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q Hematopoiesis is an ordered process in which stem cells, through sequential division, differentiate into mature blood cells. The process of hematopoiesis is regulated by adhesive interactions between the Hematopoietic Stem Cells (HSCs) and Hematopoietic Progenitor Cells (HPCs) within the Bone Marrow (BM) microenvironment. HPCs can be mobilized into the peripheral blood by chemotherapeutic drugs and/or hematopoietic growth factors. Intravenously infused HPCs can migrate from the peripheral blood to the BM, a process called homing. It is still unclear what environment cues intitiate mobilization and homing of adult HPC to normal and injured tissue s The ability of multipotential adult stem cells to cross lineage boundaries (transdifferentiate) is of critical importance s Hematopoiesis is the best-studied stem cell system; the progenitor hierarchy has been defined along with the cytokine requirements and transcriptional regulators. Hematopoietic stem cell transplantation is one of the major advances in cancer therapy that gave rise to a Nobel prize

Cells that Contribute to the Tissue Microenvironment

Stromal cells: derivatives of common precursor cells Mesenchyme - The part of the embryonic mesoderm, consisting of loosely packed, unspecialized cells set in a gelatinous ground substance, from which connective tissue, bone, cartilage, and the circulatory and lymphatic systems develop Fibroblasts - Connective tissue cells which differentiate into chondroblasts, collagenoblasts, and osteoblasts Myofibroblasts - Histological term for fibroblast like cells that contain substantial arrays of actin microfilaments, myosin and other muscle proteins arranged in such a way as to suggest that they produce contractile forces. Are commonly described as occurring in granulation tissue (formed during wound healing) and in certain forms of arterial thickening where they are found in the intima. Behave in much the same way as smooth muscle cells and have markers characteristic of these cells Osteogenic/chondrogenic cells - Derived from or composed of bone-forming tissue Adipocytes - An animal connective tissue cell specialised for the synthesis and storage of fat. Such cells are bloated with globules of triglycerides, the nucleus being displaced to one side and the cytoplasm seen as a thin line around the fat droplet Stromal-associated cells: histogenically distinct from stromal cells, permanent residents of a tissue Endothelial cells - A thin, flattened cell, a layer of them lines the inside surfaces of body cavities, blood vessels, and lymph vessels, making up the endothelium Macrophages - Round, granular, mononuclear phagocytes found in the alveoli of the lungs. They ingest small inhaled particles resulting in degradation and presentation of the antigen to immunocompetent cells Transient cells: cells that migrated into a tissue for host defense either prior to or following an inflammatory stimulus B lymphocytes/plasma cells - Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation Cytotoxic T cells and natural killer (NK) cells - Responsible for lysing target cells and for killing virus infected cells Granulocytes - Leucocyte with conspicuous cytoplasmic granules. In humans the granulocytes are also classified as polymorphonuclear leucocytes and are subdivided according to the staining properties of the granules into eosinophils, basophils and neutrophils (using a Romanovsky type stain), some invertebrate blood cells are also referred to, not very helpfully, as granulocytes Parenchymcal cells: cells that occupy most of the tissue volume, express functions that are definitive for the tissue, and interact with all other cell types to facilitate the expression of differentiated function (1 of 11)8/31/2004 10:13:09 AM


Table I: Physical Paramaters

Cell Type Erythrocyte Neutrophils (60-70%) 1/2 life 120 days Size 7.5 ¼m Shape biconcave disc round round Band neutrophils (immature neutrophils) Eosinophils (2-4%) Basophils (less than 1%) 3-8 hours 12-15 ¼m 12-15 ¼m 6-8 ¼m small 18 ¼m large days to years 10-12 ¼m medium 12-100 hours 12-20 ¼m 2-4 ¼m round, oval, biconvex discs

6-7hrs blood 1-4days 12-15 ¼m tissue

Lymphocytes (20-50%)


Monocytes (2-10%)

Platelets (200,000-400,000 Per ml of circulating blood) 10 days Also called thrombocytes

oBone Marrow - of stem, progenitor, and precursor cells; bone marrow is circulated throughout the body via the circulatory system The soft tissue filling the cavities of bones. Bone marrow exists in two types: yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. · Megakaryocytes are very large cells with multilobed nucleus which are normally present only in bone marrow. The same stem cells in the myeloid series differentiate into megakaryoblasts. The megakaryoblasts then undergo multiple rounds of endomitosis and form megakaryocyte. Platelets shed off megakaryotes (2 of 11)8/31/2004 10:13:09 AM


