Stem cell therapy for cerebral ischemia: from basic science to clinical applications

Abstract

Recent stem cell technology provides a strong therapeutic potential not only for acute ischemic stroke but also for chronic progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis with neuroregenerative neural cell replenishment and replacement. In addition to resident neural stem cell activation in the brain by neurotrophic factors, bone marrow stem cells (BMSCs) can be mobilized by granulocyte-colony stimulating factor for homing into the brain for both neurorepair and neuroregeneration in acute stroke and neurodegenerative diseases in both basic science and clinical settings. Exogenous stem cell transplantation is also emerging into a clinical scene from bench side experiments. Early clinical trials of intravenous transplantation of autologous BMSCs are showing safe and effective results in stroke patients. Further basic sciences of stem cell therapy on a neurovascular unit and neuroregeneration, and further clinical advancements on scaffold technology for supporting stem cells and stem cell tracking technology such as magnetic resonance imaging, single photon emission tomography or optical imaging with near-infrared could allow stem cell therapy to be applied in daily clinical applications in the near future.

Figure 1

The stage of endogenous neurogenesis can be divided into three steps: proliferation, migration, and differentiation. (A) Neural stem cells proliferate at the subgranular zone (SGZ), and the cells then migrate into the granule cell layer (GCL) and differentiate mainly into neuronal cells in the postischemic dentate gyrus (DG) of gerbils. (B) Neural stem cells proliferate at the subventricular zone (SVZ), and a sub-population of these cells can migrate toward the infarcted lesion, and finally differentiate into mature neurons, which can be integrated into the neighboring neuronal network.

Figure 2

Mechanism of action of granulocyte-colony stimulating factor (G-CSF) in cerebral ischemia.

Figure 3

Scheme of bone marrow stromal cell (BMSC) transplantation for ischemic stroke. The engrafted cells migrate toward the peri-infarct area via chemokine interaction. They may rescue and repair the damaged central nervous system (CNS) tissue through the differentiation into the neural cells, the release of neurotrophic or neuroprotective factors, and the inhibition of inflammatory reactions.

Figure 4

‘Five Ws and two Hs (5W2H)' of cell therapy—the issues to be answered in preclinical studies and early-stage clinical trial of bone marrow stromal cell (BMSC) transplantation for ischemic stroke. GMP, good manufacturing practice; MRI, magnetic resonance imaging.