Intravenous Administration of Auto Serum-expanded Autologous Mesenchymal Stem Cells in Stroke

Osamu Honmou; Kiyohiro Houkin; Takuya Matsunaga; Yoshiro Niitsu; Sumio Ishiai; Rie Onodera; Stephen G. Waxman; Jeffery D. Kocsis

Disclosures

Brain. 2011;134(6):1790-1807. 

In This Article

Abstract and Introduction

Abstract

Transplantation of human mesenchymal stem cells has been shown to reduce infarct size and improve functional outcome in animal models of stroke. Here, we report a study designed to assess feasibility and safety of transplantation of autologous human mesenchymal stem cells expanded in autologous human serum in stroke patients. We report an unblinded study on 12 patients with ischaemic grey matter, white matter and mixed lesions, in contrast to a prior study on autologous mesenchymal stem cells expanded in foetal calf serum that focused on grey matter lesions. Cells cultured in human serum expanded more rapidly than in foetal calf serum, reducing cell preparation time and risk of transmissible disorders such as bovine spongiform encephalomyelitis. Autologous mesenchymal stem cells were delivered intravenously 36–133 days post-stroke. All patients had magnetic resonance angiography to identify vascular lesions, and magnetic resonance imaging prior to cell infusion and at intervals up to 1 year after. Magnetic resonance perfusion-imaging and 3D-tractography were carried out in some patients. Neurological status was scored using the National Institutes of Health Stroke Scale and modified Rankin scores. We did not observe any central nervous system tumours, abnormal cell growths or neurological deterioration, and there was no evidence for venous thromboembolism, systemic malignancy or systemic infection in any of the patients following stem cell infusion. The median daily rate of National Institutes of Health Stroke Scale change was 0.36 during the first week post-infusion, compared with a median daily rate of change of 0.04 from the first day of testing to immediately before infusion. Daily rates of change in National Institutes of Health Stroke Scale scores during longer post-infusion intervals that more closely matched the interval between initial scoring and cell infusion also showed an increase following cell infusion. Mean lesion volume as assessed by magnetic resonance imaging was reduced by >20% at 1 week post-cell infusion. While we would emphasize that the current study was unblinded, did not assess overall function or relative functional importance of different types of deficits, and does not exclude placebo effects or a contribution of recovery as a result of the natural history of stroke, our observations provide evidence supporting the feasibility and safety of delivery of a relatively large dose of autologous mesenchymal human stem cells, cultured in autologous human serum, into human subjects with stroke and support the need for additional blinded, placebo-controlled studies on autologous mesenchymal human stem cell infusion in stroke.

Introduction

Transplantation of mesenchymal stem cells (MSCs), derived from bone marrow, into rodent cerebral ischaemia models can reduce infarct size and improve functional outcome (Chen et al., 2001; Li et al., 2002; Nomura et al., 2005; Honma et al., 2006; Horita et al., 2006; Liu et al., 2006; Onda et al., 2007; Ukai et al., 2007; Omori et al., 2008; Toyama et al., 2009; Komatsu et al., 2010). MSCs can differentiate into cells of neuronal and glial lineage under appropriate cell culture conditions in vitro (Kobune et al., 2003; Kim et al., 2006) as well as in vivo (Prockop et al., 1997; Woodbury et al., 2000; Nomura et al., 2005; Honma et al., 2006). The beneficial effects of MSCs early after transplantation are thought to result from multiple mechanisms that include neuroprotective (Chen et al., 2001; Nomura et al., 2005; Honma et al., 2006; Horita et al., 2006; Liu et al., 2006), anti-inflammatory (Ohtaki et al., 2008) and/or angiogenic (Chen et al., 2003; Liu et al., 2006; Onda et al., 2007; Prockop, 2007; Ukai et al., 2007; Omori et al., 2008; Toyama et al., 2009; Komatsu et al., 2010) effects. Human MSCs genetically modified to produce trophic (Nomura et al., 2005; Horita et al., 2006; Liu et al., 2006) or angiogenic (Liu et al., 2006; Onda et al., 2007; Toyama et al., 2009) factors can markedly improve function and reduce lesion volume in rodent brain ischaemia models.

Bang et al. (2005), in a study primarily aimed at assessing safety, infused freshly prepared autologous bone marrow-derived MSCs expanded in foetal calf serum into five severely affected stroke patients 1–2 months after stroke onset. They report safety, feasibility and a suggestion of efficacy. Human MSC infusion has been studied in cancer (Koc et al., 2000; Lazarus et al., 2005) and neurological disorders other than stroke (Koc et al., 2002) and it appears that in these disorders the use of autologous cells can minimize immune reactions. These considerations, and experimental data showing that human MSC infusion leads to improved outcome and reduced lesion volume in rodent ischaemia models, provide the rationale for the present study.

MSCs constitute a small fraction of the bone marrow non-haematopoietic cell fraction and culture conditions are critical in enriching cultures with human MSCs. Human MSCs can be expanded rapidly with more stable gene expression and maintained in the undifferentiated stem cell state in autologous human serum compared with those in foetal calf serum (Kobayashi et al., 2005; Shahdadfar et al., 2005). In the present study, we assessed autologous human MSCs expanded using autologous human serum under good manufacturing practice conditions. The autologous cells used in this study were well-defined as an immature stem cell population and the molecular phenotype was consistent between patients. Moreover, the use of autologous human serum rather than foetal calf serum resulted in more rapid expansion of cells, which reduces cell preparation time, a factor that may be important for autologous transplantation studies and minimizes potential risk of transmitting viruses, prions [e.g. bovine spongiform encephalomyelitis; see Scolding et al. (2008)] and/or proteins that may cause xenogeneic immunogenicity (delayed hypersensitivity reaction) (Drach et al., 1977). In the present study, we examined feasibility and safety of cell therapy using autoserum-expanded autologous human MSCs in stroke patients. Patients with both grey and white matter ischaemic lesions were studied. A single infusion of well-characterized autologous human MSCs was delivered in the subacute or chronic phase of the stroke. Neurological and neuroradiological analysis was carried out for 1 year. Early results of this study have been reported in an abstract (Honmou et al., 2008).

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