Cell based therapies for ischemic stroke: From basic science to bedside
Introduction
Stroke remains a worldwide health burden, causing high morbidity, mortality, and costs to health care (Feigin et al., 2009, Johnston et al., 2009), and is the primary cause of serious long-term disability in the United States, leading to $38.6 billion in direct and indirect costs in 2009 (Go et al., 2013). Ischemic stroke accounts for over 80% of the total number of strokes. Currently the only validated therapy for ischemic stroke is thrombolysis, which must be administered within 4.5 h after onset (Del Zoppo et al., 2009). Due to its narrow therapeutic time window and the concern of hemorrhagic complication, thrombolysis is still not used regularly (Liu, 2012). Approximately 5% of stroke patients benefit from reperfusion therapies, and even so, only 10% of the stroke survivors return to independent living. In this context, development of neurorestorative therapies to improve neurological deficits after ischemic stroke is a great challenge for both bench scientists and clinical investigators.
After decades of research focused on acute neuroprotection and the failure of produce much in the way of tangible results (Ginsberg, 2008, Fisher, 2011), the Stroke Progress Review Group has identified neurorestoration as a major priority for stroke research (Grotta et al., 2008). Cell therapy is emerging as a viable neurorestorative therapy for stroke (Zhang and Chopp, 2009). A paucity of studies was reported in previous decades, yet the past 5 years have witnessed a remarkable surge in publications on this topic. Based on these reports, this review attempts to provide a comprehensive synopsis of preclinical evidence and clinical experience using various donor cell types, their restorative mechanisms, delivery methods, imaging strategies, future prospects and challenges for translating cell therapies as neurorestorative therapy for stroke in clinical applications.
Section snippets
Restorative mechanisms of cell-based therapies
In this section, we discuss the potential mechanisms of cell-based therapy-induced neurorestorative effects after stroke, which includes cell replacement, enhanced trophic/regenerative support from transplanted cells, immunomodulation, and stimulation of endogenous brain repair processes (such as angiogenesis, arteriogenesis, neurogenesis, synaptogenesis and white matter remodeling).
Cellular therapies from different cell sources
In contrast to Parkinson's disease or amyotrophic lateral sclerosis, which involves the degeneration of a specific population of neurons, stroke affects a heterogeneous population of brain cell types and vascular cells over large brain regions. Thus the ideal cell therapies for stroke require not only the direct replacement of multiple lost cell types and restoration of functional and appropriate neuronal connections, but also the reconstruction of disrupted vascular systems. Multiple
In vivo tracking of implanted cells
Longitudinal noninvasive tracking of grafted stem/progenitor cells in the brain will undoubtedly aid our understanding of spatiotemporal dynamics of the graft and how these cells mediate functional recovery. Several imaging methods have been developed to follow the graft in the CNS (Adamczak and Hoehn, 2012). In this section, we discuss the application of optical imaging, magnetic resonance imaging (MRI), and nuclear imaging as potential imaging strategies in stroke injury.
Cell delivery routes
As aforementioned, positive behavioral improvements have been observed with intracerebral, intracerebroventricular, intravascular and intranasal deliveries of stem/progenitor cells. Among those, is there an optimal delivery route for specific cell types? Currently, there is no definitive answer. Here we discuss the pros and cons of various delivery paradigms.
Gene modification
With regard to the paracrine-mediated mechanisms of stem/progenitor cells, enhancement of their trophic activities by overexpression of related genes would be of particular value to magnify the efficacy of cell therapies in stroke treatment (Chen et al., 2013a). A variety of genes was pre-incorporated into the implanted cells and has been reported to induce greater functional recovery. These therapeutic genes include angiogenic factors like VEGF (Zhu et al., 2005), Ang-1 (Onda et al., 2008),
Prospects and conclusion
Current evidence shows great promise for cell transplantation as a new therapeutic modality for stroke (Mir and Savitz, 2013). Nonetheless, important lessons should be learned from previous investigations on the development of stroke therapy. The past few decades witnessed over 1000 agents that have been tested as for their neuroprotective effects in stroke (O’Collins et al., 2006), and thus far, none of them has been proved to be of clinical value yet. This sobering reality should not be
Conflict of interest
None declared.
Acknowledgements
This work was supported by National Natural Science Foundation of China 31300900 (RY), 81300993 (TY), Jiangsu Provincial Special Program of Medical Science (BL2013025), National Institute on Aging of USA AG031811 (JC), and National Institute of Health of USA NS057255 (SPY), NS058710 (WL) and R41NS080329 (JC).
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Both these authors contributed equally to this work.