THE LANCET Neurology Vol 1 July 2002 144
If one therapeutic concept could be applied to neurodegenerative disease, stroke, brain tumours, Down’s syndrome, epilepsy, and schizophrenia, would it be a neurologist’s dream or nightmare? This is the potential suggested for neurogenesis therapies that target new neuron formation. But in April, when Michael Lévesque (Cedars-Sinai Medical Center, Los Angeles, CA, USA) reported the first human-adult neural stem-cell transplant, his data were greeted cautiously, and even condemned—just one indication of how the field is generating more questions than answers. Neural stem-cell research overturned fundamental clinical dogma in 1998, when Fred Gage’s team at the Salk Institute (La Jolla, CA, USA) reported that neurogenesis does occur in the adult human brain. Previously, says Stefano Geuna (Università di Torino, Italy), neural stem cells were thought, with a few exceptions, to have a role only until the early post-birth period. Recent findings, however, clearly show that neural stem cells persist in adult life, helping to maintain nervous-system integrity, he suggests.
Several groups have shown that certain precursors can differentiate into astrocytes, oligodendrocytes, and neurons, at least in animal models. “Adult human neural cells in vitro have not been fully characterised as stem cells”, notes Gage, though he and others “have isolated adult human brain cells in culture that can become neurons”. Although neurogenesis seems restricted mostly to the hippocampus and forebrain subventricular zone, Yvan Arsenijevic (Hôpital Ophtalmique Jules Gonin, Lausanne, Switzerland) and co-workers have found neural progenitors in many areas of the human CNS. However, he admits, “we do not know if they are true stem cells”.
So, while awaiting this final proof, “the recent demonstration that adult neurogenesis can be modulated by environmental factors holds very good prospects for a variety of neuronal-replacement therapies”, says Geuna. In theory, therapies could be developed from several sources, says Kiminobu Sugaya (University of Illinois at Chicago, USA)—embryonic stem cells, adult peripheral stem cells (eg, from bone marrow), or adult neural stem cells. However, societal reaction and recent reports of cell fusion occurring in culture are tempering enthusiasm for approaches that use embryonic stem cells. Sugaya, whose team is producing neurons and glia from mesenchymal stem cells in vivo, notes that autologous transplantation using adult precursors overcomes many issues, including tissue rejection.
Lévesque’s patient Dennis Turner, has already had such a transplant and is reported to have sustained improvement at least a year after his treatment for Parkinson’s disease. Ultimately, these neurogenic techniques may generate everything from GABA neurons to treat Huntington’s disease to stem cells that enhance spinal-cord regrowth and prevent scar formation. Arsenijevic and collaborators are already working on photoreceptors to repair degenerated retina, while Geuna’s team is studying the ability of adult neural progenitors to repair peripheral-nerve trauma.
Understanding the pathways of normal and pathological neurogenesis in disease is vital for the success of neural stem-cell approaches. So far, the success of embryonic neuronal transplants for PD has been limited by dyskinesias in a few patients (Nat Neurosci advanced online publication, 3 June 2002; DOI 10.1038/nn863). Moreover, defective neurogenesis is being linked with apparently unrelated conditions; epilepsy may be a result of uncontrolled neurogenesis while neurodegenerative diseases might disrupt maintenance or renewal of new neurons. Already, Sugaya’s team has found that amyloid precursor protein is involved in regulating stem-cell migration and differentiation, and mice lacking reelin show failure of neural stem-cell migration; curiously, the protein is markedly reduced in the brains of patients with psychosis. Recently, a team led by Clive Svendsen (University of Wisconsin Madison, USA) suggested that Down’s syndrome could result from defective control of genes that influence neuronal differentation (Lancet 2002; 359: 310–15).
Gage, and many others, want answers to key questions: “What controls differentiation? What controls migration? What controls survival?”. The latest publication from his laboratory points to astrocytes, which in adult rats determine the proliferation and fate of neural stem cells in a site-specific way (Nature 2002; 417: 39–44). The question everyone wants answered is what function neurogenesis plays in the healthy brain. Although a role in learning and memory seems likely, the answer is far from clear. Gage hypothesises that neurogenesis in the adult hippocampus “is involved with persistent neuronal plasticity and has a specific role in sustaining the ability to make new memories”. Sugaya notes that the number of adult neural stem cells “is highly related to the cognitive function”. Moreover, in rats, his group found that neural stem-cell transplantation improved cognitive function.
These findings beg a further crucial question, says Arsenijevic—is the brain like a muscle that needs exercise to maintain its form? And if so, how best to do that? Gage’s team reports that learning tasks, environmental enrichment, and even running can stimulate neurogenesis. Svendsen argues that variations in neurogenesis seem to depend both on the stem cell’s intrinsic properties and the local environment. As he suggests, the old nature-nurture debate is back. But this time, it’s neural.