Kim S, Chang KA, Kim JA, Park HG, Ra JC, Kim HS, Suh YH.
The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer's disease mice.
PLoS One. 2012;7(9):e45757.
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This is very exciting work. The paper by Uchida etal provides the animal model and proof in principle for the clinical trial. Although the “shiverer” mouse has been used extensively to study myelination with many types of transplanted cells obtained from rodents and humans, this study clearly demonstrates that fetal derived HuCNS-stem cells can integrate into existing axon fiber tracts and myelinate axons.
Several points in the Uchida paper are of interest:
1) The low proliferation rate of 5-7 percent of the human cells after transplantation suggests that these stem cells are generating more progeny and may provide more oligodendrocytes over time. The problem with the shiverer mouse model is that the mice do not live long enough to do behavioral studies after transplantation and to assess the extent of continuous production of myelinating cells. The data presented suggest that these cells are a good source for myelin producing oligodendrocytes.
One worry on everyone’s mind is always whether these cell will proliferate in an uncontrolled manner to produce tumors. It appears from these and other studies using these HuCNS cells that this is not the case, which is critical for human trials.
2) It is very interesting that the human cells appear to be responding to the same signals as the endogenous mouse cells by proliferating and making more healthy human oligodendrocytes. This suggests that the signals originating in the diseased brain to make more myelin producing cells are interpreted in a similar fashion by both human and mouse oligodendrocytes. What is really interesting is that the human stem cells seem to prefer to differentiate into predominantely myelin producing oligodendrocytes over the production of neurons and glial cells. This results in the generation of the needed cell type and minimizes the appearance of the “wrong” cell types.
The clinical study by Rowitch’s group shows that these human HuCNS-SCs can be transplanted into young human brains and engraft. There does not appear to be any overgrowth of transplanted cells, thus minimizing the concern of tumor formation. The data using magnetic resonance imaging methods suggest that these cells are contributing to the generation of new myelin in and around the transplantation sites. It does not appear that the cells migrate as extensively in the human brain as they do in the rodent brain, which is consistent with many other transplant studies that compare the migration of human cells and rodent cells. Human cells can migrate great distances in the rodent brain. Whether this is true in the human brain is less certain.
Nonetheless, this phase 1 study provides exciting new data that these HuCNS-SCs are well tolerated and point to future trials. One would expect that when larger regions of the brain are infused with healthy cells a better outcome could be achieved. Intervention earlier in the disease process may also produce a better outcome. The authors note that since this was a phase 1 trial, no subjects were transplanted as controls. Therefore the minor behavioral improvements observed, while very encouraging, are hard to interpret. This study should lead to another trial that may be performed on younger subjects.
I am cautiously optimistic about these results. We have also found that hippocampal viral gene delivery of FGF2 or IL-10 is beneficial in spatial learning and reducing amyloid load in APP+PS1 mice. However, it is surprising to see that xenogenetic immune rejection is not an issue by intravenous injection of human stem cells to immunocompetent mice for 13 times over 3 months in this study.
Figure S1 shows the migration of fluorescent particles labeled hASC into the brain, but it is unclear if they transmigrated across the blood brain barrier into brain parenchyma, or still stayed in the cerebrovasculature. It is also unclear if the same result was obtained after repetitive injection of hASC. The fluorescent signal could be directly from the particles but not from hASC. Some immunofluorescence or electron microscopic imaging would be helpful for future studies.
As for IL-10 or VEGF upregulation in brain after hASC injection, these factors could be from peripheral blood or the cerebrovascularture (especially VEGF is highly abundant in endothelium). If so these are rather indicative of peripheral inflammation due to hASC xenotransplantation. A comprehensive characterization of peripheral immune activation would be desirable. As for the in-vitro study, I am not sure what is reconstituted in vitro without detection of hASC-neuron-microglia interaction in Tg2576 mouse brain. It is likely that hASC injection may contribute to some beneficial effects to hippocampal function in a peripheral manner, not necessarily via migration in to the CNS. I am curious if mouse ASC from the original host would have the same effect in this study.
Nonetheless, stem cell approaches should be encouraged to be rigorously characterized to understand their therapeutic applications.
Kiyota T, Ingraham KL, Jacobsen MT, Xiong H, Ikezu T.
FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders.
Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1339-48.
Kiyota T, Ingraham KL, Swan RJ, Jacobsen MT, Andrews SJ, Ikezu T.
AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice.
Gene Ther. 2012 Jul;19(7):724-33.