Medicine: Collateral damage repaired.
Nature. 2003 Apr 17;422(6933):671-2.
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Comment by Kiminobu Sugaya This study proves our concept that neurospheres injected into ventricle migrate and incorporate into the host CNS (Qu et al., 2001). Since this transplantation method causes minimum damage compared with direct transplantation into brain tissue, immune attack to donor stem cells by the host will be reduced, and this results in better survival and efficacy of the transplanted stem cells. Although our group has repeatedly used this stem cell injection method (Kim et al., 2002), this article sets a milestone for the migration of stem cells through the ventricle wall—even the blood-brain barrier. At the same time, I would not recommend intravenous injection, because a large part of the neural stem cell may differentiate into blood or other peripheral-type cells before they reach the target area.
The next question would be whether this type of stem cell transplantation is useful for Alzheimer’s disease therapy. For the time being, I have to say: Not yet. We have transplanted neural stem cell into the lateral ventricle of AβPP-transgenic mice, and we found that the donor cells are differentiated into only astrocytes, not into neurons (in preparation for publication). This may be due to physiological functions of AβPP on stem cell differentiation (see ARF live discussion). Although we have to consider effects of the pathological disease environment on stem cell biology, intraventricle injection would be the best transplantation method for CNS stem cell therapies.
The recent manuscript by Pluchino et al. offers the intriguing possibility that cells can be delivered to all regions of the brain merely by injecting them into the bloodstream of animals. The numbers required to reach the brain for the dramatic improvements seen appear quite small. About a million were injected, which, given blood flow dynamics, can at best be in the range of thousands of cells reaching the brain. This small number appeared to be targeted to the sites of injury and thus had an effect disproportionate to their number. The authors suggest that this is because neural stem cells have a homing tendency, and they show that the cells express CD44 and other candidate homing molecules.
There were a number of points I found surprising in the manuscript.
1. In general, neural stem cells are not very migratory and, in normal development, are restricted to stem cell niches in the developing and adult brain. Stem cells, therefore, do not express homing receptors and ,indeed, labeling with CD44 antibodies does not show expression on neural stem cells in vivo or after short-term culture in vitro. CD44 expression is seen on astrocytes and astrocyte progenitors, however, and NSC cultures are known to stochastically differentiate into astrocytes, or at least express astrocytic markers after prolonged culture. In inflammatory disorders in most regions of the brain, damage does not promote stem cell proliferation (our unpublished results). While cell proliferation is observed, it can be attributed to glial progenitor cells, endothelial elements, and astrocytes. Thus, cues to ensure proliferation and direct appropriate differentiation of exogenously transplanted stem cells are unlikely to be present. Indeed, reports of direct transplantation of stem cells into spinal cord injuries has suggested that stem cells themselves do not survive well in damaged tissue. This would suggest that the cultured NSCs contained a significant fraction of astrocytes or astrocyte-like cells, which likely survived in the damaged milieu.
In the case of Alzheimer’s disease, it is unclear if such homing would direct adequate numbers of cells to appropriate sites in an Alzheimer’s brain and whether appropriate cues or an appropriate milieu would exist to direct site-specific neuronal differentiation.
2. Inflammation can alter blood-brain barrier kinetics, but that it allows stem cells or any cells other than microglia to cross the vascular endothelium is quite surprising. Local damage is known to enhance macrophage and Schwann cell invasion of the CNS, and these cells can migrate along blood vessels and can myelinate central axons. These Schwann cells, endogenous progenitors, as well as the small number of cells that transited the blood-brain barrier are likely responsible for the improvement seen.
It is unclear whether the endogenous glial progenitors proliferate in Alzheimer’s disease models or if remyelination offers therapeutic benefit. The degree of neuronal differentiation seen in the present report was small and unlikely to be a significant component of the observed benefit. It is, therefore, unclear whether a similar strategy would offer similar benefit in Alzheimer’s disease.
3. The recovery observed was dramatic and did not correlate well with the number of transplanted cells, or the degree and rate of remyelination reported. The authors correctly point out that trophic/indirect effects could be important. However, neural stem cells are not known to produce trophic molecules for astrocytes, neurons, or oligodendrocytes, and while the authors showed some production of cytokines in cultures, no quantitative data was shown.
The cytokines/trophic response required to enhance survival of endangered neurons in Alzheimer’s disease is likely to be different than the cytokine profile required for EAE-damaged cells. It is, therefore, unclear if one can assume the same therapeutic benefit would be seen in Alzheimer’s disease models.
These concerns in no way detract from the impressive nature of the results reported by Pluchino et al. Their finding that intravenous delivery of cells can deliver cells to regions that are otherwise inaccessible is an exciting finding, as well. At the very least, their results raise the possibility that growth factors and genes can be targeted to an appropriate site in a relatively straightforward manner.
At the same time, this study does raise questions about the cell population that was effective and the mechanisms underlying the observations. It will be important to determine why the cells delivered intravenously were effective before one can proceed further. It is also important to note that long-term passaged cultures are clearly different from acutely harvested cultures, and results obtained with immortalized stem cell lines have been different from acutely harvested or short-term passaged cells. Indeed, Morsehead and colleagues have suggested that stem cell character is altered in as few as 10 passages (Morshead et al., 2002). Finally, one must determine not only whether human cells behave in the same way, but also whether the blood-brain barrier will be equally permeable.