A systematic review of cellular transplantation therapies for spinal cord injury
Posted by Kim Holden, 30 Apr, 2010
A systematic review of cellular transplantation therapies for spinal cord injury by Tetzlaff et al, Journal of Neurotrauma, Feb 2010
31/03/2010
Blusson Spinal Cord Centre, International Collaboration on Repair Discoveries (ICORD)
Who wouldn't be pleased to hear that a special type of cell, with regenerative properties, had been shown to repair the damaged spinal cord? But with a lot of potential candidates, which cell is best? How good is the evidence from animal studies? Can we replace lost tissue, repair connections and get functional improvements? And how near are we to translating the basic preclinical results into clinical trials?
There are plenty of cell types to consider: Schwann cells, olfactory ensheathing cells (OECs), neural ‘stem‘ cells prepared from embryonic or adult tissues, bone marrow stromal cells. This review in the Journal of Neurotrauma in Feb looks at the evidence for each of these cell types from animal studies, and what improvements they have achieved. The hope is that the transplanted cells might be able to replace lost neurons, support or guide growing axons, bridge the injury site or replace lost myelin, leading to improvements in function.
The review only considers studies where cells have been transplanted into animals with traumatic spinal cord injuries, such as compression or cutting of the cord. The paper identified 162 studies which met criteria for inclusion.
Some general comments may be useful.
* It will be no surprise to hear that most studies use rodents (rats or mice) both as the source of cells and for the cord injury.
* Only a few studies have used human cells, which would be necessary for human trials
* Even fewer studies have trialed cord injuries in large animals or primates.
* Most cells are transplanted (or injected) directly into or near the injured region, and most are given immediately or soon after the injury (ie acute or subacute times). Very few studies have tested chronic times, relevant to so many people whose cord injury was many years ago.
Schwann cells (43 studies) have the longest history of transplantation, with trials since 1981. These cells are normally found in peripheral nerves where they support axons and make myelin. Schwann cells transplanted to the injured cord generally don't support regeneration of central axons although a few showed modest functional improvements. Combinations of Schwann cells with other treatments have been more useful. For clinical use, human Schwann cells can be obtained from nerve or skin biopsies and several centres are moving towards clinical trials.
OECs (26 studies) normally support regeneration of olfactory neurons, guiding their axons from the nose (mucosa) into the brain (olfactory bulb). OECS from the nose and brain have different properties and most studies have used rodent bulb cells. The OECs integrate well with cord tissue, although results on regeneration and functional recovery have been conflicting. Sorting out the reasons for the discrepancies between cells from different sources and their outcomes will need a better understanding of OEC biology. Another approach, using pieces of nasal mucosa, is now in clinical trial in Portugal, with 11 out of 20 patients showing improvements in movements, sensation or bladder control. Importantly, in this trial, all patients receive intensive rehabilitation programs both before and after transplantation. The role of rehabilitation is thus another factor that needs to be considered in any clinical trial.
Neural ‘stem' or precursor cells (37 studies) can be obtained from embryos or the adult nervous system, which contains precursors for neurons and glial cells. Studies have tested human cells and embryonic and adult rat cells as well as a number of cell lines. Most cells integrate well in the cord and become glial cells rather than neurons. The transplants have generally reported improvements in function, including a study of human cells into a cervical injury in monkeys. However, a report of pain following an adult stem cell transplant signals the need for caution. Use of neural or glial precursor cells (ie more differentiated cells than ‘stem' cells) have been tested in a few studies. Such differentiation allows good characterization of the cells and 1 line has obtained FDA approval for a clinical trial to improve myelination (but is currently on hold).
Bone marrow stromal cells (BMSCs, 43 studies) can be fairly easily obtained from bone marrow as a crude mixture of cells and both human and rat cells have been tested. The cell mix varies between sample and donors and is a likely explanation for the variable results after trasplantation, with both improvements and no effect reported. Similarly cell survival within the cord is good in some cases, poor in others. Positive effects could be through the trophic factors which these cells produce, giving neuroprotection, as well as the ability of BMSCs to bridge a damaged area of cord. Several human studies have been reported but tend to have poorly characterized cells and small numbers of patients.
In summary, we have come a long way in establishing what happens to transplanted cells when they are in the spinal cord but functional outcomes are highly variable. From the point of view of translation to clinical trials, this review indicates that we need more studies that trial:
* chronic injuries
* human cells
* a range of species other than rodents, especially larger animal models
* contusion injuries which mimic human injury better than cutting the cord
* cervical injuries and tests of arm/hand function, as these are common injuries in people and have high priority
* side effects such as pain
On a personal note, not mentioned in this paper, I would also add that we need more studies which evaluate autonomic functions (eg bladder, bowel, blood pressure, and sexual function) all of which are high priorities for patients but are seldom tested in the animal studies.
Phil Waite, March 2010
Link to abstract: www.ncbi.nlm.nih.gov/pubmed/20146557
Link to PDF: Tetzlaff et al, J Neurotrauma Feb, 2010
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Contact: Kim Holden
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The CatWalk Trust is a non-government funded non-profit organisation with the principal aim of raising funds to support the search for a cure for Spinal Cord Injury (SCI) paralysis. Whilst there are a number of organisations providing valuable rehabilitative support to those with SCI, the CatWalk Trust aims to challenge the current boundaries of research, enabling SCI victims to walk again. Ten years ago if you... More Info
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