Grafting Supportive Treatments

In our opinion, the most important factor deciding the fate of the future graft is the trophic support offered by the intrinsic milieu, the host environment, or administered in vivo postgrafting. Neurotrophic factors have been the focus of intense studies discussing them as therapeutic agents in neurodegenerative diseases. Future testing in primate models will be necessary. In the field of neurotransplantation, the studies proposing NTF as in vitro and in vivo adjuvants to the graft have been significantly more successful. Overwhelming evidence from developmental neuroscience experiments demonstrated that growth factors are crucial in the differentiation of neural progenitor cells or, in general, less differentiated cells that are abundant in the fetal grafts. Among these factors, epidermal and fibroblast growth factors were most important in promoting the mitogenic capacity of neuroglial progenitors. Whereas work by Gage and colleagues established FGF as a principal mitogenic factor in the developing neuronal population, other growth factors may participate in the expansion and differentiation of the neuronal precursor cell population, as demonstrated by in vitro and in vivo experiments with insulin-like growth factor and hepatocyte growth factor. Interestingly, the latter seems to function as a primer for other trophic signals.

Hepatocyte growth factor is only one of the newer trophins for the CNS. Today, the family of growth and trophic factors proposed to affect the survival and development of neuroprogenitor cells is probably the largest in this ever expanding field. Factors like cytokines, once considered to be exclusively neuro-toxic (e.g., TNF), are now studied for neurotrophic properties. Among them, leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF), in addition to more traditional growth factors like platelet-derived growth factor (PDGF), are considered to be potent promoters of neuroprogenitor cell proliferation and eventually differentiation. In vivo, CNTF produced by reactive astrocytes can prevent the degeneration of dopaminergic neurons in adult rats. Astrocytes and endothelial cells surrounding or infiltrating the transplant are susceptible to the effects of PDGF, which may control the survival of graft through neovascularization.

In addition to the proliferative support offered to neuroprecursor cells, NTFs are key players in their differentiation to the mature phenotype. This function may be critical for the graft integration in the host environment. It was shown that, at least when cell lines were used (e.g., PC12), in vitro pretreatment with NGF is crucial for the in vivo phenotype of the graft: differentiated (NTF-treated cells) versus nondifferen-tiated, tumorlike (nontreated cells). The in vivo effects of NGF become even more obvious when fetal grafts are continuously treated through in situ injection or when regeneration is promoted through gene delivery using transformed cells.

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