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Stam Cell Niche
 

Stam Cell Niche

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  • The bone marrow is contained in the central medullary cavity of bone. The main blood source to the bone marrow is provided by the nutrient artery. The nutrient artery crosses the cortex through the nutrient canal into the medullary cavity, where it divides into ascending and descending arteries, from which radial arteries arise. The radial arteries enter the cortex through the endosteum, which lines the medullary cavity, and become cortical capillaries. Blood from these capillaries can then mix with blood from periosteal capillaries (not shown) and endosteal capillaries. The cortical capillaries enter the medullary vascular sinuses, which form a dense network through the medullary cavity. The sinuses eventually collect and enter the central sinus from which the blood leaves the bone marrow. The medullary vascular sinuses are lined with endothelial cells and surrounded by adventitial reticular cells. Haematopoiesis occurs in the extravascular spaces between the sinuses. (Figure modified from Ref. 1.)
  • The multipotent human hematopoietic stem cell cannot be morphologically distinguished from other small mature lymphocytes in the bone marrow or peripheral blood. The hematopoietic stem cell is defined by phenotypic marker studies and represents a small subset (~1%) of the cells in the lymphocyte gate in the peripheral blood and bone marrow that are CD34+. Cells representing further differentiation into the common lymphoid precursor (CLP), common myeloid precursor (CMP), early T-lineage precursor (ETP), granulocyte/monocyte precursor (GMP), and megakaryocyte/erythrocyte precursor (MEP) also cannot be morphologically identified. Cells that correspond to the various stages of antigen-independent B-cell development in the bone marrow and T-cell development in the thymus also cannot be morphologically identified.
  • زوائد استخوانی داخل مغز استخوانspiculeStro-1=markers of primitive human marrow stromal cells and their more differentiated progenySTRO-1STRO-1 is a cell surface protein expressed by bone marrow stromal cells and erythroid precursors. The frequency of colony forming units-fibroblast (CFU-F) is enriched 100-fold in the STRO-1+/Glycophorin A- population from bone marrow cells. The subset of marrow cells that expresses the STRO-1 antigen is capable of differentiating into multiple mesenchymal lineages including hematopoiesis-supportive stromal cells with a vascular smooth muscle-like phenotype, adipocytes, osteoblasts, and chondrocytes.
  • فاکتورهایی محیطی که در تنظیم سیستم سلول بنیادی در بافت دخیل هستند بتصویر کشیده شده اند.1-معماری و شکل مکان2-درگیری فیزیکی بین سلولهای همجوار3-مسیر های القا شده4-اثرات پاراکرین و اندوکرین سیتوکین ها5-اعصاب6-محصولات متابولیک در نتیجه فعالیت بافتی
  • . هماتوپوئزيس سلول‌هاي استخوان و سلول‌هاي استرومال مغز استخوان. در مغز استخوان HSCها در مجاورت استئوبلاستهاي نارسايي اندوستيل مستقر مي‌شوند يا در مجاورت سلول‌هاي اندوتليال رگهاي سينوزوئيدال. بعد از هر تقسيم، سلول دختري استخوان را ترك مي‌كند تا به رده‌هاي متعددي تكثير و تمايز يابد. HSCها و دودمان آنها توسط سلولهاي استرومال مشتق از سلولهاي بنيادي مزانشيمال، احاطه شده‌‌اند. استئوبلاستها M-CSF، RANKL و OPG را بيان و IL7 را توليد مي‌كنند. اين سلولها رشد سلولهاي لمفوئيد و استئوكلاست را تنظيم مي‌نمايند
  • . نيچ‌هاي استئوبلاستيك و رگي در مغز استخوان. در يك حالت فيزيولوژيك طبيعي، HSCها در نيچ استئوبلاستيك يا رگي مستقر مي‌شوند. قسمتي از سلولهاي دختري HSC، در پاسخ به تغييرات در سطح SDF1 در مغز استخوان، نيچ را ترك گفته و شروع به حركت و گردش مي‌كنند. لانه گزيني HSCها عملي مخالف است و در پاسخ به ميزان افزايش يافته SDF1 در مغز استخوان انجام مي‌شود. نيچ استئوبلاستيك ممكن است HSCها را به فاز خاموشي سوق دهد در مقابل نيچ رگي مهاجرت از ديواره رگي، HSCها را تسهيل مي‌كند (حركت يا لانه‌گزيني) و ممكن است تمايز و تكثير آنها را منجر شود.
