17 April 2003. Stem cells injected into the cerebral ventricles-or even injected intravenously-find their way to sites of inflammation in an animal model of multiple sclerosis (MS), according to a report in today’s Nature. Once there, they replace the damaged myelin, clean up astrocytic scarring, and help reduce inflammation. Most importantly, the treatment abolishes the motor deficits of the disorder.
Focal transplantation of stem cells offers hope in a disease such as Parkinson's, where much of the disease can be traced to a well-delineated area of neurodegeneration in the substantia nigra; however, disorders such as MS and Alzheimer's disease involve much more widespread neurodegeneration. MS and similar demyelinating disorders also have other interesting points of intersection with Alzheimer's disease, including inflammatory processes in the areas of neurodegeneration.
Gianvito Martino, Angelo Vescovi, and their colleagues at the San Raffaele Hospital in Milan, Italy, injected mice with antibodies to a component of myelin to produce the well-known model experimental autoimmune encephalomyelitis (EAE). They then injected the mice with neurospheres-small aggregates of stem cells and their progeny derived from the cerebral ventricular zones of adult mice.
Whether introduced via the cerebral ventricles or the blood stream, these cells spread throughout the neural axis and differentiated into both myelin-producing oligodendrocytes and neurons. Interestingly, most of the transplanted cells were drawn to largely demyelinated areas of inflammation, where they gave rise to new myelin-producing cells. Concomitant with this repopulation, mice appeared to regain almost normal movement, beginning at about day 15 after transplantation.
A further benefit was that these transplanted cells mediated the reduction of "scarring" caused by overgrowth of astrocytes in the demyelinated areas. This step can itself be beneficial, because reactive astrogliosis hampers remyelination. The stem cells also appear to have played a role in reducing inflammatory processes by decreasing levels of inflammatory molecules (e.g., tumor-necrosis-factor-α) and metalloprotesases.
"One point of particular interest here is that these cells hitch a ride into damaged sites by using α4 integrin-the very molecule that mobilizes the immunological attack," notes Lawrence Steinman of Stanford University in California in his News and Views comment. α4 integrin is an adhesion molecule found on the surface of the immune cells that attack myelin in EAE. Apparently, the presence of this molecule allows the stem cells to cross the blood-brain barrier and move to areas of active inflammation in the CNS.
"To the best of our knowledge, this work provides the initial evidence showing how neural precursors may represent a renewable source of cells which, when transplanted into the cerebroventricular system or into the blood stream, can reach multiple areas of a chronically injured adult CNS, enter the brain tissue and seek damaged areas where they promote structural and functional recovery," conclude the authors.
For Alzheimer's researchers, a central question is whether this same method can deliver stem cells to areas of putative inflammation surrounding neurodegeneration in models of AD. And if so, can they work the same restorative magic that they did for this model of MS?-Hakon Heimer.
Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani
G, Dina G, Galli R, Del Carro U, Amadio S, Bergami S, Furlan R, Comi G, Vescovi AL, Martino G. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 2003 Apr 17;422:688-94. Abstract
Steinman L. Medicine: Collateral damage repaired.
Nature. 2003 Apr 17;422(6933):671-2. No abstract available. Abstract
Q & A with Gianvito Martino:
Q: Could this be applied to AD?
A: To make neural stem cells travel into the right areas where demyelination was ongoing, we took advantage of the inflammation occurring in the experimental MS model that we have been using. Thus, I do not see how can we apply this experimental therapeutic model "tout court" to AD. As I understand it, inflammation in AD takes place in the later stages of the disease and is milder than in MS. To me, inflammation in AD is just a physiological reaction to neurodegeneration; in MS the scenario is the opposite, whereby inflammation causes neurodegeneration. Thus, I do not know if inflammation in AD is enough to make cells travel to the right place and replace nonfunctioning neurons.
Q: Will you take this work into AD mouse models?
A: We have not, to date, planned to work in AD mice; however, it would be extremely interesting to see such experiments. We have been impressed by what we found in EAE; we frankly did not expect these results in the very beginning. Therefore, it is time to go in AD, as well, and see what can happen, but I would suggest someone who is more deeply involved in AD research try this. I would be delighted to share my experience on that.
Q: Are current mouse models adequate for such an experiment?
A: I think that AD models in mice are suitable. The time frame when you inject the cells is crucial. The mode of action of our cells in EAE mice is bimodal. They not only differentiate into ensheathing oligodendrocytes, but they also mediate the proliferation of endogenous oligodendrocyte precursors and down-regulate proliferation of endogenous astroglia possibly via a humoral mechanism.