Brain transplants

Brain transplantation of human neural stem cells in mouse model of Batten s disease. Basu, S B., Belichenko, P.V., Uchida, N., Tamaki, S., Eckert, K., Udani, V., Tsukamoto, A., Mobley, W.C. (2003). Abstr SocNeurosci, 335.7. 

Foetal mesencephalic tissue has been implanted in the striatum of patients with the juvenile form of Parkinson s disease and has been shown to develop functional axons this has enabled the dose of L-dopa to be reduced. Both imaging and pharmacological studies have now shown that functional dopaminergic neurons can develop in the brain of the patient following tissue transplantation. However, a major ethical objection has been raised to such transplants as six to seven foetal brains are required to obtain sufficient tissue. In addition, only about 20% of neurons survive transplantation. The ethical problem may be overcome by using brain transplants from domestic animals such as pigs. Such xenotransplants have been shown to survive in the human brain but the main problem with the extensive use of such transplants is the possible spread of viruses and prion infections. 

Kruger, S., Sievers, J., Hanson, C., Sadler, M., and Berry, M., Three morphologically distinct types of interface develop between adult host and fetal brain transplants implications for scar formation in the adult central nervous system, J. Comp. Neuml., 249, 103, 1986. 

Sievers, J., Kruger, S., Hansen, C. H., and Berry, M., Integration of fetal brain transplants into adult brain. Morphological study of the host/graft interface, in Neural Grafting in the Mammalian CNS, Bjorklund, A. and Stenevi, U., Eds., Elsevier, Amsterdam, 1985, pp. 159. 

From the experience with fetal mesencephalic brain transplantation programs, where hundreds of patients were treated in open trials before investigators became aware of serious side-effects prohibiting the program continuation, it is clear that obtaining controlled data is mandatory from the beginning of a clinical development program. 

Zhong J, Chan A, Morad L, Komblum H, Fan G and Carmichael S T (2010), Hydrogel matrix to support stem ceU survival after brain transplantation in stroke . Neurorehabilitation <8 Neural Repair, 24, 636—44. 

Since he had to get a brain transplant, he decided that the wise thing to do was to shop around. So, in shopping around he went to this center that had a number of brains in supply. The director of the center started to show him around and said, we have a number of brains that we would like to show you. He took the individual looking for the brain over to a refrigerated unit and said,... 

Calcineurin is involved in cardiac hypertrophy and in cognitive and behavioral defects in the brain. Inhibitors of calcineurin such as cyclosporine A and FK 506 are used clinically in transplant rejection and autoimmune diseases. 

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. 

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.)... 

P-glycoprotein, a plasma membrane transport protein, is present in the gut, brain, liver, and kidneys 42 This protein provides a biologic barrier by eliminating toxic substances and xenobiotics that may accumulate in these organs. P-glycoprotein plays an important role in the absorption and distribution of many medications. Medications that are CYP3A4 substrates, inhibitors, or inducers are also often affected by P-glycoprotein therefore, the potential for even more DDIs exists in transplant recipients.42... 

Stewart PA, Wiley MJ. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells a study using quail-chick transplantation chimeras. Dev Biol 1981 84 183-192. 

Espinosa de los Monteros, A., Zhang, M. and de Vellis, J. 02A progenitor cells transplanted into the neonatal rat brain develop into oligodendrocytes but not astrocytes Proc. Natl Acad. Sci. U.S.A. 90 50-54,1993. 

About 40% of this population express markers of oligodendrocytes, and a similar proportion have astrocytic markers. To test the potential of these cells in vitro, ES cells propagated in this fashion were transplanted into the spinal cord or cerebral ventricles of myelin-deficient rats. Two weeks after transplantation, ES derived cells were present in the dorsal columns of the spinal cord both at the implant and several millimeters in both directions from that site. The mouse origin of the ES cells transplanted into rat was confirmed by analysis of mouse satellite DNA in the grafts. Similarly, intraventricular transplanted cells formed myelin in multiple brain regions [29]. These and other results support the further study of stimulated ES cells for potential therapies in the nervous system. 

Yandava, B. D., Billinghurst, L. L. and Snyder, E. Y. Global cell replacement is feasible via neural stem cell transplantation evidence from the dysmyelinated shiverer mouse brain. Proc. Natl Acad. Sci. U.S.A. 96 7029-7034,1999. 

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],... 

Weimann J. M., Charlton C. A., Brazelton T. R. et al. (2003). Contribution of transplanted bone marrow cells to Purkinje nemons in human adult brain, PNAS, 100, 2088 2093. 

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