  • Figure 1 (a) A model of bone marrow niches. In the marrow,osteoblasts and endothelial cells constitute the major cellularcomponents contributing to the endosteal and vascular niches thatserve as the microenvironment for maintaining hematopoietic stemcells (HSCs; ‘HSC niche’). Osteoblasts and endothelial cells arederived from mesenchymal stem cells (MSCs) and hemangioblasts,respectively. Recent data suggest that MSCs themselves may reside inniches that are in close proximity to the HSC niche. In addition, thereis growing evidence that HSCs and MSC co-regulate activities of eachother. In the model presented, overlap of HSC, MSC, vascular andendosteal niche function occurs and is required for the coordinatedfunction of the marrow.
  • (b) A model of the neoplastic niche. Increasingevidence suggests that disseminated tumor stem cells reside in nichesthat facilitate the metastasis and survival of tumors in distant tissues.Much like HSCs and MSCs, the residence of metastatic cells in theniche provides signals that regulate dormancy and escape fromchemotherapy and radiotherapy. As such, the residence of metastaticcells in the niche constitutes a molecular parasite of the normal hostregulatory functions that exist to supply a constant flux of HSC andMSC progeny throughout the lifetime of the individual.
  • Figure 2 A model of the hematopoietic stem cell (HSC) niche in long bones. (a and b) Organization of long bones and location of the HSC niches.Recent studies demonstrate that endostealosteoblasts and their precursors play a critical role the stem cell ‘niche’ (c). In addition, endothelial cellsare likely to contribute to niche function (c). Central to these hypotheses are the demonstration of osteoblast (OB)- or endothelial cell-expressedregulatory components that influence stem cell function are likely to include cell-to-cell receptors, and soluble and cell-surface associatedcytokines and growth factors. (d) Egress into and out of the marrow by HSCs facilitate transit into and out of the vascular niche, which is permissivefor proliferation and differentiation. The endosteal niche facilitates HSC maintenance and quiescence. Reciprocal interactions between stem cellsand their niches are likely to play key roles in the establishment and maintenance of the stem cell niche in the bone marrow (not shown). (e)Factors produced by osteoblasts that influence HSC. Stem cell fate is influenced by specialized microenvironments that remain poorly defined.Osteoblasts produce soluble hematopoietic-supportive secreted and cell-associated factors that work in concert so that HSCs derive regulatoryinformation from bone, accounting for the localization of hematopoiesis in bone marrow (homing/localization receptors e.g. Annexin II, VCAM-1,CXC chemokine receptor 4 (CXCR4)/CXC chemokineligand 12 (CXCL12)). Quiescence factors (e.g. bone morphogenic factors, fibroblast growthfactors, Flt-3 ligand, Tie2/Ang-1, granulocyte and granulocyte-macrophage colony-stimulating factors, hepatocyte growth factor (HGF), leukemiainhibitory factor (LIF), osteopontin and high levels of extracellular calcium) and cell-associated factors are known to include but are limited toosteopontin, granulocyte and granulocyte-macrophage colony-stimulating factors and transforming growth factors (TGFs). Soluble factors knownto influence HSC function include parathyroid hormone and erythropoietin (Epo). . نمايي ديگر از نيچ استئوبلاستيك و نيچ رگي. استئوبلاست پذيرنده فاكتورهاي متعددي توليد مي‌كنند كه در سرنوشت HSCها بسيار مهم هستند. براي مثال پذيرنده‌هاي لانه گزيني مثل آنكسين II، VCAM-1، CXCL12/CXCR4. از فاكتورهاي فاز خاموشي مي‌توان به فاكتورهاي مورفوژنيك استخوان، فاكتور رشد فيبروبلاست، ليگاند FLT-3، Tie2/Ang-1، CSF-G و CSF-GM و فاكتور رشد هپاتوسيت.
  • . ماكروفاژهاي جزاير اريتروبلاستيك. (A) تصوير TEM از يك جزيره اريتروبلاستيك مغز استخوان موش. به اتصالات سلولي توجه كنيد. (B) تصوير SEM از يك جزيره اريتروبلاستيك. در تصوير يك اريتروبلاست در حال خارج كردن هسته و يك رتيكولوسيت چند قطعه‌‌اي (multilobulated) نمايش داده شده است.
