Brain Transplants?

Science  18 Dec 1998:
Vol. 282, Issue 5397, pp. 2213
DOI: 10.1126/science.282.5397.2213a

We have grown accustomed to the idea of human organ transplantation. Transplants of solid organs such as hearts, kidneys, and livers, as well as bone marrow, have become the life-saving treatments of choice for some diseases. Investigators are even looking at ways to successfully transplant organs from animals such as pigs into humans. But what about transplanting a human brain?

Although transplanting an entire human brain seems far-fetched, transplanting individual cell populations is not. In fact, the transfer of fetal donor neural grafts has been shown in repeated studies to correct some of the motor defects found in patients with Parkinson's disease. Turning to rodents as a study system, investigators have gone on to show that neural stem cells (NSCs) can also be isolated and used as donor cells. NSCs can be isolated from dissociated rodent brains and propagated in vitro by addition of extracellular growth factors (such as EGF or bFGF) or the introduction of growth-promoting genes (such as v-myc or large T-antigen).

As a natural follow-up to the rodent work, these authors set out to develop a graftable system of human NSCs. First, they isolated cell suspensions from the periventricular region of a 15-week-old human fetus, an area that is a rich source of NSCs in rodents. Next, they cultured these cells in an alternating mixture of EGF and bFGF for several months, screened the population for its ability to engraft, and then cloned out individual, stable cell lines. (They also introduced the growth-promoting v-myc gene in some experiments, but this proved unnecessary in the end.) By simply changing the culture medium to one containing serum, these NSC lines differentiated into neural and oligodendroglial cells in vitro. Coculture with primary murine central nervous system tissue was needed to drive differentiation most effectively down the astroglial pathway, another lineage that is naturally derived from the NSC in vivo and is the last cell type normally born during development; hence, the coculture may well have “recreated” the in vivo environment.

To determine how these NSC clones would react in situ, the authors transplanted them into the ventricles of newborn mice. In order to follow some of these clones in vivo, they were first transfected with a retrovirus that expresses the β-galactosidase gene that could serve as an unambiguous visual marker for human cells in a mouse brain. Following introduction, the human NSCs engrafted readily into the murine brain and migrated along pathways that have previously been demonstrated as natural routes for these cells in vivo. For example, microscopic examination of the introduced β-galactosidase tag showed that the cells moved to the mouse subcortical and cortical white matter, corpus callosum, and olfactory bulb. The human NSCs intercalated with native neurons and glia, and differentiated appropriately depending on the surrounding cell types and cues. They also integrated into the germinal zones at the opposite end of the brain and became appropriate neural cell types there. This proved that despite cell culture, cloning, and gene transfection, the NSCs retained their pluripotent status in vivo. In addition, the cells showed the ability to express a foreign gene seamlessly within the fabric of the brain.

The group went on to demonstrate the possibility of using NSCs in gene therapy applications in an in vitro setting. These cells express the alpha subunit of β-hexosaminidase, the gene that is defective in Tay-Sachs disease in humans. They then mixed in mouse brain cells that had the gene deleted to serve as a host for the cells. By enzyme analysis, they showed that significant quantities of the active β-hexosaminidase were produced by the cell mixture and resulted in diminished accumulation of pathologic material in the Tay-Sachs nerve cells.

As an in vivo test of the engrafting potential of the human NSC lines, they introduced NSC clones into the brains of another defective mouse strain, the meander tail (mea) strain. This particular mutant has a defect that prevents many granule neurons from developing or surviving in portions of the cerebellum. In mea mutants, after introduction into the external granule layer of the cerebellum, the human NSCs migrated to the proper layer of the cerebellum and differentiated into cells that appeared identical to normal mouse granule neurons. This feat is remarkable given the fact that the original cells used to create the NSC lines were derived from the human fetal periventricular region, not the postnatal cerebellum. This accomplishment demonstrates the plasticity of these cells and the retention of a response to normal differentiation cues in the animal.

Thus, human neural progenitor and stem cells can now be isolated and manipulated in vitro and in vivo. The amazing property of these cells to differentiate in situ in the recipient brain may eventually allow targeted introduction of cells into defined regions to correct specific defects, as well as to integrate in a more disseminated way for many types of neurologic diseases with widespread pathology.


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