Mechanisms and use of neural transplants for brain repair

Abstract

Under appropriate conditions, neural tissues transplanted into the adult mammalian brain can survive, integrate, and function so as to influence the behavior of the host, opening the prospect of repairing neuronal damage, and alleviating symptoms associated with neuronal injury or neurodegenerative disease. Alternative mechanisms of action have been postulated: nonspecific effects of surgery; neurotrophic and neuroprotective influences on disease progression and host plasticity; diffuse or locally regulated pharmacological delivery of deficient neurochemicals, neurotransmitters, or neurohormones; restitution of the neuronal and glial environment necessary for proper host neuronal support and processing; promoting local and long-distance host and graft axon growth; formation of reciprocal connections and reconstruction of local circuits within the host brain; and up to full integration and reconstruction of fully functional host neuronal networks. Analysis of neural transplants in a broad range of anatomical systems and disease models, on simple and complex classes of behavioral function and information processing, have indicated that all of these alternative mechanisms are likely to contribute in different circumstances. Thus, there is not a single or typical mode of graft function; rather grafts can and do function in multiple ways, specific to each particular context. Consequently, to develop an effective cell-based therapy, multiple dimensions must be considered: the target disease pathogenesis; the neurodegenerative basis of each type of physiological dysfunction or behavioral symptom; the nature of the repair required to alleviate or remediate the functional impairments of particular clinical relevance; and identification of a suitable cell source or delivery system, along with the site and method of implantation, that can achieve the sought for repair and recovery.

Transsynaptic tracing and its emerging use to assess graft-reconstructed neural circuits

“…Indeed, since the inception of the neural cell replacement field, there has been a steady accumulation of evidence suggesting that many aspects of host‐graft connectivity recapitulate functionally relevant aspects of healthy endogenous connectivity after grafting new neurons to repair various damaged cerebral and spinal circuitries . Additionally or alternatively, the functional impact of grafted neurons in certain contexts may also be attributed to a number of mechanisms other than cell replacement, including the normalization of disordered host neuronal activity or the trophic support of spared host neurons, without a prerequisite that the graft‐derived connectivity recapitulates that of the intact system.…”

Neuronal Replacement as a Tool for Basal Ganglia Circuitry Repair: 40 Years in Perspective

“…Ultrastructural studies have shown that the cortical and thalamic afferents from asymmetric synaptic contacts with the grafted striatal neurons. As in the intact striatum, the contacts are made on both dendritic spines and shafts with a predominance of spine synapses, although the relative proportion of spine synapses tends to be lower than in the normal striatum (Wictorin et al, 1989a;Xu et al, 1991;Clarke and Dunnett, 1993;Dunnett and Björklund, 2017). The nigral TH-positive afferents provide a dense innervation of the DARPP32-positive striatum-like patches (Figures 2G,H) and have been shown to make synaptic contacts onto dendrites and spines of medium spiny grafted neurons (Wictorin et al, 1988(Wictorin et al, , 1989b.…”

“…Neural transplantation is a classic approach in cold-blooded vertebrates, salamanders, fish, and frogs, that goes back to the early decades of the last century. Similar studies in mammals were initially unsuccessful due to shortcomings of the methods used at the time, and it was not until the 1970s, with the introduction of histochemical methods and modern tract-tracing techniques, that the effective tools for the study of survival and growth of neural tissue became available (for reviews of these early developments see Thompson and Björklund, 2015;Dunnett and Björklund, 2017). Subsequent progress has been critically dependent on the development of increasingly more refined and powerful techniques for studies of neuronal connectivity that has taken place over the last decades.…”

Gene and Cell-Based Therapies for Parkinson's Disease: Where Are We?

“…The move to trial hfVM in the clinic came on the back of robust reproducible preclinical findings in neurotoxic animal models of PD that had been carried out in many different laboratories around the world. These studies showed that allografts of the developing VM into rats lesioned unilaterally with 6-hydroxy-dopamine (6-OHDA) could survive, make and receive connections from the host brain, release DA, and restore behaviors to normal in these animals (reviewed in [ 174 ]). This was also shown in NHP, most notably marmosets [ 175 ], and it was on this background that patients were first grafted in the late 1980s and thereafter till the end of the century.…”