Experimental spinal injury (dark area) in a mouse (DOI: 10.1371/journal. pone.0017126)
Spinal cord injuries are mostly caused by trauma, often incurred in road traffic or sporting incidents, often with devastating and irreversible consequences, and unfortunately having a relatively high prevalence (250,000 patients in the USA; 80% of cases are male). High-profile campaigners like the late actor Christopher Reeve, himself a victim of sports-related spinal cord injury, however, have placed high hopes in stem cell therapy.
Stem cell therapy involves administering special self-regenerating cells (“stem cells“), with the hope that these cells will then colonise the damaged area, assume the properties of their neighbours and reinstate at least some of the function that’s been compromised by injury or disease. Stem cells have to be isolated from the patient or a donor, or generated afresh by tricking ordinary non-regenerating cells into becoming stem cells. Stem cell therapy has become fairly standard for re-colonising bone marrow that has been ravaged by cancer chemotherapy, but its application to other damaged tissues, including spinal cord injury, is still very much at the experimental stage.
In using stem cells for spinal cord injury, scientists are looking to repopulate damaged areas of the spinal cord (see the picture above), with the hope of improving the ability of patients to move (“motor outcomes”) and to feel (“sensory outcomes”) beyond the site of the injury. Many studies have been performed that involve animal models of spinal cord injury (mostly rats and mice), but these are limited in scale by financial, practical and ethical considerations. These limitations hamper each individual study’s statistical power to detect the true effects of the stem cell implantation. As explored previously on Biologue, there are also problems of bias (“It’s official – the animal study literature is biased… but whose fault is it?“).
Lab rats (Image credit: Flickr user kittenfc)
How can we get round these shortcomings and find out how likely it is that stem cell therapy will improve the lot of spinal cord injury patients? This is the question addressed in a paper just published in PLOS Biology by Ana Antonic, David Howells and colleagues. They overcame the problem by conducting a “meta-analysis” – a sophisticated and systematic cumulative statistical reappraisal of many previous laboratory experiments. In this case the authors assessed 156 published studies that examined the effects of stem cell treatment for experimental spinal injury in a total of about 6000 animals.
Overall, they found that stem cell treatment results in an average improvement of about 25% over the post-injury performance in both sensory and motor outcomes, though the results can vary widely between animals. For sensory outcomes the degree of improvement tended to increase with the number of cells introduced – scientists are often reassured by this sort of “dose response”, as it suggests a real underlying biologically plausible effect. So the good news is that stem cell therapy does indeed seem to confer a statistically significant improvement over the residual ability of the animals both to move and feel things beyond the spinal injury site.
The authors went on to use their analysis to explore the effects of bias (such as whether the experimenters knew which animals were treated and which untreated), the way that the stem cells were cultured, the way that the spinal injury was generated, and the way that outcomes were measured. In each case, important lessons were learned that should help inform and refine the design of future animal studies. The meta-analysis also revealed some surprises that should provoke further investigation – there was little evidence of any beneficial sensory effects in female animals, for example, and it didn’t seem to matter whether immunosuppressive drugs were administered or not.
The authors conclude: “Extensive recent preclinical literature suggests that stem cell-based therapies may offer promise; however the impact of compromised internal validity and publication bias means that efficacy is likely to be somewhat lower than reported here.”
Ana Antonic, Emily S. Sena, Jennifer S. Lees, Taryn E. Wills, Peta Skeers, Peter E. Batchelor, Malcolm R. Macleod, & David W. Howells (2013). Stem Cell Transplantation in Traumatic Spinal Cord Injury: A Systematic Review and Meta-Analysis of Animal Studies PLoS Biology, 11 (12) DOI: 10.1371/journal.pbio.1001738