24 June 2002. The current on-line edition of Nature features two reports on generating functional adult cells, including neurons, from stem cells.
Catherine Verfaillie and colleagues at the University of Minnesota in Minneapolis found a rare type of mesenchymal stem cell in adult mouse and rat bone marrow that retains the ability to differentiate along other mesodermal pathways, but also along endodermal and ectodermal pathways. In the presence of neural signaling molecules, these mesanchymal adult progenitor cells (MAPCs) could be induced to become neural-like cells, many of which expressed markers indicative of serotonergic, dopaminergic, or GABAergic neurons. They had polar structures with tau-containing axon-like processes and MAP2-containing somatodendritic compartments.
In a second round of experiments, Jiang et al. injected MAPCs injected into 3.5-day-old blastocysts. Most animals killed at 6-20 weeks contained the progeny of MAPCs along with their own cells. The "foreign" cells were distributed throughout many tissues, including the brain, where the authors spotted both neurons and glia derived from the injected MAPCs. Interestingly, the majority of granule cells of the hippocampal dentate gyrus were derived from the mesenchymal stem cells.
Finally, the authors injected MAPCs into the blood of adult animals. They again found evidence of incorporation in a variety of tissues, though not in brain, where the blood-brain barrier would keep out anything as large as a cell floating by.
Adult-derived stem cells like MAPCs have potential advantages over embryonic stem (ES) cells, not the least of which is the ethical storm surrounding the use of 5-day-old human embryos to derive ES cells. However, ES cells have the advantage of unlimited proliferation in culture and may offer more potential for genetic manipulations to ensure the appropriate development of particular cell types.
In the other report, Ron McKay and colleagues at the National Institute of Neurological Disorders and Stroke, in Bethesda, Maryland, sought to overcome the problem that existing generation of dopaminergic (DA) neurons ES cells is unreliable. Kim et al. increased the likelihood of producing DA cells by introducing the transcription factor nuclear receptor-related 1( Nurr1) into the genome of mouse ES cells. They further encouraged differentiation into DA cells by treating the cultures with fibroblast growth factor 8 (FGF8) and sonic hedgehog (SHH), which are essential for the differentiation of DA cells in the midbrain in vivo.
With these manipulations, they nudged about 80 percent of their ES cells into becoming fully functional dopamine-releasing cells. When the cells were grafted into a Parkinson's disease model (6-hydroxy-dopamine lesioned mice), they survived, extended axons into the host animal's striatum (the target of substantia nigra dopamine neurons lost in PD), and formed functional synapses. The grafted cells' performance under electrophysiological recording was similar to that of endogenous dopamine neurons. Finally, lesioned mice with grafts performed significantly better than lesioned, non-grafted mice on a number of motor assessments used in PD models, the authors write.
A concern with ES cell grafts is that they have shown a propensity to develop tumors. In this study, McKay's team found no evidence of continuing cell division within the grafts up to 8 weeks after surgery.-Hakon Heimer.
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keenek CD, Ortiz-Gonzalez XR,
Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Lowk WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002 Jul 4;418(6893):41-9. Abstract
Kim J-H, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N, Lee S-H, Nguyen J, Sanchez-Pernaute R, Bankiewicz K, McKay R. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature. 2002 Jul 4;418(6893):50-6. Abstract