Background and Purpose-Although stem cell-based treatments for neurodegenerative diseases have advanced rapidly, there is currently no clinically available method to monitor the fate of transplanted cells in the brain. Methods-To use magnetic resonance imaging for tracking transplanted stem cells in the ischemic rat brain, we used the cellular labeling substance Effectene to transfect a standard contrast agent (Gd-DTPA) into immortalized human bone marrow stromal cells. Results-The transfection efficiency of this method was up to 90%, which is substantially better than pure spontaneous endocytosis or other transfection agents. In addition, cellular uptake of Gd-DTPA in vitro was maintained for Ͼ28 days. Therefore, we could follow transplanted stem cell migration and homing into the penumbric area. Using double immunofluorescence, the transplanted cells were seen to differentiate into glial cells, neurons and vascular endothelial cells. Cortical neurochemical activity as evaluated by proton magnetic resonance spectroscopy ( 1 H-MRS) also increased considerably after immortalized human bone marrow stromal cell transplantation. Conclusion-This method of tracking immortalized human bone marrow stromal cells is highly efficient and allows for nontoxic labeling of cells.

d-Opioid receptor (DOR) is an oxygen-sensitive protein whose function in the rat retina is unknown. We examined whether DOR is involved in hypoxic preconditioning (HPC)-mediated retinoprotection following intraocular pressure (IOP) elevation. Rats were exposed to intermittent hypoxia (10% oxygen) to induce HPC. Unilateral retinal ischemia/reperfusion injury was induced by elevating IOP to 100 mmHg for 1 h. HPC attenuated the loss of neuronal marker expression and increased pro-apoptotic caspase 3 activity in the IOP retina. Excess superoxide production and 8-iso-prostaglandin F2a accumulation caused by enhanced oxidant protein expression and reduced antioxidant enzyme level after IOP elevation were largely abrogated by HPC. HPC markedly increased the expression of hypoxia-inducible factor-1a (HIF-1a) and DOR, but intravitreal administration of HIF-1a-specific small interfering RNA abrogated the up-regulation of DOR. This suggested that DOR functions downstream of HIF-1a. However, the endogenous content of leucine enkephalin in retinas was not affected by HPC or IOP. Treatment of retinas with the DOR antagonist naltrindole attenuated the HPC-induced protection and activation of extracellular signal-regulated kinase. These results suggest a novel mechanism of HPCmediated retinoprotection whereby HIF-1a induces the expression of DOR, and DOR-mediated activation of extracellular signal-regulated kinase triggers cellular events that correct the redox imbalance in the post-ischemic retina.

Stem cell therapies, such as bone marrow transplantation, are a promising strategy for the treatment of stroke. Bone marrow-derived stem cells (BMSCs) including both hematopoietic and mesenchymal stem cells (HSCs and MSCs) can exhibit tremendous cellular differentiation in numerous organs. BMSCs may also promote structural and functional repair in several organs such as the heart, liver, brain, and skeletal muscle via stem cell plasticity. Interestingly, ischemia is known to induce mobilization of BMSCs in both animal models and humans. The tissue injury is "sensed" by the stem cells and they migrate to the site of damage and undergo differentiation. The plasticity, differentiation, and migratory functions of BMSCs in a given tissue are dependent on the specific signals present in the local micro-environment of the damaged tissue. Therefore, the ischemic micro-environment has critical patho-biological functions that are essential for the seeding, expansion, survival, renewal, growth and differentiation of BMSCs in damaged brain remodeling. Recent studies have identified the specific molecular signals, such as SDF-1/CXCR4, required for the interaction of BMSCs and damaged host tissues. Understanding the exact molecular basis of stem cell plasticity in relation to local ischemic signals could offer new insights to permit better management of stroke and other ischemic disorders. The aim of this review is to summarize recent studies into how BMSCs reach, recognize, and function in cerebral ischemic tissues, with particular regard to phenotypical reprogramming of stem cells, or "stem cell plasticity".

