Stroke Literature Synopses: Basic Science
Stem cell transplantation may be a promising therapeutic approach to repair damaged central nervous system tissue. Three recent articles introduced below provide novel insights into mechanisms and methods for cell transplantation to stroke damaged brains.
As a donor cell, neural stem cell (NSC) has been one of the major candidates for cell transplantation to brain. However, hostile host environments during the acute phase of stroke reduce the efficacy of NSC transplantation. Wakai et al (Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice [published online ahead of print October 27, 2015]. J Cereb Blood Flow Metab. doi: 10.1177/0271678X15613798) demonstrated that hypoxic preconditioning would enhance NSC resilience to the hemorrhagic stroke environments. In vitro cell culture experiments first confirmed that hypoxic preconditioning (sublethal hypoxic stress; 5% hypoxia for 24 hours) enhanced cell proliferation/survival of NSCs and increased NSC tolerance against hemoglobin cytotoxicity. In addition, the hypoxic preconditioning upregulated a prosurvival Akt phosphorylation via hypoxia inducible factor-1α and also enhanced vascular endothelial growth factor secretion from NSCs. When NSCs were transplanted to intracerebral hemorrhage mice, more transplanted NSCs survived when NSCs were preconditioned with mild hypoxia than the nonpreconditioning group. Furthermore, mice that received hypoxia-preconditioned NSCs exhibited more vascular endothelial growth factor expressions along with enhanced functional recovery and perilesional tissue protection. These data suggest that hypoxic preconditioning to NSCs may improve the efficacy of stem cell therapy in intracerebral hemorrhage.
Besides NSCs, other stem cells have been proposed for cell transplantation to damaged brain. Uchida et al (Transplantation of unique subpopulation of fibroblasts, Muse cells, ameliorates experimental stroke possibly via robust neuronal differentiation. Stem Cells. 2015;34:160–173. doi: 10.1002/stem.2206) examined whether multilineage-differentiating stress-enduring (Muse) cells can be a novel source of transplantable stem cells for stroke. Muse cells, which are a unique stem cell population within fibroblasts, can self-renew and differentiate into cells representative of all 3 germ layers. In this study, the authors separated Muse cells and non-Muse cells, as control, from adult-skin–derived human dermal fibroblasts by flow cytometry. When these Muse or non-Muse cells were further subjected to single-cell suspension culture, only Muse cells formed characteristic clusters that expressed pluripotency markers Oct3/4, Nanog, and Sox2. In addition, cells expanded from the Muse cell–derived clusters on gelatin-coated plates expressed neural markers, suggesting that Muse cells would differentiate into neural-lineage cells. Then the authors stereotaxically transplanted Muse or non-Muse cells into the rat brain 2 days after stroke onset. At day 84, there were no significant differences in infarct volume between Muse-transplanted, non–Muse-transplanted, and vehicle (PBS only) groups. However, transplanted Muse cells survived in the host brains at least ≤84 days, and they integrated into the sensory-motor cortex with extended neuritis into cervical spinal cord. Finally, Muse cell–transplanted rats exhibited better neurological outcomes. Hence, Muse cells would be a feasible and promising cell source for cell-based therapy for stroke.
The use of multiple cell types may accelerate the process of reconstructing damaged tissues after stroke. However, one of major challenges in the transplantation of multiple cell types is to selectively and noninvasively visualize these implanted cells. Nicholls et al (Simultaneous MR imaging for tissue engineering in a rat model of stroke. Sci Rep. 2015;5:14597. doi: 10.1038/srep14597) proposed a novel method in assessing the distribution of transplanted NSCs and endothelial cells (ECs) simultaneously. The authors used 2 paramagnetic chemical exchange saturation transfer (PARACEST) agents. Although T2 agents have been to date mainly used to visualize implanted cells, T1 and T2 agents within the same voxel are difficult to be separated. In contrast, the PARACEST approach can afford a selective visualization of independent PARACEST agents with better sensitivity. In this study, the human striatal NSC line STROC05 was labeled with Eu-HPDO3A, and the human cerebral microvascular EC hCMEC/D3 was labeled with Yb-HPDO3A. After the simultaneous detection of NSCs and ECs in the same voxel with a ratio of 4:1 NSCs:ECs was confirmed by in vitro experiments, the authors transplanted the mixture of labeled cells into the stroke cavity of rats (2 weeks after 70-minute middle cerebra occlusion by filament insertion). The magnetic resonance image successfully visualized the implanted NSCs and ECs in vivo brains simultaneously and noninvasively, which was later validated by histological analysis. Therefore, this noninvasive imaging technique would be useful to understand how implanted cells contribute to formation of de novo brain tissues.
These 3 studies demonstrate novel tools and mechanisms in stem cell therapy for stroke. Replacing lost tissues by cell transplantation in stroke brain will be challenging, but further investigation into how transplanted cells would reconstruct damaged neurovascular environment and alter the biochemical environment for neurovascular recovery/repair may eventually lead to effective approaches in cell-based therapy for stroke patients.
- © 2016 American Heart Association, Inc.