Figure 1. A bone consists of a tough, calcium mineral shell with openings to allow for blood vessels. Erythrocytes (red blood cells), platelets, and leukocytes (white blood cells) are produced in the bone marrow.

o Cell Adhesion ­ Interactions between the bone marrow (BM) microenvironment and hematopoietic stem and progenitor cells (HSPC) are essential for the regulation of commitment, proliferation, and differentiation of HSPC that is for the regulation of blood cell formulation. Most stromal-hematopoietic cell interactions are mediated by mutual recognition of adhesive receptors/ligands located at the surface of both HSPC and stromal cells as well as in the surrounding extracellular matrix (ECM). · Integrins ­ cell adhesion receptors that are involved in cell-extracellular matrix adhesion The integrin class of adhesion receptors are heterodimers of the noncovalently associated and chains. There are at least 18 different and 8 different chain types. The integrins have specific binding sites on the extracellular matrix (ECM) ligands. Activation and inactivation of integrin function occur, possibly by conformational changes or phosphorylation s Functionally active integrins ­ integrins which are involved in binding of cells to ligands in the ECM s Functionally inactive integrins ­ integrins which are present in the cell membrane, but are not bound (3 of 11)8/31/2004 10:13:09 AM


o Stem Cells ­ cells who have no function and have yet to differentiate · Pluripotent ­ stem cells which are able to differentiate into a certain lineage, or differentiate to a limited group of potential cells · Totipotent ­ stem cells that are able to differentiate into any type of cell · Factors that effect differentiation: s Microenvironment ­ the area of the body that the stem cell is exposed to s cell-cell interaction s Growth Factors (GF) ­ proteins, nutrients s Extra cellular Matrix (ECM) ­ Any material produced by cells and secreted into the surrounding medium, but usually applied to the noncellular portion of animal tissues. The ecm of connective tissue is particularly extensive and the properties of the ecm determine the properties of the tissue. In broad terms there are three major components: fibrous elements particularly collagen, elastin or reticulin), link proteins (e. g. Fibronectin, laminin) and space filling molecules (usually glycosaminoglycans). The matrix may be mineralised to resist compression (as in bone) or dominated by tension resisting fibres (as in tendon). The basal lamina of epithelial cells is another commonly encountered ecm. Although ecm is produced by cells, it has recently become clear that the ecm can influence the behaviour of cells quite markedly, an important factor to consider when growing cells in vitro: removing cells from their Figure 2. Transendothelial migration of hematopoietic normal environment can have far reaching progenitor cells occur in the Bone Marrow during mobilization effects. and homing, hence playing an important role in the trafficking s activation/deactivation of genes of HSCs. Adhesion molecules and chemokines play an important role in the process. oSelf-Renew ­ replication of stem cells OR oDifferentiate - Stem cells eventually mature into progenitor cells, and then precursor cells; form muscle, bone, fat, nervous, and other cells (4 of 11)8/31/2004 10:13:09 AM


o Mobilization ­ a process involving release of HSCs into the periphery: A multi-step process in which adhesion interactions, which mediates anchorage of hematopoietic progenitors to the bone marrow stromal cells in response to stimulation with cytokines and chemokines, needs to be disrupted. · Useful for patients after receiving radioactive treatments (chemotherapy and etc.) because it allows for increased circulation of stem cells in the body · Apheresis ­ process of collecting stem cells via circulating blood; mobilization allows for increased density of stem cells collected in this process · CXCR4 is the receptor, or binding site, for the chemical ligand SDF-1(a chemokine, Stromal Derived Factor ); a decrease of active signaling of CXCR4/SDF-1 is required in homing o Homing ­ processing by which stem cells are injected into the bloodstream and later "home" into the bone marrow · CXCR4 is the receptor, or binding site, for the chemical ligand SDF-1(a chemokine, Stromal Derived Factor ); an increase of active signaling of CXCR4/SDF-1 is required in homing · Treatment of lethally irradiated mice grafted with isogeneic BM cells showed that at least two migration pathways are important for stem-cell homing to the BM, whereas only one of them is involved in lodging of colony-forming unit-spleen (CFU-S) in the spleen. We confirm that the VLA-4/VCAM-1 adhesion pathway is important for stem-cell homing to the BM only and show that CD44 is involved in CFU-S lodging in both BM and spleen.

Figure 3. Chemokine-mediated mobilization of endothelial and hematopoietic stem and progenitor cells is a dynamic multistep process (5 of 11)8/31/2004 10:13:09 AM


(Rabbany et al., Trends in Molecular Medicine 9;3:109-117, 2003).

