The goals of tissue engineering are to create a living cellular replacement part for organism to furnish the vehicles needed to deliver the engineered cells to organism.(3) to create tissue model for the study of behavior of many disease.(4) Explore new ways to make non living biomedical apparatus less likely to induce immune system responses within their host.
A widely used basic strategy of tissue engineering is to gather cells from a patient, culture it invitro, and seed them onto a scaffold that provides a biomechanical environment and physical and chemical cues for the differentiation that drives formation of the required tissue until the cells produce their own extracellular matrix.
Tissue-engineering scaffold should be analogous to native extracellular matrix (ECM). To develop such a scaffold a basic understanding about the natural ECM is required.
Extracellular matrix is the cell's direct environment. It is composed of complex 3D network of fibrillar proteins, proteoglycans and glycosaminoglycans (GAGs). It is the combination of cells and ECM which define the tissue in our body. In bone, ECM is highly mineralized providing the rigidity of that tissue. Molecular components of ecm are (1) Collagen: most abundant protein in the ECM, give structural support to resident cells. (2) Elastin : give elasticity to tissues. These are the structural proteins having fibers with diameters ranging from several ten to several hundred nanometers. The nanoscaled protein fibers enmesh with each other to form a nonwoven mesh that provides tensile strength and elasticity for the tissues. Both these contribute to the mechanical properties of ECM. (3) Fibronectin and laminin helps in cell adhesion which provide specific binding site for cell adhesion, (4) GAGs contribute to the gel like characteristics of ECM. eg: Chondroitin sulfate, Heparin sulfate, hyaluronic acid.
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Functions of ecm are it provides mechanical support for cells and tissues. It provide substrates with specific ligands for cell adhesion and migration, and regulates cellular proliferation and function by providing various growth factors. ECM regulates cellular differentiation and metabolic function. It acts as lattice for cell movement
It plays a critical role in cell signalling and tissue homeostasis. ECM acts as a sensor, conveying information from the exterior of the cell to the inside and vice-versa.
Cells are exposed to a number of different signals and the balance between internal and external signals will educe a cellular response. The way cells sense and respond to the stimulus provided by ECM is mainly via membrane receptors called integrins and/or mechanosensitive ion channels.
Integrins comprise a large family of cell surface receptors, and are transmembrane glycoproteins .These are the principal cell adhesion receptors for ECM proteins and serve as transmembrane bridges between the ECM and actin-containing filaments of the cytoskeleton. The integrin transmembrane receptors are heterodimeric molecules composed of Î± and Î² subunits, with extracellular domains which bind to the ECM, and cytoplasmic domains which associate with the actin cytoskeleton and affiliated proteins, including vinculin, talin and Î± -actinin. They are heterophilic cell adhesion molecules, ie extracellular domain interacts either with other cell adhesion molecules(CAMs) or the extracellular matrix . Most integrins function in cell-matrix interactions, some mediate cell-cell interactions, and a few participate in both types of contacts. Integrins create an `integrated' link between the outside and the inside of the cell. Many integrins show the ability to bind multiple ligands. Ligands of integrins are often large ECM proteins such as collagen, laminin, vitronectin or fibronectin. Integrins mediate different signaling pathways regulating a variety of cellular functions, including spreading, proliferation, apoptosis and migration. Therefore, integrins are important not only for the structure and architecture of tissue but also for signal transduction leading to regulation of many biological functions in a cell
Fibronectins (FNs) are high molecular weight glycoproteins found in blood plasma (plasma FN) and in the extracellular matrix (cellular FN). Fibronectin is one of most important ligand of integrins. FN is recognized by at least ten cell surface receptors of the integrin family. Most cell types in the body can adhere to fibronectin via these receptors, and thereby fibronectin is involved in many different biological processes. It is present as a polymeric fibrillar network in the ECM and as soluble protomers in body fluids. The RGD motif in fibronectin and other cell adhesion proteins is the most important recognition site for most of the integrins. It is found that a particular cell adhesion protein can bind to more than one type of integrin. Fibronectin is an extreme case and can bind to at least ten cell surface receptors of the integrin family. Integrin Î±5Î²1 (VLA5) is expressed by many cell types and is probably the major fibronectin receptor.
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Bone marrow is a cellular structure present within the hollow cavities of hard bone.It Â is of two typesÂ red marrow consisting mainly ofÂ hematopoietic tissue and yellow marrow consisting mainly ofÂ fat cells. Bone marrow contains three types ofÂ stem cells (1) Hematopoietic stem cells which are multipotentÂ stem cellsÂ that give rise to all the blood cell types. (2) Mesenchymal stem cells also termed marrow stromal cells are multipotent stem cells that can differentiate into cells of the connective tissue lineages.(3) Endothelial stem cells differentiate into cells that make up the lining of blood vessels. Hematopoiesis occurs in bone marrow which is in close proximity with the stromal microenvironment, which supports haemopoietic stem cell growth and differentiation. BM stroma is composed of a variety of different cell types which provide structural and functional support for hematopoiesis .It includes endothelial cells, adipocytes, smooth muscle cells, reticular cells, osteoblasts and stromal fibroblasts. Among these cell types,stromal fibroblasts are of particular biologic importance. They synthesize membrane bound GFs, ECM components and cytokines.
Haematopoietic stem cells (HSC) are the best-characterized adult stem cells. HSCs maintenance, commitment, regulation of self-renewal, differentiation and proliferation require complex interactions with the specific marrow microenvironment, called the haematopoietic stem-cell niche." A stem-cell niche can be defined as a spatial structure in which stem cells are housed and maintained by allowing self-renewal in the absence of differentiation." It is an anatomical unit located in the endosteum within the bone marrow cavity that is composed of osteoblasts, osteoclasts and stromal fibroblasts. Endosteum is the cellular lining separating bone from bone marrow. HSCs are situated in close proximity to osteoblasts at the endosteal surface of bone.
Major function of the niche is to anchor stem cells, and is mediated by adhesion molecules. Stem cell niche maintains stem cell quiescence by providing proliferation inhibiting cues. Stem cell number, division, self-renewal, and differentiation are regulated by the integration of intrinsic factors and extrinsic cues provided by niche. The interaction of the stem cell with niche elements is a key regulatory mechanism in maintaining the self-renewal and differentiation capacities. It also provides proliferation or differentiation-inducing signals when high numbers of progenitors are needed that quickly can give rise to all committed cell lineages. Niche controls normal asymmetrical division of stem cells. Niche and its components protect stem cells from stress, such as accumulation of reactive oxygen species and DNA damage. HSC quiescence, self-renewal and differentiation are regulated by both intrinsic and extrinsic mechanisms. Once physical association between the osteoblast and the HSC occurs there will be release of different growth factors which will trigger diverse signal transduction pathways that will initiate expression of target genes.