The therapeutic potential of human stem cells seems a little more realistic, thanks to results published in this month's Nature Biotechnology. Two groups have succeeded in transplanting human neural progenitors into neonatal mice. From there, the progenitors were seen to migrate and differentiate into cells of the three major neuronal lineages, neurons, astrocytes, and oligodendrocytes.
Led by Tamir Ben-Hur, Hadassah University Hospital, Jerusalem, and James Thomson, University of Wisconsin, the teams used slightly different approaches to isolate the neuronal progenitors prior to transplantation. Thomson's group induced differentiation of the ES cells by first detaching them from their layer of feeder cells and propagating them as embroid body (EB) suspensions that were then plated with bFGF. Ben-Hur's group allowed differentiation to occur during prolonged incubation on a fibroblast feeder layer until cells expressing the neural marker N-CAM (neural cell adhesion molecule) were detected. Thomson's group used the enzyme dispase to selectively remove neural precursors, while the Israeli lab did this mechanically. Both labs propagated the cells as suspensions of neural spheres that, upon plating, differentiated into neurons, astrocytes, and oligodendrocytes as determined by the presence of lineage-specific markers.
Both labs report similar results from transplantation of precursors into neonatal mouse brain ventricles. Detected by their incorporation of human-specific probes, grafted cells were found in the majority of host brains four to eight weeks after transplantation, and had migrated to the cortex, hippocampus, olfactory bulb, thalamus, hypothalamus, and corpus callosum. Neurons and astrocytes made up the majority of the differentiated cells, though Ben-Hur et al. also found cells expressing oligodendrocyte markers.
In an accompanying News and Views article, Lorenz Studer, Memorial Sloan-Kettering Cancer Center, New York, commends this work as taking crucial initial steps towards exploiting stem cell technology but raises the bar for future studies, commenting that "neurophysiological studies will be required to assess whether the cells are integrated into the host brain at a functional level." It is also doubtful that older mice would integrate the transplanted cells as easily as do neonatal ones.
... and Tracking
Meanwhile the same issue of Nature Biotechnology, carries a report by Joseph Frank et al. from the Laboratory of Diagnostic Radiology Research, NIH, on an improved method for detecting transplanted stem cells with magnetic resonance imaging. They have developed magnetodendrimers. These tiny paramagnetic iron oxides embedded in a synthetic mesh exhibit enhanced magnetic properties and can be readily detected at levels as low as 10 pg iron/cell. Frank et al. introduced these superparamagnetic tracers into rat neural stem cells, which could then be traced for up to eight weeks after transplantation.
"This is definitely a very promising method for tracing cell lines non-invasively," commented David Alsop, an MRI specialist from Beth Israel Deaconess Medical Center, Boston.—Tom Fagan
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- Reubinoff BE, Itsykson P, Turetsky T, Pera MF, Reinhartz E, Itzik A, Ben-Hur T. Neural progenitors from human embryonic stem cells. Nat Biotechnol. 2001 Dec;19(12):1134-40. PubMed.
- Bulte JW, Douglas T, Witwer B, Zhang SC, Strable E, Lewis BK, Zywicke H, Miller B, van Gelderen P, Moskowitz BM, Duncan ID, Frank JA. Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol. 2001 Dec;19(12):1141-7. PubMed.
- Studer L. Stem cells with brainpower. Nat Biotechnol. 2001 Dec;19(12):1117-8. PubMed.
- Zhang SC, Wernig M, Duncan ID, Brüstle O, Thomson JA. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol. 2001 Dec;19(12):1129-33. PubMed.