Neuronal tissues can survive transplantation into the brain, and the brain is in certain respects particularly suitable as a target organ for transplantation. For transplantation of CENTRAL NERVOUS SYSTEM (CNS) neurons, it is necessary to use embryonic or (at the latest) neonatal donor tissues. In particular, neurons only survive transplantation at the stage in their DEVELOPMENT when they are undergoing final cell division and are just beginning active and directed NEURITE outgrowth. There is a brief developmental time window for each neuronal population that needs to be determined empirically. By contrast GLIAL CELLS and PERIPHERAL NERVOUS SYSTEM (PNS) tissues (such as ADRENAL GLAND or other endocrine ganglia) can survive transplantation even in adulthood, which is believed to be related to the fact that these cell populations can also undergo cell division throughout life. The brain is an efficient transplantation target, provided the graft is placed in a position that will permit rapid and efficient vascularization and incorporation into the host blood and CEREBROSPINAL FLUID circulation. IMMUNOLOGY factors are less important than for organ transplants since the brain is an immunologically privileged site, at least relatively. Embryonic neural ALLOGRAFTS (that is, grafts within the same species) survive well when grafted in the brain, whereas skin or organ transplantation across the same barriers results in rapid rejection. Although XENOGRAFTS (that is, grafts between different species) are generally rejected, they can be effectively maintained with standard IMMUNOSUPPRESSION. Grafts of embryonic neuronal tissues not only survive, but have been shown to grow, and establish reciprocal connections in a number of different model systems in the brain. They can also provide functional restoration of damage in the CNS by a number of distinct mechanisms (each of which have been demonstrated to apply in different model systems). These mechanisms include: (1) non-specific aspects of surgery; (2) TROPHIC stimulation of restorative processes in the host brain; (3) provision of bridges or growth substrates for regeneration of host axons; (4) diffuse release of specific NEUROTRANSMITTERS or neuromodulators (or NEUROHORMONES); (5) glial replacement for reconstruction of brain environment, including remyelination (see MYELIN) and restoration of conductance of axons; (6) REINNERVATION and reactivation of denervated targets; (7) reciprocal connections and repair of damaged circuits.
Clinical applications of neural transplantation are under active development for a variety of neurological and neurodegenerative disorders. Transplantation of embryonic DOPAMINE cells is now demonstrated to be effective in PARKINSON’S DISEASE.
The grafts can alleviate both akinetic and rigid symptoms (see AKINESIA and RIGIDITY), reduce the required levels of L-DOPA medication and abolish many of the most troubling dyskinetic (see DYSKINESIA) side-effects. The grafts are typically less effective on TREMOR and AXIAL symptoms. Active trials are in development for several other diseases: embryonic cells from the STRIATUM in HUNTINGTON’S CHOREA, PRECURSOR CELLS of oligodendrocytes for MULTIPLE SCLEROSIS, and encapsulated cells engineered to secrete CILIARY NEUROTROPHIC FACTOR (CNF) in AMYOTROPHIC LATERAL SCLEROSIS (ALS). Each of these diseases involves a circumscribed degeneration of identified populations of cells. Present transplantation techniques hold less prospect of finding clinical application in diseases that involve more widespread damage of multiple cell types, such as in ALZHEIMER’S DEMENTIA or MULTI-INFARCT DEMENTIA, STROKE or TRAUMA.
Whereas embryonic neurons have proved effective for functional transplantation in experimental animals, and initial clinical trials are promising, widespread clinical application is likely always to be limited by both ethical and practical constraints on the availability of human foetal cells. There is therefore active investigation of alternative sources of suitable tissues for clinical transplantation. These include: (1) improvements in the methods of cell preparation, HIBERNATION, CRYOPRESERVATION and implantation that allow better survival and more efficient use of available embryonic tissues. (2) Expansion of STEM CELLS and precursor cells in vitro, so that limited supplies of embryonic tissue can generate large quantities of cells that can be banked for use as and when required rather than just as and when available. (3) GENETIC ENGINEERING of ethically neutral cells, in particular allografts for ex vivo gene transfer. This has so far proceeded to the first clinical trials in ALS of spinal implantation of encapsulated baby hamster kidney cells engineered to secrete CNTF. The critical problems still to be resolved for both in vivo or ex vivo gene transfer relate to safety issues and the stability of long-term expression of the gene inserts. Moreover, this strategy is only likely to prove effective (at least in the foreseeable future) for delivery of diffusible neurotransmitters (see VOLUME TRANSMISSION), HORMONES or TROPHIC FACTORS, and not for neuronal reconstruction. (4) XENOGRAFTS of (for example, porcine) foetal cells. Although this provides the best long-term prospect for easily available neuronal tissues, problems related to long-term immunosuppression and the safety factors related to risks of cross-species transfer of new viruses are yet to be fully resolved.
Reference
Dunnett S.B. & Björklund A. (eds.) (1994) Functional Neural Transplantation, Plenum Press: New York.
STEPHEN B.DUNNETT
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