This video discusses how the hormone leptin inhibits expansion of T regulatory cells. Theoretically blocking of leptin may be one method of repairing the immune defects in multiple sclerosis and in other types of autoimmune conditions.
Treatment of multiple sclerosis patients with their own fat derived stem cells has generated promising results which we recently published. There are several mechanisms by which this treatment may mediate therapeutic effects. One particular mechanism that we will discuss here is production of soluble factors by fat derived mesenchymal stem cells that may be protective to neurons.
In the paper (Wei et al. Adipose stromal cells-secreted neuroprotective media against neuronal apoptosis. Neurosciences Letters. 2009 Jun 21) conditioned media from fat derived mesenchymal stem cells was assessed for therapeutic activity in terms of ability to protect neurons from cell death. The idea being that the fat stem cells produce factors that can inhibit apoptosis of brain cells.
The investigators used a model of neuronal cell death by culturing cerebellar granule neurons in absence of serum and potassium in order to induce apoptosis. A dose-dependent inhibition of neuronal apoptosis was observed when adipose stem cell conditioned media was added to the cultures. Inhibition of caspase-3 activity was observed in the protected neurons (which would make sense since caspase-3 is involved in the vast majority of apoptotic signalling). Additionally, the adipose stem cell conditioned media was capable of stimulating the anti-apoptotic akt signalling pathway.
In order to investigate what specific molecules were in the adipose stem cell conditioned media that induced protective effects on the neurons, it was found that neutralization of insulin growth factor (IGF)-1 resulted in loss of anti-apoptotic activity.
This study brings up several interesting questions.
Firstly, would the supernatant from the adipose derived stem cells also have effects on oligodendrocytes? In multiple sclerosis there is eventual neuronal death, however, activation of oligodendrocytes is very important in terms of re-myelinating the injured tissue. We do know that bone marrow cells are capable of inducing remyelination under specific conditions, so the question would be if adipose stem cell supernatant may also mediate such an effect. This would be relatively easy to test in an in vitro system, or using the experimental allergic encephalomyelitis model. However the issue would be whether the supernatant would also mediate immune modulatory properties that may mask the effects of potential remyelinating activity.
The second question is whether the adipose stem cell supernatant would have effects on other models of neuronal apoptosis. In the context of multiple sclerosis, neuronal apoptosis mediated by excess glutamate seems to be an important factor. Alternatively, the adipose stem cell supernatant may increase astrocyte uptake of glutamate.
The third question would be whether various conditions can be applied to the adipose stem cells so as to enhance secretion of protective factors in the conditioned media. For example, there are publications demonstrating that mesenchymal stem cells cultured in the presence of low oxygen actually increase secretion of various therapeutic factors, including IGF-1. This may be because the mesenchymal stem cells “feel” the lack of oxygen and as a natural reparative mechanism start secreting factors that protect other cells. This may be possible given that mesenchymal stem cells have been demonstrated to inhibit neuronal cell death in vivo in models of stroke. Alternatively, another way to “stress” mesenchymal stem cells in vitro may be treatment with inflammatory cytokines such as TNF-alpha. At the recent FOCIS meeting in San Francisco, data was presented demonstrating that mesenchymal stem cells secrete higher levels of antiinflammatory factors after exposure to immunological stress, as in the form of a mixed lymphocyte reaction. Collection of supernatant of stem cells under various conditions of stress may be one interesting way to increase efficacy of the approach described in the current paper.