Mobilization is induced by a wide number of molecules: Cytokines: G-CSF, GM-CSF, IL-7, IL-3, IL-12, SCF,and FLT-3 ligand Chemokines: IL-8, Mip-1, GroB, or SDF-1 Chemotherapeutic agents: Cyclophosphomide (Cy) and Paclitaxel *The molecules differ in their time frame to achieve mobilization o Survival · Nutrients ­ mouse feeder cells are commonly used in vitro to allow the release of nutrients for the stem cells · Stroma ­ a framework that allows stem cells to begin to self-renew and differentiate, ultimately forming into organs · Growth Factors (GF) o Differentiate - Stem cells eventually mature into progenitor cells, and then precursor cells; form muscle, bone, fat, nervous , and other cells · Progenitor cells ­ begin to mature into a certain lineage · Precursor cells ­ begin to demonstrate functions of the end-resulting cell

Figure 4. Hematopoietic and Stromal Cell Differentiation []. (6 of 11)8/31/2004 10:13:09 AM


o Cell Motility ­ Cells have the ability the ability to migrate when placed in a culture/solution. There are several cell motility factors that have been discovered; though only recently has research been performed into these factors, such as PDGF (platelet-derived growth factor), GFG (basic fibroblast growth factor), and hepatocyte growth factor. Stem cell motility, directed movement, and homing represent an important area in hematopoietic stem cell biology. Although the hematopoietic stem cell homing field is still in its infancy, its basis was created by studies defining a wide variety of adhesion receptors and other ligands that mediate cell-to-matrix and cell-to-cell interactions. These include the selectins, the integrins, the Ig family, and others. · Chemotaxis ­ motion of cells from lower concentration to higher concentration in solutions of soluble chemicals , such as growth factors (VEGFA, TGF-beta) · Haptotaxis ­ motion of cells from lower concentration to higher concentration in bound or insoluble chemicals, such as gradients in bound cell-ECM adhesion molecules such as Integrin's · Mechanotaxis ­ motions of cells due to mechanical stimuli

Figure 5. Heart muscle repair with adult stem cells [].

Conclusion: Stem cell biology has focused on long-term engraftment as the defining characteristic of a hematopoietic stem cell, and homing is the first step in this engraftment process. In general, the role of homing per se in long-term engraftment has not been separated from proliferation and/or differentiation, in part because of the rare cell problem noted above. (7 of 11)8/31/2004 10:13:09 AM


Hematopoietic Growth Factors Growth Factor Name Interleukin-1 Interleukin-2 Interleukin-3 Interleukin-4 Interleukin-5 Interleukin-6 Interleukin-7 Interleukin-8 Interleukin-9 Interleukin-10 Interleukin-11 Interleukin-12 Interleukin-13 Erythropoietin Monocyte-CSF Granulocyte-CSF Granylocyte-macrophageCSF Stem cell factor Macrophage inflammatory protein Leukemia inhibitory factor Tumor necrosis factor Transforming growth factor Flk -2 ligand Thrombopoietin o References flt -3 ligand Megakaryocyte-CSF,c = mpl ligand c-kit ligand, Mast cell growth factor Stem cell inhibitor Colony-stimulating factor-1 NK cell stimulatory factor Cytokine synthesis inhibitory factor Neutrophil activating peptide-1 B-cell-stimulatory factor-2 Multicolony-stimulating factor B-cell-stimulatory factor-1 Other Names Hemopoietin-1 Abbreviations IL-1 IL-2 IL-3, Multi-CSF IL-4, BSF-1 IL-5 IL-6, BSF-2 IL-7 IL-8, NAP-1 IL-9 IL-10, CSIF IL-11 IL-12, NKSF IL-13 Epo M-CSF, CSF-1 G-CSF GM-CSF CSF, KL, MGF MIP-1, SCI LIF TNF TGF FL Tpo, MK-CSF Reference Dinarello at el., 1981 Smith, 1988 Ihle et al., 19871 Yokota et al., 1988 Yokota et al., 1988 Kishimoto, 1989 Tushinski et al., 1991 Herbert and Baker, 1993 Donahue et el., 1990 Zlotnik and Moore, 1991 Du and Williams, 1994 Wolf et al., 1991 Minty et al., 1993 Krantz, 1991 Metcalf, 1985 Metcalf, 1985 Metcalf, 1985 Zsebo et al., 1990 Graham et al., 1990 Metcalf, 1991 Pennica et al., 1984 Sporn and Roberts, 1989 Hannum et al., 1994 De Sauvage et al., 1994 (8 of 11)8/31/2004 10:13:09 AM


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