No abstract

Ciliary neurotrophic factor (CNTF) is known as an important factor in the regulation of retinal cell growth. We used both recombinant CNTF and an adenovirus carrying the CNTF gene to regulate retinal photoreceptor expression in a retinal degenerative animal, Royal College of Surgeons (RCS) rats. Cells in the outer nuclear layer of the retinae from recombinant-CNTF-treated, adenoviral-CNTF-treated, saline-operated, and contralateral untreated preparations were examined for those exhibiting CNTF photoreceptor protective effects. Cell apoptosis in the outer nuclear layer of the retinae was also detected. It was found that CNTF had a potent effect on delaying the photoreceptor degeneration process in RCS rats. Furthermore, adenovirus CNTF gene transfer was proven to be better at rescuing photoreceptors than that when using recombinant CNTF, since adenoviral CNTF prolonged the photoreceptor protection effect. The function of the photoreceptors was also examined by taking electroretinograms of different animals. Adenoviral-CNTF-treated eyes showed better retinal function than did the contralateral control eyes. This study indicates that adenoviral CNTF effectively rescues degenerating photoreceptors in RCS rats.

As a result of the progressive decrease in efficacy of drugs used to treat Parkinson's disease (PD) and the rapid development of motor complications, effective alternative treatments for PD are required. In a 6-hydroxydopamine (6-OHDA)-induced Parkinson's rat model, intracerebral peripheral blood stem cell (CD34(+)) (PBSC) transplantation significantly protected dopaminergic neurons from 6-OHDA-induced neurotoxicity, enhanced neural repair of tyrosine hydroxylase neurons through up-regulation of Bcl-2, facilitated stem cell plasticity, and attenuated activation of microglia, in comparison with vehicle-control rats. The 6-OHDA-lesioned hemi-Parkinsonian rats receiving intrastriatal transplantation of PBSCs also showed: 1) enhanced glucose metabolism in the lesioned striatum and thalamus, demonstrated by [(18)F]fluoro-2-deoxyglucose positron emission tomography (FDG-PET), 2) improved neurochemical activity as shown by proton magnetic resonance spectroscopy ((1)H-MRS), and 3) significantly reduced rotational behavior in comparison with control lesioned rats. These observations might be explained by an up-regulation of growth-associated protein 43 (GAP-43) expression because improvements in neurological dysfunction were blocked by injection of MK-801 in the PBSC-treated group. In addition, a significant increase in neurotrophic factor expression was found in the ipsilateral hemisphere of the PBSC-treated group. In summary, this protocol may be a useful strategy for the treatment of clinical PD.

Neurodegenerative diseases (NDs), at least including Alzheimer’s, Huntington’s, and Parkinson’s diseases, have become the most dreaded maladies because there are no precise diagnostic tools or definite treatments for these debilitating diseases. The increased prevalence and a substantial impact on the social–economic and medical care of NDs propel governments to develop policies to counteract the impact. Although the etiologies of NDs are still unknown, growing evidence suggests that genetic, cellular, and circuit alternations may cause the generation of abnormal misfolded proteins, which uncontrolledly accumulate to damage and eventually overwhelm the protein-disposal mechanisms of these neurons, leading to a common pathological feature of NDs. If the functions and the connectivity can be restored, alterations and accumulated damages may improve. The gene-editing tools including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats–associated nucleases (CRISPR/CAS) have emerged as a novel tool not only for generating specific ND animal models for interrogating the mechanisms and screening potential drugs against NDs but also for the editing sequence-specific genes to help patients with NDs to regain function and connectivity. This review introduces the clinical manifestations of three distinct NDs and the applications of the gene-editing technology on these debilitating diseases.

Our results suggest that G-CSF reduces optic ischemia-induced retinal cell loss, possibly through STAT3-regulated mobilization of hematopoietic progenitor cells to the retina.