Nerve damage as a result of type 2 diabetes, surgical amputation, chemotherapy and other conditions can lead to chronic pain. Such chronic pain can resist painkiller medications and other treatments and is debilitating.
New studies from scientists at Duke University with mice have shown that injections of bone marrow-derived stem cells might be able to relieve this type of chronic, neuropathic pain. This study was recently published in the Journal of Clinical Investigation and might be the springboard for advanced cell-based therapies to treat chronic pain conditions, lower back pain and spinal cord injuries.
Ru-Rong Ji, professor of anesthesiology and neurobiology at the Duke School of Medicine and his team used bone marrow stromal cells (BMSCs) that were isolated from bone marrow aspirations. BMSCs have been shown in a variety of clinical trials and basic research experiments to produce an array of healing factors and can differentiate into many cell types of cells in the body. BMSCs are being tested in small-scale clinical studies with people who suffer from inflammatory bowel disease, heart damage and stroke. BMSCs might also be useful for treating pain, but it’s not clear how they work.
“Based on these new results, we have the know-how and we can further engineer and improve the cells to maximize their beneficial effects,” said Professor Ji. In his team’s study, stromal cells were used to treat mice with pain caused by nerve damage. The cells were delivered by means of lumbar puncture, which infused the BMSCs into the cerebrospinal fluid (CSF) that bathes the spinal cord.
Mice treated with the bone marrow stromal cells were much less sensitive to painful stimuli after their nerve injury in comparison with untreated mice.
“This analgesic effect was amazing,” Ji said. “Normally, if you give an analgesic, you see pain relief for a few hours, at most a few days. But with bone marrow stem cells, after a single injection we saw pain relief over four to five weeks.”
When the spinal cords of the treated animals were examined in detail, Ji and others observed that the injected stem cells had clustered together along the nerve cells in the spinal cord.
To understand how the stem cells alleviated pain, Ji and his coworkers measured levels of anti-inflammatory molecules that have been linked to pain suppression. One of these molecules in particular, TGF-β1, was present in higher amounts in the CSF of the stem cell-treated animals compared with the untreated animals.
Immune cells typically secrete TGF-β1, which is a small protein, and it is found at low concentrations throughout the body. According to Professor Ji, people with chronic pain have been shown to possess too little TGF-β1.
In the new study, when Ji and others chemically neutralized TGF-β1 in the stem cell-treated animals, the pain-killing benefit of the infused BMSCs was reversed. This suggests that the secretion of this protein by BMSCs was a major reason these are able to abate neuropathic pain. When Ji and his crew directly injected TGF-β1 into the CSF, it provides significant pain relief, but only for a few hours, according to Ji.
However, infused BMSCs, remain at the site of infusion for as long as three months after their administration. This is just the right length of time for the cells to persist, according to Ji, because if the stem cells permanently persisted in the CSF, they have an increased risk of becoming cancerous.
Even more significantly, infused BMSCs also migrate to the site of injury. The ability of these cells to migrate to the site of injury depends on a molecule secreted by the injured nerve cells called CXCL12 (which, incidentally, has also previously been linked to neuropathic pain). CXCL12 (also known as stromal cell-derived factor-1) acts as a homing signal, since BMSCs have on their cell surfaces, a receptor for CXCL12 called CXCR4, CXCL12 acts as a kind of stem cell attractant.
In the next set of experiments, Ji and his colleagues would like to find a way to make the stromal cells more efficient. “If we know TGF-β1 is important, we can find a way to produce more of it,” Ji said. Additionally, the cells may produce other pain-relieving molecules, and Ji’s group is working to identify those.