted immune-deficientmice. Apublication inNatureBiotechnologyby Ishikawaet al. (2007) describes a new animalmodel to study chemotherapy-resistant, quiescent humanAMLCD34+CD38 stem cells, which are retained in the Endosteum region. Characterization of the bone marrow (BM) microenvironment supporting growth and survival of normal and malignant hematopoietic stem cells presents a major challenge. Early ob-servations revealed that bone frac-tures, blood that has just passed through bone, and trauma and injury to the endosteal milieu all provide a primitive CD34+CD38 and more dif-ferentiated, immature CD34+CD38+ populations sorted from patient sam-ples into newborn NOD/SCID/IL2rgnull immune-deficient mice. These mice are currently the most immune-defi-cient recipients and thus the most permissive for human stem cell trans-plantation and identification of serially determined that human CD34+CD38 LSCs primarily homed to and were retained in greater numbers in the end-osteum region of the femur. It has been shown previously that normal enriched primitive murine progenitor cells pref-erentially home to this site, while more committed progenitors favore
-
the Endosteum region keeps human leukemic stem cells alive
Cell Stem Cell, 2007Co-Authors: Tsvee Lapidot, Polina Goichberg, Kfir Lapid, Abraham Avigdor, Orit KolletAbstract:Only a subset of hierarchically arranged, primitive human AML progenitor cells can initiate the disease in transplanted immune-deficient mice. A publication in Nature Biotechnology by Ishikawa et al. (2007) describes a new animal model to study chemotherapy-resistant, quiescent human AML CD34+CD38− stem cells, which are retained in the Endosteum region.
-
the multiple roles of osteoclasts in host defense bone remodeling and hematopoietic stem cell mobilization
Annual Review of Immunology, 2007Co-Authors: Orit Kollet, Ayelet Dar, Tsvee LapidotAbstract:Bone remodeling by bone-forming osteoblasts and bone-resorbing osteoclasts dynamically alters the bone inner wall and the Endosteum region, which harbors osteoblastic niches for hematopoietic stem cells. Investigators have recently elucidated mechanisms of recruitment and mobilization; these mechanisms consist of stress signals that drive migration of leukocytes and progenitor cells from the bone marrow reservoir to the circulation and drive their homing to injured tissues as part of host defense and repair. The physical bone marrow vasculature barrier that is crossed by mobilized cells actively transmits chemotactic signals between the blood and the bone marrow, facilitating organ communication and cell trafficking. Osteoclasts play a dual role in regulation of bone resorption and homeostatic release or stress-induced mobilization of hematopoietic stem/progenitor cells. In this review, we discuss the orchestrated interplay between bone remodeling, the immune system, and the endosteal stem cell niches in the context of stem cell proliferation and migration during homeostasis, which are accelerated during alarm situations.