Are We Ready for Cell Therapy to Treat Stroke?

Abstract

Clinical trials of cell therapies that target stroke started at the beginning of this century and they have experienced a significant boost in recent years as a result of promising data from basic research studies. The increase in the information available has paved the way to carry out more innovative and varied human studies. Efforts have focused on the search for a safe and effective treatment to stimulate neuro-regeneration in the brain and to reduce the sequelae of stroke in patients. Therefore, this review aims to evaluate the clinical trials using cell therapy to treat stroke published to date and assess their limitations. From 2000 to date, most of the published clinical trials have focused on phases I or II, and the vast majority of them demonstrate that stem cells are essentially safe to use when administered by different routes, with transient and mild adverse events that do not generally have severe consequences for health. In general, there is considerable variation in the trials in terms of statistical design, sample size, the cells used, the routes of administration, and the functional assessments (both at baseline and follow-up), making it difficult to compare the studies. From this general description, possibly the experimental protocol is the main element to improve in future studies. Establishing an adequate experimental and statistical design will be essential to obtain favorable and reliable results when conducting phase III clinical trials. Thus, it is necessary to standardize the criteria used in these clinical trials in order to aid comparison. Shortly, cell therapy will be a key approach in the treatment of stroke if adequate and comprehensive levels of recovery are to be achieved.

The Impact of Cerebral Perfusion on Mesenchymal Stem Cells Distribution after Intra-Arterial Transplantation: A Quantitative MR Study

“…Transplantation of mesenchymal stem cells (MSCs) is a novel approach to the treatment of many severe neurological disorders causing irreversible damage of neural tissue, including traumatic brain injury, spinal cord injury, multiple sclerosis, neurodegenerative diseases, and stroke [ 1 , 2 , 3 ]. In the case of stroke, different routes of MSCs administration, including direct intracerebral, intrathecal, intraventricular, intravenous, intra-arterial, intranasal, and others have been tested in animal studies [ 4 , 5 ]. Among them, the intra-arterial (IA) delivery appears one of the most effective, probably because it guarantees targeted cell delivery to the brain vascular system [ 6 , 7 , 8 ].…”

“…Moreover, rapid development of the endovascular mechanical thrombectomy technique and its widespread use in acute stroke treatment made IA transplantation more feasible for routine clinical practice [ 9 , 10 ]. According to the ClinicalTrials.gov site, five-phase I and II clinical trials focused on IA administration of MSCs or bone marrow mononuclear cells into patients with subacute or chronic ischemic stroke have been registered throughout the world and some of them have been already completed (reviewed in [ 4 , 11 ]). The published results of the clinical trials indicate that IA transplantation of cells is essentially safe in humans and can promote some neurological improvement after stroke.…”

“…However, the obtained results on the efficacy of the treatment were not conclusive [ 12 , 13 , 14 , 15 , 16 , 17 ]. One of the most likely reasons for the uncertainty of the trial results may be the imperfect study design recommending suboptimal patient recruitment criteria, cell dose, time window, number and frequency of transplantations, and other parameters [ 4 ]. Further investigation and better understanding of the mechanisms of MSCs’ therapeutic effects, as well as the assessment of cell distribution and homing after transplantation may help to resolve these issues [ 5 ].…”

Cell Therapy of Stroke: Do the Intra-Arterially Transplanted Mesenchymal Stem Cells Cross the Blood–Brain Barrier?

“…Transplantation of different types of stem cells has the potential to develop into an effective method of stroke therapy [ 6 , 7 ]. Specifically, over the past two decades, multiple basic studies and clinical trials have demonstrated that transplantation of the mesenchymal stem cells (mesenchymal stromal cells, MSCs) is safe [ 8 ] and can promote recovery after stroke (reviewed in [ 9 , 10 ]). According to the International Society of Cell Therapy criteria, MSCs are defined as multipotent non-hematopoietic stem cells that are adherent to plastic and can differentiate into adipocytes, chondroblasts, osteoblasts, and myocytes in vitro.…”

“…Several routes of MSC transplantation in stroke, including the intra-arterial (IA), intravenous (IV), intraperitoneal, intracerebral, intraventricular, intrathecal, and intranasal delivery were tried and showed therapeutic efficacy [ 10 , 31 ]. However, the best delivery route, as well as the ‘therapeutic window’ duration have not been so far agreed upon.…”