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Therapeutic Approaches for Cellular and Tissue Therapy
Posted on: April 10, 2006

Tissue engineering can be defined as the use of biomaterials with or without small molecules, cells, genes, or gene products to maintain, replace, or repair organ function with the objective of correcting the underlying pathology. This new field of medicine is based on the use of engineered cells, tissues, and synthetic materials that can potentially extend and improve a patient�s life. At the present time, treatments for organ or tissue loss include organ transplants, surgical reconstruction, the use of mechanical devices, and, recently, cellular therapy. The research and development of tissues and cell-based products have taken many approaches to advance the field of regenerative medicine. This involves the use of ≥1 cell lines and the inclusion of an extracellular matrix, thus forming a tissue architecture, which allows communication through cell-to-cell interactions and cell-to-matrix interactions. Such interactions are essential for providing tissue support and functionality through the release of a variety of cytokines and growth factors.

Three general strategies are currently used in the development of tissue-engineered products. The first strategy involves the use of cells without matrix. When transplanted, these cells restore function to an injured organ or organ system. Stem cell therapy and autologous cell transplant are examples of this approach. The second strategy involves the development of synthetic polymers or biomaterials that act to restore organ system function when used alone (i.e. synthetic scaffold materials) or with the addition of proteins, such as growth factors and cytokines, which may be released in a controlled fashion. The last therapeutic approach involves the use of cells within a 3-dimensional matrix. For example, bilayered skin substitutes composed of keratinocytes and fibroblasts incorporate into biologic collagen matrices or synthetic bioabsorbable scaffolds before implantation and serve to enhance or promote tissue repair processes.

A stem cell is an undifferentiated cell with the capacity for self-renewal that gives rise to ≥1 highly differentiated cell type. Stem cells are derived from either embryonic cells, referred to as pluripotent stem cells, or from fetal and adult tissue, both referred to as multipotent stem cells.

Embryo-derived stem cells are pluripotent, capable of giving rise to most tissues. They can be derived from the inner cell mass of the preimplantation blastocyst or primordial germ cells of embryos and are used for the development of many cell-derived products because of their unique ability to divide for an indefinite period of time in cell culture and to give rise to many lines of specialized cells.

Fetal stem cells, like adult-derived stem cells, are multipotent stem cells derived from either fetal or adult tissues, which possess a high degree of plasticity. These cells can be obtained from mesodermal tissues, such as muscle and bone marrow, including hematopoietic, mesenchymal, and endothelial stem cells, as well as ectodermal and endodermal tissues, including neural, epidermal, intestinal, liver, and pancreatic stem cells. Multipotent stem cells are the result of further specialization of pluripotent cells into particular cell lines, such as blood and skin. Both fetal and adult-derived stem cells are being successfully developed for multiple indications, including cardiomyocyte replacement for heart conditions, chondrocyte replacement for osteoarthritis, and neuronal replacement, which has led to symptom reversal for Parkinson and Huntington diseases. Recently, multiple studies have demonstrated that adult stem cells possess a broader developmental capacity than was previously thought. The plasticity of adult-derived stem cells was illustrated when brain-derived adult neural stem cells from mice contributed to the formation of a chimeric chick and mouse embryo and gave rise to all germ layers. Although adult-derived stem cells have shown this broad developmental capacity, additional studies are needed to confirm the in vitro and in vivo fate of these cells. The bone marrow contains a population of stem cells. These cells include hematopoietic stem cells, which give rise to blood and lymphoid cells; mesenchymal stem cells, or marrow stromal cells, which regenerate bone and marrow cells (adipocytes, reticular cells); and endothelial stem cells. Bone marrow�derived mesenchymal stem cells have been used to derive a range of cell types, including hepatocytes and neurons. Thus, although mesenchymal stem cells are potentially less plastic than embryonic stem cells and possess a predetermined differentiation capability, they may be reprogrammed to derive new cell types through extracellular signaling processes that revert precursor cells to multipotential stem cells. For example, oligodendrocyte precursor cells can be reprogrammed to revert to multipotential neural stem cells and give rise to various neural tissues, including neurons, astrocytes, and mature oligodendrocytes. Advancements in new cell culture techniques and a growing knowledge about optimal oxygen levels are enhancing the development of commercial quantities of stem cells. Lowered oxygen levels (3%) in cell culture have been shown to reduce apoptosis, increase the number of central nervous system precursors, and increase differentiation rates, all of which have resulted in a significant increase in cell yield. The potential therapeutic uses of stem cells in the advancing field of regenerative medicine currently under development include cell transplantation, the development of bioartificial tissues, and the induction of resident stem cell proliferation and differentiation 4. There are, however, many safety and ethical issues associated with the use of stem cells. Uncontrolled plasticity and proliferation with the potential for teratocarcinomatous formation and epigenetic instability, along with immunorejection and contamination, are some of the disadvantages associated with this approach. At the present time, only differentiated somatic cells are available for commercial use, including allogeneic- derived keratinocytes and fibroblasts (Apligraf for wound healing; Novartis, East Hanover, NJ), autologousderived keratinocytes (EpiDex [MODEX The?rapeutiques SA, Lausanne, Switzerland] and Epicel [Genzyme Biosurgery, Cambridge, MA] for epidermal repair), and chondrocytes (Carticel for osteoarthritis; Genzyme Biosurgery).

Source: Pablo A. Jimenez, M.D., Sydney E. Jimenez, M.D; Tissue and cellular approaches to wound repair; The American Journal of Surgery 187 (Suppl to May 2004) 56S�64S
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