X. PROSPECTS FOR STEM CELL THERAPIES
ES cells are not the only source for possible therapeutics. Adult stem cells (ASC) can be coaxed into differentiated cells not normally associated with their "committed" state (131). Examples include hematopoietic stem cells from bone marrow that developed into neural, myogenic, and hepatic cell types, neural or skeletal muscle stem cells that developed into the hematopoietic lineage (33, 83, 131, 133, 148, 170, 269), stromal stem cells differentiating into cardiac myocytes (215), and mesenchymal stem cells into adipocytic, chondrocytic, or osteocytic lineages (273). The question therefore arises whether adult stem cells are the cell type of choice for cell therapies. While the differentiation potential of some adult stem cells (hematopoietic and mesenchymal) are well-characterized in vivo (HSC) or in vitro (MSC), the transdifferentiation potential of most adult stem cells remains controversial (235, 378, 379), partly as a consequence of culture conditions (175), contaminations, and cell fusion events (3, 358). Conversely, a major advantage in the use of ASC for cell replacement therapy is that they will not provoke immune-system rejection, should not become malignant, and may differentiate into a finite number of cell types.
Based on our present knowledge, ASCs, compared with ES cells, do not have the same developmental capacity. Injection of ASCs (hematopoietic or neuronal) into a mouse blastocyst can contribute to a variety of tissues, but the contribution differs in each embryo. Injection into animal models also leads to varying tissue contributions, the degree of which may depend on previous cultivation steps, since freshly isolated HSCs do not seem to transdifferentiate with high efficiency (378). Obviously, somatic stem cells of the adult organism may yet have a high plasticity, and their developmental potential may not be restricted to one lineage, but could be determined by the tissue environment in the body (383). The identification of such reprogramming factors will be one of the challenges of the future. These studies will show whether it may be possible to reprogram, not only adult somatic nuclei by fusion to enucleated eggs (64), but also to (retro- and/or trans-)differentiate adult somatic stem cells in response to "reprogramming" factors (see Ref. 379).
Finally, four therapeutic concepts using stem cells are currently being envisaged.
1) The direct administration of stem cells includes strategies for the administration of (adult) stem or progenitor cells directly to the patient, either locally or systemically, in such a way that the cells colonize the correct site of the body and differentiate into the desired cell type ("homing") under the influence of tissue-specific factors ("niche"). This strategy cannot be applied with ES cells, without prior isolation of ES-derived adultlike stem or progenitor cells (see Fig. 9), because of tumor formation (see sect. VIIIC), but it has been successfully employed in rodent models with a variety of stem cells isolated as primary isolates, following cultivation in vitro or following genetic modification (219, 384).
2) Transplantation of differentiated stem cell progeny is a strategy that involves stem cell cultivation in vitro, differentiation and selection prior to transplantation into a target organ. As stated earlier, this may result in a number of genetic or epigenetic modifications, but it has an advantage, in that purified cell progeny can be isolated. The normalization of blood glucose levels by insulin-secreting cells represents one example. In the case of diabetes, it would be necessary that a cellular graft respond to high glucose levels in the bloodstream by controlled insulin release. At the present time, hES cells do not show this ability (13, 283, 324). The first attempts using genetically modified mouse ES cells in (streptozotocin-treated) diabetic mice are encouraging (38, 207), but at present, we are far from applicable cell therapy strategies for the treatment of diabetes.
3) Recent progress in tissue engineering using stem cells offers the possibility of organizing the cells into three-dimensional structures that can be used to repair damaged tissues. Tissue engineering often takes advantage of biodegradable scaffolds or novel peptide-based biomaterial scaffolds to form three-dimensional structures, which can be seeded with cells (stem cells and their progeny), grown in culture and subsequently grafted into the organ as needed. Examples include bone, cartilage, tendon, and muscle. The principles behind tissue engineering have been extensively reviewed elsewhere (119, 161, 200, 371).
4) The stimulation of endogenous stem cells is based on the possibility that self-repair could be induced or augmented by stimulating the patient's own stem cells by administrating growth factors. Bone marrow cells, for example, can be mobilized by stem cell factor and granulocyte-colony stimulating factor. In the case of myocardial infarction, these mobilized cells seem to be home to an infarcted region to promote myocardial repair (257). It is currently unclear whether the activation process or the release of factors from activated stem cells is more important to this therapeutic approach. A recent study showed that transplantation of adult bone marrow-derived cells reduces hyperglycemia in diabetic mice by initiating endogenous pancreatic tissue regeneration. Engraftment of bone marrow-derived cells to ductal and islet structures was accompanied by rapid proliferation of recipient pancreatic cells and neogenesis of insulin-producing cells of recipient origin. This strategy may represent a previously unrecognized means by which bone marrow-derived cells can contribute to tissue restoration (156). Many potential endogenous stem cell sources (liver, brain, skin, heart, bone marrow, intestine) are now recognized to be present in humans. Stimulation of endogenous sources of stem cells is currently only achievable from bone marrow. With the rapid advance of stem cell research, it is likely, however, that further advances will be made so that endogenous supplies can be mobilized to more readily repair and replace damaged tissues following injury.
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