  • ‘‘Definitive’’ Erythropoiesis in the Fetus
  • . يك مدل سه‌بعدي از يك مغز استخوان طبيعي موش به تصوير كشيده شده. در اين مدل كره بزرگ مگاكاريوسيت (m) است، و (s) سينوس‌‌ها، (M) ماكروفاژها و دسته‌هاي كوچك دايره‌‌اي، اريتروبلاست‌‌ها مي‌باشند.

Stam Cell Niche Stam Cell Niche Presentation Transcript

  • Stem Cell Niche Department of Hematology School of Medical Sciences Najmaldin saki Tarbiat Modares
  • CLP GMP HSCs CMP MKEP MSCs
  • Cell fates available to a stem cell Quiesce Differentiate Self-renew Apoptose
  • Self-renewal or differentiation
  • Ratio in BM : 1̸10000 to 1̸100000 Characteristic: Mobilizing: Stemness: Sca-1 G-CSF or rh G-CSF Thy.1 LOW Jagged-1 M-CSF Lin-(HLA-DR, CD71, CD45 SCF N-Cadherin RA,CD38) IL3  rTpo(C-MPL) Tpo CD133+ MIP-1α CD34+ CD117+
  • Clathrin-Coated pits ED Cells: VWF Ulex europeaus CD22 Col IV Ab CD34 Lam VCAM1 Selectin E CD34+ CD14+ CD45- SDF-1 IL6
  • Characteristic: receptor for: Alp + Nerve growth factor CD10+ CD13+ HLA I Alpha smoth-muscle actin Vementin Laminin Fibronectin Coll I,III,IV CD34-
  •  BM reticular cells ………..Adipocyte Starvation Saturated fatty acid Express: Maturin in vitro inhibited by: Leptin IL1 & IL11 Osteocalsin Prolactin receptor VEGF Leptin vs EPO Stem cell erythroied
  • CD14- Secret: CD34- Secret: GM-CSF CD45- Coll M-CSF VCAM-1+ Fibrinectin CSF Laminin IL6 α-smooth muscle protien(ASP) α-smooth muscle actin(ASA) LIF Proteog Receptor for : glycopro bFGF PDGF EGF TGFβ
  • Markers: markers of primitive human marrow stromal cells and their CD34- more differentiated progeny STRO-1+ RANKL Secret: N-cad+ TGFβ osteoblast Spindle shaped N-cadherin positive osteoblast B-FGF N-cad- BMP-2 M-CSF G-CSF GM-CSF IL1 IL6 PTH ALP Wnt/βcatenin Ostepontin(OPN) Osteocalcin Coll fibronectin OPG
  • CD34+ M-CSF has a critical rol in Osteoclastojenesis STRO-1- TRAP+ RANK CD51+ CD54+ CD68+ Secreat: MMP Catepsin K
  • Endosteal niche M-CSF & RANKL & OPG niche Vascular IL7
  • HSC O2 O2 HSC
  • RANKL/OPG ratio MM CD138 Ob Os OPG RANKL RANK
  • Enucleation of late-stage erythroblasts leads to the formation of two cells – a reticulocyte and a pyrenocyte
  • • Notch • Hedgehog • Bmi-1 • Wnt
  • Extracellular space Wnt adenomatous polyposis coli glycogen synthase kinase 3 APC B-catenin B-catenin GSK3 P NUCLEUS Axin B-catenin B-catenin CYTOPLAS
  • frizzled-related protein Dickkopf (Dkk) families Extracellular space Wnt inhibitory factor 1 low-density lipoprotein receptor–related Sclerostin(SOST gene product) Wnt protein 5 and 6 (LRP5/6) DKK SOST L L L R Kremen R R P P P NUCLEUS Interaction of the Dkk/LRP complex with kremen internalizes the complex for degradation, thus diminishing the number of Wnt coreceptors available for signaling CYTOPLASM
  • Wnt L R P Dsh APC B-catenin B-catenin GSK3 B-catenin B-catenin B-catenin Axin
  • T cell factor/lymphoid enhancer binding factor silencing mediator of retinoid and thyroid receptors and nuclear receptor corepressor B-catenin