Stem Cells Effective in Acute Setting

Posted by Sam Maddox in Research News on February 01, 2016 # Research

Here is a look at a recently published scientific study related to spinal cord injury. This comes from the Jerry Silver lab at Case Western in Cleveland, a program with a long history of looking at glia, the cells that support neurons in the spinal cord. We have discussed Silver's work often, in particular his efforts to get once-vibrant nerves in the spinal cord to grow through a scar-like barrier created by glial cells.

This paper isn't about glial cells per se; it's about modifying the immune response after trauma. This describes an acute stem cell experiment that led to improvement in motor function deemed "significant" by the lab. The cell therapy also brought back a meaningful degree of bladder function. The work in the lab was mainly done by Marc A. DePaul, Ph.D., with a lot of help from Athersys, a biotech company based in Cleveland that has a versatile off-the shelf stem cell product, MultiStem – multipotent adult progenitor cells (MAPCs). These same cells are already in clinical trials for ischemic stroke, acute myocardial infarction and inflammatory bowel disease, and are used in this SCI study.

What they did: rats with contusion injuries – bruise-like injuries similar to what occurs in most human SCI – were given an intravenous injection of MAPCs. Given immediately after injury, the cells (4 million optimal dosage) had no effect. Waiting a day before injections, though, brought about locomotor and urinary improvements. Upon inspection, they found that the transplanted cells don't go to the spinal cord at all, but rather head for the spleen. So what gives?

The effect of the MAPCs is not, as you might expect, on spinal cord neurons or on axon growth itself but rather on the immune system and its response to injury. It's well established that trauma to the spinal cord comes in stages, the first being the force on the cord caused by impact. Immediately after that, a wave of responses attack the area of injury, clearing out cellular debris and causing a chemical mayhem that in coming hours and days is toxic to cells in the injury zone. The immune response is a two-sided affair: it clears the area but also seals it off, thus blocking possible nerve growth.

Apparently, the cell injections tweaked the immune response, muting the damaging effect of macrophage inflammation. Macrophage, which is Greek for "big eater," digest foreign substances, microbes and anything else recognized as non-body. The process is called phagocytosis. In the brain and spinal cord, the first responder immune cells, the resident macrophage, are a subset of glia called microglia, which brings this experiment more in line with Silver's career emphasis.

In a Case Western press release, Silver speculated that the stem cells held back a more aggressive type of macrophage; the ones that did come to the site of SCI were "kinder, gentler macrophages," Silver said. "They do the job, but they pick and choose what they consume. The end result is spared tissue. We don't know what makes these nicer macrophages more subdued, but this is a subject we are researching in the lab."

From the release:

MAPCs injected into lab animals one day post-injury travelled primarily into their spleens, a reservoir for immature macrophages, resulting in a beneficial macrophage immune response that spared more spinal cord tissue. Consequently, animals that received treatment demonstrated markedly improved hind-paw motor control and urinary function. It takes approximately a day for the immune system to recognize and then begin to respond to a threat caused by injury or illness. When MAPCs were administered too soon (immediately after injury) or not at all (the control group), the lab animals received no benefit.

From the paper, which appeared on, "Intravenous multipotent adult progenitor cell treatment decreases inflammation leading to functional recovery following spinal cord injury:"

Here we show that a single intravenous dose of human MAPCs delivered one day following contusive SCI remarkably improves both locomotor and urinary functions. Interestingly, MAPCs rarely enter the nervous system, however, a significant increase of white matter sparing and a marked change in macrophage/microglia activation is observed in the spinal cord. This study highlights the promise of therapies directed at altering the peripheral response to immune-mediated CNS pathologies and establishes human MAPCs as a novel therapy for the treatment of acute SCI.

The paper notes that animals improved to an average BBB score of 13.31 at 70 days post injury. That corresponds to "consistent hindlimb stepping with frequent coordination between the four limbs."

Taken together with previous data in other models of CNS injury, this result supports the intriguing hypothesis that MAPC-mediated tissue sparing is not due to a direct interaction at the spinal cord injury site, but an indirect effect through modulation of infiltrating immune cells from the periphery.

Said Silver, "Although a great deal of research needs to be undertaken in the field, we are pleased to see that MultiStem therapy is efficacious in promoting the recovery of locomotor and urinary functions in rodents. I am especially excited with this therapy as it circumvents the need for directed therapeutic delivery into the vulnerable, recently injured spinal cord."

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