Intracerebral Grafting: A Tool for the Neurobiologist Review (1991)

Fred H. Gage and Lisa J. Fisher Department of Neurosciences School of Medicine University of California, San Diego La Jolla, California 92093-0624 Introduction Grafting tissue into the CNS has often been regarded as an intriguing field of study, conjuring visions of transferring characteristics or neural processes of one species to another. In fact, grafting is a well-estab- lished and powerful tool for addressing basic ques- tions concerning the development, function, and plasticity of the CNS. As early as the beginning of thiscentury, resultsobtained from the implantation of peripheral tissue into the brain helped to formulate the concept of a neurotrophic influence on neural growth (Tello, 1911a, 1911b). In more recent work, the use of grafting has contributed to the elucidation of factors involved in the differentiation, migration, guidance, and synaptogenesis in neural systems. Theuseofgraftingextends beyond theexamination of the developmental properties of the CNS. Im- planting neurons or neural tissue into the brain has contributed to an understanding of interrelationships between neural systems, as well as characterizing the structural and/or functional properties of the brain. Furthermore, with the reports in the late 1970s that neural grafts can restore functioning in an animal model of Parkinson’s disease (Bjorklund and Stenevi, 1979; Perlow et al., 1979), grafting is evolving into a feasible technique for replacing tissues or molecules lost in human neurological disorders. In this review, we highlight recent progress in neu- robiology attained through the use of intracerebral grafting. This discussion will focus on studies that have used intracerebral grafting to explore three gen- eral areas: basic principles in the development of the brain; structure/function relationships within the adult brain; and treatment of neurological disorders. In addition, the recent merging of gene transfer meth- odology with intracerebral grafting, which has the po- tential for expanding the utility of grafting, will be described. We hope to establish in this review that intracerebral grafting is not a scientific discipline or field of study; rather, it is a diverse tool to be used to address fundamental issues in neurobiology. Factors Important for Graft Survival Several important variables have been identified as crucial in the survival of intracerebrally implanted tis- sue. First, as a general principle, the donor tissue must be prenatal, and even more specifically, there are “windows” of embryonic development during which specific cell populations can be optimally dissected and successfully grafted to the brain. These windows are influenced by a number of developmental se- quences, such as the histogenic stage of the tissue of interest and the presence of fiber outgrowths from the developing neurons (Das et al., 1980; Seiger, 1985). Second, grafts survive better within young hosts; both the number of surviving neurons within a graft and the size of the graft are decreased in aged compared with young hosts (Hallas et al., 1980; Gage 1983; Crutcher, 1990). The most striking effect of host age on grafted neurons is in limiting the extent of fiber outgrowth from the grafted cells into adult or aged brain (Gage et al., 1983; Crutcher, 1990). Third, access to appropriate target sites influences graft survival. Cells implanted within an inappropriate target survive poorly and extend few axons when compared with the survival rates and axonal extension of cells implanted into an appropriate target (Foster et al., 1985, 1988). Fourth, denervation of a target area enhances graft survival and outgrowth (Gage and Bjorklund, 1986a). Deafferentation or damage may induce the produc- tion of trophic factors that support graft survival (Nieto-Sampedro et al., 1983,1984). Fifth, it is essential that grafts are rapidly vascularized (Stenevi et al., 1976), particularlywhen nondissociated chunks of tis- sue or large cell suspension grafts are implanted in the brain. Sixth, genetic matching of the donor and recipient tissues enhances graft survival. Obtaining survival of grafted tissue that is genetically foreign to the hosttypically requiresthe useof immunosuppres- sion (Widner and Brundin, 1988). Mechanisms of Graft Function The expectation of how an implanted cell would func- tion differs for each experimental paradigm. In many cases, the way in which grafts exert functional and regulated influences on specific host cells is unknown. Several possible mechanisms of action for implanted cells have been proposed: -Delivery of atrophic molecule: implanted cells may make and secrete trophic molecules that directly or indirectly support the survival and function of dam- aged or dying neurons (Figure 1). The specificity of the effect of the graft would be mediated by the pres- ence of specific receptors on the host cell. Regulation of the concentration of product would be influenced by the number of cells implanted and the distance of the implant from host target cells. -Transmitter/hormone secretion: grafted cells may make and secrete a neurotransmitter or neurohor- mone to replace a missing transmitter or hormone or to augment a deficient one (Figure 2). Once again, the specificity of the effect would be determined by the specificity of receptors on the host cells, and regu- lation of the concentration product would be influ-