PubMed · 15443473
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V P FILATOV. [Principal problems in tissue-extract therapy].. https://pubmed.ncbi.nlm.nih.gov/15443473/
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Diseases of the brain and spinal cord represent especially daunting challenges for cell-based strategies of repair, given the multiplicity of cell types within the adult central nervous system, and the precision with which they must interact in both space and time. Nonetheless, a number of diseases are especially appropriate for cell-based therapy, in particular those in which single phenotypes are lost, and in which the re-establishment of vectorially specific connections is not entirely requisite for therapeutic benefit. We review here a set of potential therapeutic indications that meet these criteria as potentially benefiting from the transplantation of neural stem and progenitor cells. These include: (i) transplantation of phenotypically restricted neuronal progenitor cells into diseases of a single neuronal phenotype, such as Parkinson's disease; (ii) implantation of mixed progenitor pools into diseases characterized by the loss of a limited number of discrete phenotypes, such as spinal cord injury and the motor neuronopathies; (iii) transplantation of glial and nominally oligodendrocytic progenitor cells as a means of treating disorders of myelin; and (iv) transplantation of neural stem cells as a means of treating lysosomal storage disorders and other diseases of enzymatic deficiency. Among the diseases potentially approachable by these strategies, the myelin disorders, including the paediatric leucodystrophies as well as adult traumatic and inflammatory demyelinations, may present the most compelling targets for cell-based neurological therapy.
Members of the vascular endothelial growth factor (VEGF) family of proteins are critical regulators of angiogenesis. VEGF concentration gradients are important for activation and chemotactic guidance of capillary sprouting, but measurement of these gradients in vivo is not currently possible. We have constructed a biophysically and molecularly detailed computational model to study microenvironmental transport of two isoforms of VEGF in rat extensor digitorum longus skeletal muscle under in vivo conditions. Using parameters based on experimental measurements, the model includes: VEGF secretion from muscle fibers; binding to the extracellular matrix; binding to and activation of endothelial cell surface VEGF receptors; and internalization. For 2-D cross sections of tissue, we analyzed predicted VEGF distributions, gradients, and receptor binding. Significant VEGF gradients (up to 12% change in VEGF concentration over 10 mum) were predicted in resting skeletal muscle with uniform VEGF secretion, due to non-uniform capillary distribution. These relative VEGF gradients were not sensitive to extracellular matrix composition, or to the overall VEGF expression level, but were dependent on VEGF receptor density and affinity, and internalization rate parameters. VEGF upregulation in a subset of fibers increased VEGF gradients, simulating transplantation of pro-angiogenic myoblasts, a possible therapy for ischemic diseases. The number and relative position of overexpressing fibers determined the VEGF gradients and distribution of VEGF receptor activation. With total VEGF expression level in the tissue unchanged, concentrating overexpression into a small number of adjacent fibers can increase the number of capillaries activated. The VEGF concentration gradients predicted for resting muscle (average 3% VEGF/10 mum) is sufficient for cellular sensing; the tip cell of a vessel sprout is approximately 50 mum long. The VEGF gradients also result in heterogeneity in the activation of blood vessel VEGF receptors. This first model of VEGF tissue transport and heterogeneity provides a platform for the design and evaluation of therapeutic approaches.
Many common neurological disorders, such as Parkinson's disease, stroke and multiple sclerosis, are caused by a loss of neurons and glial cells. In recent years, neurons and glia have been generated successfully from stem cells in culture, fueling efforts to develop stem-cell-based transplantation therapies for human patients. More recently, efforts have been extended to stimulating the formation and preventing the death of neurons and glial cells produced by endogenous stem cells within the adult central nervous system. The next step is to translate these exciting advances from the laboratory into clinically useful therapies.