Neuron transplantation

Non-neuronal transplants such as adrenal chromaffin cells have been tried but do not survive although some L-dopa-producing cell lines (e.g. PC 12) or glomus cells of the carotid body do produce DA in vivo and may provide the equivalent of a continuous infusion of dopa (and DA) directly into the brain. Expression of tyrosine hydroxylase to promote dopa and DA synthesis in striatal cells by direct gene transfer in vivo or in cultures for subsequent transplanting, may also be possible. (See Dunnett and Bjorklund 1999 for a review of these approaches.)... 

Cellular therapy is the replacement of lost or dysfunctional tissues with new ones. Various cell types have been evaluated and considered for therapy. In the CNS, fetal neuronal tissue has been particularly evaluated for its merit in treating neurological diseases and injuries [1]. While numerous experimental and clinical transplantation studies showed that fetal neuronal transplants improve functional deficits in models of CNS diseases [2-5], others reported less positive outcomes [6, 7]. In addition, the rate of survival of fetal neuronal cells transplanted into the adult brain is relatively low, requiring large quantities of tissue, generally from several fetuses, for therapy. Researchers are looking at other opportunities for cellular therapy, particularly in the CNS. 

DOPAMINERGIC NEURON TRANSPLANTATION IN THE WEAVER MOUSE MODEL OF PARKINSON S DISEASE Edited by Lazaros C. Triarhou... 

Cellular therapies in transplantation and cancer are based on specific cells separated or sorted from human blood, bone marrow, or cord blood by means of their specific cell surface markers or cell differentiation antigens, e.g., CD3, CD4, CD8, CD 14, CD 19, and CD34. For example, the CD34+ stem cells, especially those derived from human embryos, have the capacity to differentiate in culture to generate different somatic cells, e.g., liver cells, heart cells, neurons, etc. This exploding field of research is now termed regenerative medicine. 

Clearly a disorder eombining (1) with (a) would mean that little improvement could be expeeted by manipulating the lost NT, since the nerves are no longer there to release it physiologieally. The main hope then would be to try to replenish the neurons with transplants (regeneration may be possible one day) and hope they become appropriately innervated, or modify the action of some other NT which has become exaggerated (or redueed), as a result of the primary NT loss. By contrast it is easier to treat a disorder, whether eharaeterised by neuronal degeneration ((1) above) or not (2), if it is suffieient just to provide NT (b), as appears to be the case in Parkinsonism. 

Unfortunately transplants require 6-7 foetal brains to obtain enough transplantable material for one patient, which itself raises ethical considerations, and as the tissue cannot diffuse its influence is restricted, even with multiple injection sites, and only a fraction (approx. 20%) of the neurons survive. Also without knowledge of the cause of PD the transplant could meet the same fate as the original neurons. The concept, however, demands perseverance and a number of variants are being tried. 

Eehner In string mutants, not everything works. We have heard from Bill Chia that the first neuroblast divisions follow a very stereotyped program that is also realized after transplantation or in vitro. If you do not allow divisions, the program is not realized and late neuron types are never specified. 

A basic property of differentiated neuronal cells is the expression of one classical neurotransmitter and several neuropeptides. In vivo studies with NC cells first demonstrated that the choice of neurotransmitter phenotype could be altered by the environment. In these studies, NC cells were examined by means of chimera transplantation. Two of the final NC cell phenotypes are sympathetic,... 

Stem cell transplantation to replenish neurons lost in Parkinson s disease 512... 

Weimann, J. M., Johansson, C. B., Trejo, A and Blau, H. M. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat. Cell Biol. 5 959-966, 2003. 

Finally, cellular transplantation approaches have also been tried. These therapies are aimed at replacing the striatal neurons. However, in view of the widespread pathology, it remains doubtful that this disorder can be treated successfully with these interventions. 

Freed,C.R.,Greene,P.E.,Breeze,R. E.etal.Transplantation of embryonic dopamine neurons for severe Parkinson s disease [Comment]. N. Engl. J. Med. 344 710-719, 2001. 

The cerebral endothelial cells of the blood-brain barrier originate from the middle germinal sheet of the embryo, the mesoderm [17]. Concomitant with migration and proliferation of capillary endothelial cells during formation of the cerebral vascular network occurs the imprinting of the cells. Thereby, induction by the cellular surrounding plays an important role [18-21], The relevance of the cellular environment for the development of the barrier function of cerebral microvessels was first demonstrated by Stewart and Wiley [22], who transplanted embryonic brain tissue of a quail into embryonic gut tissue of chicken and vice versa. The cerebral transplant was vascularized by intestinal vessels, in which properties of the blood-brain barrier had been induced. In transplanted brain vessels, however, no characteristics of a barrier could be demonstrated, due to the lack of a neuronal environment. These results indicated that the cerebral microvessels are of extraneuronal origin, with properties that are induced by the cellular environment. In addition, brain tissue has the capability to induce blood-brain barrier characteristics also in noncerebral vascular tissue [23],... 

NGF chemically conjugated to 0X26 6.2 pg/ injection i.v. injection 4x every 2 weeks Rat intraocular forebrain Survival of cholin-transplant ergic neurons ... 

Studies of mammals subjected to SCN destruction and transplantation have revealed that the hypothalamic SCN contains a master circadian oscillator which is involved in a number of behaviours and hormonal secretions. The circadian oscillatory activity of SCN neurons is directly demonstrated by the measurement of [ " C] glucose metabolic activity and field potentials assessed by electro-physiological devices. The clock oscillatory genes mPer1 and mPer2 are expressed rhythmically in most neurons in the SCN. Thus, thousands of clock cells in the SCN might generate the rhythm. 

A potentially promising, although very controversial, approach to the treatment of Parkinson s disease is replacement of dopaminergic neurons. The grafting of fetal substantia nigra tissue, which contains the dopamine neurons, into the striatum of parkinsonian patients has been modestly successful. The procedure will remain experimental, however, until the many practical problems and ethical issues associated with the use of fetal tissue are resolved. The discovery of pluripotent stem cells is also being viewed as a possible way of developing dopamine neurons for transplant purposes. 

Fricker, R.A., Carpenter, M.K., Winkler, C., Greco, C., Gates, M.A., and Bjorklund, A. (1999) Site-specific migration and neuronal differentiation of human neural progenitor cells after transplantation in the adult rat brain. / Neurosci 19 5990-6005. 

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