Stem Cell-Based Therapy for Experimental Stroke: A Systematic Review and Meta-Analysis

Abstract

Stem cell therapy holds great promise in medicine, but clinical development should be based on a sound understanding of potential weaknesses in supporting experimental data. The aim of this article was to provide a systematic overview of evidence relating to the efficacy of stem cell-based therapies in animal models of stroke to foster the clinical application of stem cell-based therapies and to inform the design of large-scale clinical trials. We conducted a systematic search for reports of experiments using stem cells in animal models of cerebral ischaemia, and performed DerSimmonian and Laird random effects meta-analysis. We assessed the impact of study characteristics, of publication bias and of measures to reduce bias. We identified 6059 publications, 117 met our prespecified inclusion criteria. One hundred eighty-seven experiments using 2332 animals described changes in structural outcome and 192 experiments using 2704 animals described changes in functional outcome. Median study quality score was 4 (interquartile range 3 to 6) and less than half of studies reported randomization or blinded outcome assessment; only three studies reported a sample size calculation. Nonrandomized studies gave significantly higher estimates of improvement in structural outcome, and there was evidence of a significant publication bias. For structural outcome autologous (i.e. self-derived) stem cells were more effective than allogeneic (donor-derived) cells, but for functional outcome, the reverse was true. A significant dose-response relationship was observed only for structural outcome. For structural outcome, there was an absolute reduction in efficacy of 1·5% (-2·4 to -0·6) for each days delay to treatment; functional outcome was independent of the time of administration. While stem cells appear to be of some benefit in animal models of stroke the internal and external validity of this literature is potentially confounded by poor study quality and by publication bias. The clinical development of stem cell-based therapies, in stroke and elsewhere, should acknowledge these potential weaknesses in the supporting animal data.

Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke

“…This includes many different types of stem cell therapeutic candidates. 4,5 Mesenchymal stromal cells (MSCs) (also known as marrow stromal cells and marrow stem cells) are a form of multipotent adult stem cells that have received considerable attention, in part because of their relative ease of isolation from tissues such as bone marrow and their immunoprivileged status. The International Society for Cellular Therapy defines MSCs on the basis of adhering to plastic in standard culture conditions, expressing characteristic surface antigens (e.g., CD105 and CD90, but not CD45 or HLA-DR), and having the ability to differentiate in vitro to osteoblasts, adipocytes, and chondroblasts.…”

“…The current review, by focusing on one specific cellular therapy for one specific clinical indication, builds on prior meta-analyses that took a broader approach to stem cell therapy. 4,5,15 First, in accordance with recent Stroke Therapy Academic Industry Roundtable (STAIR) recommendations 16 and a recent NIH workshop, 17 the quality of the studies was reviewed. Second, the effect size of MSCs was determined for the most frequently used behavioral and histologic outcomes.…”

Is Immunomodulation a Principal Mechanism Underlying How Cell-Based Therapies Enhance Stroke Recovery?

“…MSCs have been shown to exert profound immunomodulatory properties and have gained approval as a treatment in certain countries for graft versus host disease. Several meta-analyses have consistently demonstrated their treatment effects in various animal models of stroke [19][20][21][22][23][24]. In fact, MSCs are likely the most widely studied type of cell therapy in the preclinical stroke literature [1][2][3].…”

Clinical trial design for stem cell therapies in stroke: What have we learned?

“…[17][18][19] There is resulting reduction in infarct volume and functional recovery has generally been enhanced. Publication and reporting bias is evident in the animal literature, study quality has been inconsistent, and effect sizes may be overestimated as a result, 17,19 although meta-analysis of studies of mesenchymal stem cells (MSCs) in rodent stroke suggested larger effect sizes with greater study quality.…”

“…[17][18][19] There is resulting reduction in infarct volume and functional recovery has generally been enhanced. Publication and reporting bias is evident in the animal literature, study quality has been inconsistent, and effect sizes may be overestimated as a result, 17,19 although meta-analysis of studies of mesenchymal stem cells (MSCs) in rodent stroke suggested larger effect sizes with greater study quality. 18 There is no compelling evidence favouring one type of cell over another, 20 with a wide range of (predominantly human) cell types having similar effects in rodent focal ischaemia models, including MSCs, mixed bone marrow mononuclear cell (BMMCs), CD34+ haematopoietic progenitor cells, umbilical cord blood cells and many others.…”