There have been five human studies using the intra-arterial route for delivery of a range of different bone marrow-derived stem cells. All have shown that this approach is feasible and safe, including in the early phase after ischaemic stroke, writes Soma Banerjee, London, UK.
Stem cell therapy is an emerging therapeutic modality in the treatment of stroke. Its basis stems from the observation that certain parts of the adult brain are capable of regeneration.
It was in 1998 that Erikkson et al first demonstrated evidence of neurogenesis in the human adult brain. After this, a study of patients with ischaemic stroke was able to demonstrate evidence of neurogenesis in the ischaemic penumbra, where cells were found to preferentially localise to the vicinity of blood vessels indicating an endogenous repair process. However, whilst the regenerative capacity of certain parts of the brain has been demonstrated, it is clear that this neuro-reparative process is unable to overcome the devastating damage to brain tissue that occurs after acute, severe stroke. Cell-based therapies have the potential to open up new avenues of treatment in this arena. Targets for stem cell therapy include neuro-protective approaches, which are aimed at protecting the at-risk tissue during the acute phase of stroke, as well as neuro-reparative approaches, which may involve direct replacement of damaged brain tissue or, alternatively, promote endogenous repair processes of the brain.
Animal studies have shown significant benefits of stem cell therapy, using a range of different stem cell types, as well as different methods of delivery. There are three main routes of central nervous system delivery that have been tested in stroke patients: intravenous, intra-arterial, or direct surgical cranial implantation. Stereotactic surgical approaches can be problematic in the context of acute stroke given the risks of general anaesthesia (especially in medically unstable patients), and the potential for worsening cerebral inflammation and oedema. Conversely, in intravenous delivery the overwhelming majority of transplanted cells are absorbed in non-target organs before they can reach the brain. Direct arterial delivery, therefore represents an intermediate strategy that offers directed therapy with fewer of the risks of major surgery.
Animal studies have compared the different routes of delivery, using different types of stem cells in models of acute ischaemic stroke. One such study showed superior cell delivery using the intra-arterial approach when compared to intra-cisternal implantation or intravenous delivery routes. There was also a more diffuse distribution pattern of injected cells in the affected hemisphere with intra-arterial delivery, over and above the other routes. However, in that study, there were concerns regarding excess mortality in the intra-arterial subgroup. On further reflection, this may have been related to the experimental procedures used. Other animal studies comparing the intra-arterial to the intravenous route have also shown superior cell delivery with the former, due to significant cell trapping in the peripheral organs, especially the lungs, liver and spleen, when using the latter route.
The timing of delivery for stem cells after a stroke also remains a contentious issue. The intra-arterial route may be more suited to an early timescale after ischaemic stroke, owing to the up-regulation of chemoattractant pathways early after an ischaemic insult. For example, the SDF-1 (stromal derived factor-1)/CXCR4 (CXC chemokine receptor 4) chemo-attractant pathway is upregulated early after an ischaemic stroke, and is responsible for homing of CD34+ stem cells (which express the CXCR4 receptor) to the area of insult in the brain (where SDF-1 is up regulated). The IA route can use such chemoattractant pathways (Eg for CD34+ stem cell therapy), to help optimise delivery of cells to the area of ischaemic damage.
There have been five human studies to date, using the intra-arterial route for delivery of stem cells. These have used a range of different time points from three days up to three months after the stroke to measure the effect of treatment. These five studies used a range of different bone marrow derived stem cells. All have shown that this approach is feasible and safe, including in the early phase after ischaemic stroke. There was no increased mortality or recurrent strokes reported in any of the trials. Efficacy, however, has yet to be proven in human patients, given that these were small phase I/II trials.
The intra-arterial route certainly holds great promise, particularly with the advent of endovascular treatments for acute ischaemic stroke. Future applications such as stem cell-coated stents may represent a way forward in improving cell delivery via the desired intra-arterial route, with the potential to provide a steady release of stem cells to the area of need. There, however, remains a long way to go before the impressive results seen in animal models of stroke are translated to our patients. Future trials will need to concentrate on some of the many unanswered questions that remain regarding the most optimal timing, route, and type of stem cell used to achieve the best results.
Soma Banerjee is a consultant physician in stroke medicine, and Stroke Unit clinical lead, Imperial College Healthcare NHS Trust, London, UK. She has reported no disclosures relevant to this article.
