A cytokine called leukemia inhibitory factor (LIF) plays a critical role in adult neurogenesis in the olfactory bulb in vivo, according to a report in the current Journal of Neuroscience.
Various molecules have demonstrated effects on stem cell division or differentiation in vitro, but it has been difficult to identify such effects in vivo. A research team from several institutions in France and the United States, led by Paul Patterson of the California Institute of Technology in Pasadena and Sylvan Bauer of the University of Lyon in France, has focused its attention on the progenitor cells that support the constant turnover of olfactory sensory neurons in the olfactory epithelium (OE). When the target of these sensory neurons-the olfactory bulb-is experimentally ablated, the result is a wave of apoptosis in the OE, followed by a wave of mitosis in the resident progenitor cells.
Using this experimental paradigm in adult mice, Patterson and colleagues assayed for the various cytokines and growth factors that have been reported to stimulate olfactory neurogenesis in vitro and found that only leukemia inhibitory factor was reliably induced by the lesion. Some of this LIF is expressed in the damaged OE neurons, though some may also be produced by macrophages. When the researchers repeated the experiment in LIF knockout mice, the olfactory bulb ablation failed to induce neurogenesis, indicating that LIF is essential for OE cell proliferation. Finally, the researchers showed that transfecting exogenous LIF to the OE via a viral vector in intact animals increases OE cell turnover.
There is also evidence that LIF regulates cell proliferation in granule cells of the dentate gyrus in the hippocampus, a population of stem cells of particular interest to AD research. Last year, researchers in Japan (Maekawa et al., 2002) demonstrated increased LIF expression in the rat hippocampus following kainic acid-induced seizures. Maekawa and colleagues noted an initial upregulation of LIF mRNA in the dentate granule cell layer, followed in turn by increases in the polymorph molecular layers, and then increases in strata oriens and radiatum of the CA1 and CA3 subfields.
"We are very keen to test LIF in AD mouse brains to see if it can help produce new neurons," Patterson told the Alzheimer Research Forum.—Hakon Heimer
- Minami M, Maekawa K, Yamakuni H, Katayama T, Nakamura J, Satoh M. Kainic acid induces leukemia inhibitory factor mRNA expression in the rat brain: differences in the time course of mRNA expression between the dentate gyrus and hippocampal CA1/CA3 subfields. Brain Res Mol Brain Res. 2002 Oct 30;107(1):39-46. PubMed.
- Bauer S, Rasika S, Han J, Mauduit C, Raccurt M, Morel G, Jourdan F, Benahmed M, Moyse E, Patterson PH. Leukemia inhibitory factor is a key signal for injury-induced neurogenesis in the adult mouse olfactory epithelium. J Neurosci. 2003 Mar 1;23(5):1792-803. PubMed.