688 Neuronal progenitors as tools for cell replacement in the nervous system Oliver Bristle 1 and Ronald DG McKay 2 The clinical prospect of using neural precursor cells for reconstructive approaches in the nervous system has received strong impetus from a recent series of important experimental findings. Transplantation studies in the developing brain have demonstrated that migration and differentiation of neural precursor cells are regulated predominantly by environmental signals. Several observations suggest that the mature CNS retains at least some of these guidance cues. These findings, together with recent evidence for the persistence of neural stem cells in the adult mammalian brain, have made precursor cell recruitment a new focus in CNS reconstruction. Addresses Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-4092, USA 1 e-mail: brustle@codon.nih.gov 2e-rnail: mckay@codon.nih.gov Abbreviations BDNF bFGF EGF HIV IGF-1 MPTP NCAM NGF PD PSA TH brain-derived neurotrophic factor basic fibroblast growth factor epidermal growth factor human immunodeficiency virus insulin-like growth factor 1 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine neural cell adhesion molecule nerve growth factor Parkinson's disease polysialic acid tyrosine hydroxylase Currant Opinion in Neurobiology 1996, 6:688-695 @ Current Biology Ltd ISSN 0959-4388 Introduction Transplantation is one of the most effective strategies for restoring lost cell and tissue function. Widely used in a variety of organ systems, transplant approaches in the nervous system are still in their infancy. The complexity of the tissue and our limited knowledge about the mech- anisms required for neuronal integration have restricted therapeutic efforts to reconstitute local, well characterized neurotransmitter deficits, such as restoring the nigrostriatal dopaminergic system in Parkinson's disease (PD) patients (see e.g. [1,2,3°]). Naturally, such an approach puts a lot of emphasis on the donor cell population, and a considerable effort in the transplant field is still directed at establishing and improving dopaminergic donor cells. In general, this strategy can be referred to as deterministic. It includes pinpointing a local cellular deficit and ameliorating this deficit by implanting a defined cell population (Figure la). Although used successfully in PD patients, the prospect of using such a strategy for the treatment of more widespread neurological diseases or for the reconstruction of ischemically or traumatically lesioned brain regions is less encouraging. Reconstruction of a damaged brain region would require a large variety of neuronal and glial donor cells, and each would have to be equipped with detailed information on how to interact with the host environment. Non-cell-autonomous concepts provide a more promising perspective. These concepts emphasize the plasticity of individual precursor cells and regard region-specific differ- entiation as a response of pluripotent precursor cells to lo- cal environmental cues. While the importance of non-cell- autonomous signaling is well accepted in developmental biology, it is only recently that precursor cell plasticity and environmental signals have been successfully exploited for the local integration of transplanted neural precursor cells (Figure lb). In covering transplantation studies in developmental neurobiology alongside advances in the field of classic neural transplantation, this review describes the new challenges in CNS reconstruction. Classic neural transplantation Transplantation of solid or dissociated embryonic CNS tissue into the lesioned brain or spinal cord is the most direct approach towards restoration of lost nervous system function. Initiated long before the age of neurotrophins and gene therapy, it is also the approach that originally established neural transplantation as a therapeutic tool. On the basis of many years of experimental work in rodents and non-human primates, this approach naturally was the first to hit clinical reality. Today, fetal nigral transplantation represents an experimental treatment for PD. While a continuous flow of published clinical follow-up studies suggests that most of the transplant recipients show some improvement in motor features [1,2], it is only recently that transplants of fetal human mesencephalic tissue to the caudate-putamen of PD patients have been shown convincingly to survive and differentiate into mature tyrosine hydroxylase (TH)-positive neurons [3"]. Currently, there is great interest in standardizing the transplant procedure as well as the subsequent evaluation of the patients. The initiation of a placebo-controlled study in which control patients undergo a sham surgery (i.e. they undergo surgery but do not receive donor cells) has received widespread and controversial attention [4-6]. However, standardized and appropriately controlled clinical trials are required to determine the therapeutic value of this procedure and its applicability to a broad spectrum of patients.