Intravenous Autologous Bone Marrow Mononuclear Cell Transplantation for Stroke: Phase1/2a Clinical Trial in a Homogeneous Group of Stroke Patients

Abstract

The goal of this clinical trial was to assess the feasibility and safety of transplanting autologous bone marrow mononuclear cells into patients suffering severe embolic stroke. Major inclusion criteria included patients with cerebral embolism, age 20–75 years, National Institute of Health Stroke Scale (NIHSS) score displaying improvement of ≤5 points during the first 7 days after stroke, and NIHSS score of ≥10 on day 7 after stroke. Bone marrow aspiration (25 or 50 mL; N = 6 patients in each case) was performed 7–10 days poststroke, and bone marrow mononuclear cells were administrated intravenously. Mean total transplanted cell numbers were 2.5 × 108 and 3.4 × 108 cells in the lower and higher dose groups, respectively. No apparent adverse effects of administering bone marrow cells were observed. Compared with the lower dose, patients receiving the higher dose of bone marrow cells displayed a trend toward improved neurologic outcomes. Compared with 1 month after treatment, patients receiving cell therapy displayed a trend toward improved cerebral blood flow and metabolic rate of oxygen consumption 6 months after treatment. In comparison with historical controls, patients receiving cell therapy had significantly better neurologic outcomes. Our results indicated that intravenous transplantation of autologous bone marrow mononuclear cells is safe and feasible. Positive results and trends favoring neurologic recovery and improvement in cerebral blood flow and metabolism by cell therapy underscore the relevance of larger scale randomized controlled trials using this approach.

Chronic global analysis of vascular permeability and cerebral blood flow after bone marrow stromal cell treatment of traumatic brain injury in the rat: A long-term MRI study

“…After 1-week, however, similar injury status in the two hemispheres characterized by Ki and CBF was observed, suggesting that focal trauma eventually results in pathological alterations throughout the brain, and that cell transplantation influences both hemispheres of the injured brain. These findings are consistent with the previous observation that TBI affects the brain diffusely, and cell engraftment exerts modulatory effects over a considerable spatial extent (Aertker et al, 2015; Dori et al, 2016; Li et al, 2011; Li et al, 2012; Taguchi et al, 2015). Our data also reveal that compared to un-injured brain (dotted lines in Fig.…”

“…4A), ameliorates these injury-induced vascular and hemodynamic abnormalities with time after TBI. These physiological alterations in response to the treatments (saline or cell) support the idea of chronic diaschisis (Garbuzova-Davis et al, 2014) and the therapeutic action of cell therapy on cerebral vasculature (Taguchi et al, 2015). …”

“…The physiological changes in diaschisis, present not only in the ipsilateral but also in the contralateral brain hemisphere, include compromised BBB integrity (Garbuzova-Davis et al, 2013; Garbuzova-Davis et al, 2014) plus corresponding edema (Izumi et al, 2002), hypoperfusion and hypometabolism (Carrera and Tononi, 2014). By improving blood flow and metabolism in both hemispheres of ischemia-injured brain, cell therapy has been shown to facilitate the normalization of diaschisis-associated physiological changes, particularly at the level of cerebral vasculature (Taguchi et al, 2015). Our data confirm the observations (Beaumont et al, 2000; Dietrich et al, 1998; Hayward et al, 2011; Hendrich et al, 1999; Kim et al, 2010; Park et al, 2015; Pasco et al, 2007; Su et al, 2015) that an unilateral focal impact leads to BBB opening and hemodynamic alteration, as detected by Ki and CBF, which spread into the remote brain areas both ipsilateral and contralateral to the primary injury (Carrera and Tononi, 2014; Taguchi et al, 2015).…”

“…By improving blood flow and metabolism in both hemispheres of ischemia-injured brain, cell therapy has been shown to facilitate the normalization of diaschisis-associated physiological changes, particularly at the level of cerebral vasculature (Taguchi et al, 2015). Our data confirm the observations (Beaumont et al, 2000; Dietrich et al, 1998; Hayward et al, 2011; Hendrich et al, 1999; Kim et al, 2010; Park et al, 2015; Pasco et al, 2007; Su et al, 2015) that an unilateral focal impact leads to BBB opening and hemodynamic alteration, as detected by Ki and CBF, which spread into the remote brain areas both ipsilateral and contralateral to the primary injury (Carrera and Tononi, 2014; Taguchi et al, 2015). Within an initial short period (less than 1-week) post-injury, a difference in the degree of traumatic injury influence on Ki and CBF between the two hemispheres was found regardless of intervention (cell or saline) and cell treatment strategy (6h or 1-week), with significantly more severe effects present in the ipsilateral-side than in the contralateral-side of the brain (Fig.…”

Stem Cell Therapies in Ischemic Stroke

“…Önemli bir yan etki olmadan güvenli kullanılabiliyor olmaları önemlidir ancak, henüz mezenkimal kök hücre tedavisinin inmeli hastada iyileşmeye bir etkisi olup olmadığını söylemek için çok erkendir. Elimizdeki çalışmaların bir kısmı, tasarlanmasında kısıtlılıklar bulunan, bir kısmı erken sonlandırılan, bir kısmı klinik özellik dikkate alınmadan, bir kısmı ise daha homojen hasta gruplarına uygulanmış olan çalışmalardır (18)(19)(20)(21)(22).Günümüzde çoğu pilot çalışma özelliğinde olan çalışmalardan elde edilen bilgilerle daha kapsamlı yeni çalışmalar planlanmaktadır. İskemik inmeli hastalarda planlanan ve devam etmekte olan çalışmalar aşağıda özetlenmiştir.…”