*University of Miami, Miller School of Medicine, Miami, Florida
‡Stanford University School of Medicine, Stanford, California
The road to regenerating components of the central system is notoriously long and torturous. For the longest time, the idea of postdevelopmental neuroplasticity and recovery was viewed as unattainable or fraught with inconsistent outcomes. Now, we are just a little closer to understanding how we can engage the central nervous system to repair injury.
Many scholars have targeted specific components of the regenerative pathway to modulate, whether it be growth factors, neuronal transplantation, or even the use of different types of neurostimulation.1-3 Ischemic stroke is a major cause of physical and functional disability worldwide. Approximately 795 000 patients suffer new or recurrent episodes of stroke each year in the United States.4 It also creates a substantial financial and social burden on the healthcare system, because stroke patients require a high level of short- and long-term care.
The current standard of care for acute ischemia includes tissue plasminogen activator and endovascular thrombectomy.5 Effective therapy for chronic ischemic stroke remains elusive and today involves intensive rehabilitation and stroke prevention. Now, however, the hypothesis of inducing central nervous system plasticity is being tested with great success, and stem transplantation is beginning to demonstrate impressive results.
In a recent study in Stroke by Dr Gary Steinberg and the members of the Study of Modified Stem Cells in Stable Ischemic Stroke clinical trial group,6 the safety and efficacy of stem cell transplantation were reported in a select group of patients.
Steinberg et al6 enrolled 18 patients with chronic stroke, defined as patients who suffered an ischemic stroke at least 6 months before stem cell therapy, who also had a definitive motor deficit. The phase 1/2a clinical trial was designed to assess the safety dose and adverse event profile of the injection. Bone marrow–derived mesenchymal stem cells (SB623, SanBio Inc, Mountain View, California) were delivered via an intracerebral injection. A magnetic resonance image–based stereotaxic implantation to the target site was performed after a single burr hole craniotomy. Three different cell amounts (2.5 × 106, 5.0 × 106, or 10 × 106 SB623 cells) were delivered to 3 cohorts (6 patients each) in 1 single dose. In addition to adverse effect, European Stroke Scale, National Institutes of Health Stroke Scale, modified Rankin Scale, and Fugl-Meyer scores were recorded for outcome assessment.
This study reported tolerable adverse effects and no serious treatment-emergent adverse effects related to the cell therapy or dose. There was 1 case of an asymptomatic subdural fluid collection and 1 case of seizure that was related to the surgical procedure. One patient with carotid stenosis underwent stent implantation, and there was 1 case of transient ischemic attack that was not related to either cell therapy or surgery. Besides the adverse effects, the improvement in neurological function appears to be the most surprising outcome. European Stroke Scale, National Institutes of Health Stroke Scale, Fugl-Meyer motor, and Fugl-Meyer total scores were revealed to have significant improvement sustained 12 months after cell implantation. There was also magnetic resonance imaging T2 fluid-attenuated inversion-recovery signal changes in 13 patients that appeared 1 or 2 weeks after cell implantation, and the size of signal change was statistically correlated to positive neurological improvement, although the mechanism is not clear.
Previous cell transplantation and stem cell clinical trials have demonstrated safety and feasibility, and some have shown neurological improvement outside North America. This is the first reported intracerebral delivery of human stem cells for stroke trial in North America. Does this open the door for neuroregeneration in the treatment of other pathologies? Dr Steinberg and colleagues indicate that “we will see a paradigm shift in our ability to treat many chronic neurologic disorders, which until recently was considered hopeless.”
This could be encouraging to patients with chronic stroke because this study was aimed at those sustaining a stroke for >6 months and because most of the neurological recovery reached a plateau 6 months after the cerebrovascular accident. Is there an ideal window during which stem cell transplantation should be attempted? Steinberg et al6 explain:
This is not currently clear. On the basis of preclinical animal studies, we initially thought that stem cell treatment in the subacute period was optimal to achieve neurological recovery. However, our recent experience with patients with chronic stroke undergoing intracerebral stem cell transplantation 6 months to 3 years after stroke suggests that certain patients have the ability to recover function even years after their injury.
The mechanism of the dramatic motor improvement, however, remains unclear. Steinberg et al say:
We are still investigating the mechanisms underlying the remarkable recovery we observed in some of our patients. Our preclinical animal studies suggest the stem cells do not necessarily integrate into the brain, but secrete powerful growth factors, trophic factors angiogenesis factors, other proteins and molecules that enhance endogenous recovery or plasticity, by promoting native axonal outgrowth, dendritic branching, synaptogenesis, neovascularization and immunomodulation. We also don't know what role (if any) the needle placement plays, in addition to the stem cells.
It is fairly clear that neuroscience is well on its ways to understanding the role of neuroplasticity and regeneration after injury. The promising results of this study help support the notion that, with the appropriate microenvironment, it may be possible to restore neurological function.
1. Azad TD, Veeravagu A, Steinberg GK. Neurorestoration after stroke. Neurosurg Focus. 2016;40(5):E2.
2. Wu JC, Huang WC, Chen YC, et al. Acidic fibroblast growth factor for repair of human spinal cord injury: a clinical trial. J Neurosurg Spine. 2011;15(3):216–227.
3. Wu JC, Huang WC, Tsai YA, Chen YC, Cheng H. Nerve repair using acidic fibroblast growth factor in human cervical spinal cord injury: a preliminary phase I clinical study. J Neurosurg Spine. 2008;8(3):208–214.
4. Writing Group Members, Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics–2016 update: a report from the American Heart Association. Circulation. 2016;133(4):e38–e60.
5. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285–2295.
6. Steinberg GK, Kondziolka D, Wechsler LR, et al. Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study. Stroke. 2016;47(7):1817–1824.