Autoimmune disorders of the central nervous system (CNS) such as multiple sclerosis are characterized by chronic inflammation. This inflammation leads to neurodegenerative features such as the loss of myelin, the protective coating around nerves, and the loss of parts of nerves called axons. An Italian research team has found, however, that transplanting neural stem cells called multipotent precursor cells (NPCs) can protect the brain against inflammation by inducing the death of certain cells that promote such inflammation. The researchers used a mouse model of relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), which mimics the chronic autoimmune CNS inflammation of human multiple sclerosis, to test the therapeutic potential of these cells.
This neuroprotection comes from the ability of undifferentiated NPCs to induce apoptosis, or cell death, of certain T cells (called encephalitogenic cells) that have the potential to cause brain inflammation, the researchers report in the July 14, 2005, issue of Nature. Previous studies have shown that the elimination of inflammatory T cells by apoptosis, or cell death, plays an important role in the suppression of inflammation in the CNS.
“Neural stem cells use the same molecular pathways that encephalitogenic cells use to get into the central nervous system,” says Gianvito Martino of Vita-Salute University in Milan, one of the study’s authors. “Therefore, the two populations of cells sit in the very same area and cross-talk with each other.”
These T cells produce regulators that help the NPCs stay in their undifferentiated state, in which they induce apoptosis, Martino adds.
Doug Green of the La Jolla Institute of Allergy and Immunology, a leading expert on how apoptosis regulates the immune system, says that a signal at the end of the inflammation triggers the death of infiltrating cells. In this case, the signal comes from antibodies called death ligands that induce apoptosis. Since these infiltrating cells die, they do not create an immune response in the tissue.
“The basic idea is that some tissue is protected from immunologic damage by expressing these death ligands,” Green says.
Martino and his colleagues did not investigate why these NPCs do not die like most other cells do. Inflammatory molecules, especially inflammatory cytokines (immunoregulatory proteins secreted by immune cells), make the encephalitogenic T cells more prone to apoptosis by expressing death ligands on the mouse neural stem cell surface. This cell death does not occur, however, when the neural stem cells are stimulated by anti-inflammatory cytokines.
“The basic idea is that some tissue is protected from immunologic damage by expressing these death ligands.”
“The pro-apoptotic role of neural stem cells is thus very much dependent on the inflammatory reactions occurring in the microenvironment, in this case the CNS,” Martino says.
“It could be that neural stem cells do not express functional amounts of death receptors once within a pro-inflammatory environment such as the one we are dealing with. However, the intracellular mechanism by which neural stem cells resist apoptosis [in the mouse model] is still unknown.”
The Italian researchers do not yet know the practical applications of their discovery. Martino envisions injecting neural stem cells, which have the ability to reach inflamed areas of the CNS and block inflammatory reactions within these areas, intravenously in patients with neurological disorders in which inflammation is prominent, including multiple sclerosis, spinal cord injuries, and brain tumors.
Although human fetal neural stem cells are controversial, Martino says they are the only cells he envisages using in these patients because these cells share similar characteristics with the adult mouse neural stem cells used in his study.
“We still have a long way to go,” Martino says. “What we found is only the first step of a multistep process that needs to be carefully investigated and detailed before any bench-to-bed translation can occur.”