A Long-Term Follow-Up Study of Intravenous Autologous Mesenchymal Stem Cell Transplantation in Patients With Ischemic Stroke

Abstract

We previously evaluated the short-term follow-up preliminary data of mesenchymal stem cells (MSCs) transplantation in patients with ischemic stroke. The present study was conducted to evaluate the long-term safety and efficacy of i.v. MSCs transplantation in a larger population. To accomplish this, we performed an open-label, observerblinded clinical trial of 85 patients with severe middle cerebral artery territory infarct. Patients were randomly allocated to one of two groups, those who received i.v. autologous ex vivo cultured MSCs (MSC group) or those who did not (control group), and followed for up to 5 years. Mortality of any cause, long-term side effects, and new-onset comorbidities were monitored. Of the 52 patients who were finally included in this study, 16 were the MSC group and 36 were the control group. Four (25%) patients in the MSC group and 21 (58.3%) in the control group died during the follow-up period, and the cumulative surviving portion at 260 weeks was 0.72 in the MSC group and 0.34 in the control group (log-rank; p 5 .058). Significant side effects were not observed following MSC treatment. The occurrence of comorbidities including seizures and recurrent vascular episodes did not differ between groups. When compared with the control group, the follow-up modified Rankin Scale (mRS) score was decreased, whereas the number of patients with a mRS of 0-3 increased in the MSC group (p 5 .046). Clinical improvement in the MSC group was associated with serum levels of stromal cell-derived factor-1 and the degree of involvement of the subventricular region of the lateral ventricle. Intravenous autologous MSCs transplantation was safe for stroke patients during long-term follow-up. This therapy may improve recovery after stroke depending on the specific characteristics of the patients. STEM

Mesenchymal stem cells as a treatment for neonatal ischemic brain damage

“…Patients with ischemic stroke and treated with MSCs showed no adverse effects 5 y after treatment with MSCs (82). Also in a rat model, 1-y follow-up did not show any adverse effects (83).…”

“…liMiTaTions anD poTEnTial aDVErsE EFFEcTs Until now, no long-term adverse effects have been detected after MSC transplantation to treat ischemic brain injury (82,83). Patients with ischemic stroke and treated with MSCs showed no adverse effects 5 y after treatment with MSCs (82).…”

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

“…26 Ten small clinical studies of intravenous or intra-arterial cell delivery, including 136 subjects, have reported findings. [27][28][29][30][31][32][33][34][35][36] The majority of these were small, single-institution safety and tolerability studies. Only three included a control group, and the value of the control groups is questionable, since in many cases they consisted of patients deemed ineligible for the cell therapy intervention, were not randomised, and did not necessarily undergo any study related procedures.…”

“…Allocation was not always concealed to either patients or investigators. Piecemeal reporting of studies 24,27,28,34 further confuses the interpretation of these reports. Since the main focus was safety, long time windows for cell administration (between days and several months after stroke) were typically permitted.…”

Immune Effects of Mesenchymal Stromal Cells in Experimental Stroke

“…In fact, stroke-induced immunodepression is characterized by autonomic dysfunction and a transient depletion of T-, B-, and natural killer-cell populations, as well as suppression of their effector functions (Prass et al, 2003). Since none of the preclinical or clinical MSC stroke trials has addressed the effects of MSC treatment on strokeinduced immunodepression (Bang et al, 2005;Chen et al, 2001;Honmou et al, 2011;Kurozumi et al, 2005;Lee et al, 2010), we studied the impact of intravenous MSC transplantation on the peripheral immune responses to transient middle cerebral artery occlusion (MCAo) in adult mice.…”