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Axonal regeneration after peripheral nerve injury is impaired in diabetes, but its precise mechanisms have not been elucidated. In this paper, we summarize the progress of research on altered axonal regeneration in animal models of diabetes and cultured nerve tissues exposed to hyperglycemia. Impaired nerve regeneration in animal diabetes can be attributed to dysfunction of neurons and Schwann cells, unfavorable stromal environment supportive of regenerating axons, and alterations of target tissues receptive to reinnervation. In particular, there are a number of factors such as enhanced activity of the negative regulators of axonal regeneration (e.g., phosphatase and tensin homolog deleted on chromosome 10 and Rho/Rho kinase), delayed Wallerian degeneration, alterations of the extracellular matrix components, enhanced binding of advanced glycation endproducts (AGEs) with the receptor for AGE, and delayed muscle reinnervation that can be obstacles to functional recovery after an axonal injury. It is also noteworthy that we and others have observed excessive neurite outgrowth from peripheral sensory ganglion explants from streptozotocin (STZ)-diabetic mice in culture and enhanced regeneration of small nerve fibers after sciatic nerve injury in STZ-induced diabetic rats. The excess of abortive neurite outgrowth may lead to misconnections of axons and target organs, which may interfere with appropriate target reinnervation and functional repair. Amelioration of perturbed nerve regeneration may be crucial for the future management of diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized. [ABSTRACT FROM AUTHOR]

Embryonic stem cells (ES cells) express a transient and heterogeneous pattern of molecules, which suggests a notable mechanism to control self-renewal avoid the differentiation into germ layers. We show that 9-O-acetyl GD3 (9OacGD3), a highly expressed b-series ganglioside in neural stem (NS) cells, is expressed in undifferentiated mouse ES cells in a heterogeneous fashion. After sorting, undifferentiated 9OacGD3+ ES cell population had higher levels of nestin and Sox2 mRNA than the 9OacGD3− cells. Even with elevated expression of these neural transcription factors, 9OacGD3+ cells did not give rise to more neural progenitors than 9OacGD3− cells. Expression of 9OacGD3 was recovered from 9OacGD3− cell population, demonstrating that expression of this ganglioside in mouse embryonic stem cells is transient, and does not reflect cell fate. Our findings show that the ganglioside 9OacGD3 is expressed heterogeneously and transiently in ES cells, and this expression corresponds to higher levels of Sox2 and Nestin transcripts. [ABSTRACT FROM AUTHOR]

Background: Chagas disease, resulting from infection with the parasite Trypanosoma cruzi (T. cruzi), is a major cause of cardiomyopathy in Latin America. Drug therapy for acute and chronic disease is limited. Stem cell therapy with bone marrow mesenchymal cells (MSCs) has emerged as a novel therapeutic option for cell death-related heart diseases, but efficacy of MSC has not been tested in Chagas disease. Methods and Results: We now report the use of cell-tracking strategies with nanoparticle labeled MSC to investigate migration of transplanted MSC in a murine model of Chagas disease, and correlate MSC biodistribution with glucose metabolism and morphology of heart in chagasic mice by small animal positron emission tomography (microPET). Mice were infected intraperitoneally with trypomastigotes of the Brazil strain of T. cruzi and treated by tail vein injection with MSC one month after infection. MSCs were labeled with near infrared fluorescent nanoparticles and tracked by an in vivo imaging system (IVIS). Our IVIS results two days after transplant revealed that a small, but significant, number of cells migrated to chagasic hearts when compared with control animals, whereas the vast majority of labeled MSC migrated to liver, lungs and spleen. Additionally, the microPET technique demonstrated that therapy with MSC reduced right ventricular dilation, a phenotype of the chagasic mouse model. Conclusions: We conclude that the beneficial effects of MSC therapy in chagasic mice arise from an indirect action of the cells in the heart rather than a direct action due to incorporation of large numbers of transplanted MSC into working myocardium. Author Summary: Chagas disease, resulting from infection with the parasite Trypanosoma cruzi, is a major cause of heart disease in Latin America. Treatment options are limited to a small number of drugs that were developed more than four decades ago and which have various drawbacks. Stem cell therapy with bone marrow mesenchymal cells (MSCs) has emerged as a novel therapeutic option for cell death-related heart diseases, but efficacy of MSCs has not been tested in Chagas disease therapy. Due to the established role of the immune system in the physiopathology of Chagas disease and the immune modulatory properties of MSC we hypothesized that MSC could be an optimal cell type for therapy in chagasic cardiomyopathy. Therefore, in this study we have used cell tracking strategies following labeling of MSCs with nanoparticles to investigate migration of transplanted MSCs in a murine model of Chagas disease, and have correlated MSCs migration with cardiac function in chagasic animals by small animal positron emission tomography imaging technique. [ABSTRACT FROM AUTHOR]

Abstract: Bone marrow mesenchymal stem cells (MSC) have been tested and proven effective in some neurodegenerative diseases, but their tracking after transplantation may be challenging. Our group has previously demonstrated the feasibility and biosafety of rat MSC labeling with iron oxide superparamagnetic nanoparticles (SPION). In this study, we investigated the therapeutic potential of SPION-labeled MSC in a rat model of Huntington''s disease, a genetic degenerative disease with characteristic deletion of striatal GABAergic neurons. MSC labeled with SPION were injected into the striatum 1h after quinolinic acid injection. FJ-C analysis demonstrated that MSC transplantation significantly decreased the number of degenerating neurons in the damaged striatum 7days after lesion. In this period, MSC transplantation enhanced the striatal expression of FGF-2 but did not affect subventricular zone proliferation, as demonstrated by Ki67 proliferation assay. In addition, MSC transplantation significantly reduced the ventriculomegaly in the lesioned brain. MRI and histological techniques detected the presence of the SPION-labeled cells at the lesion site. SPION-labeled MSC produced magnetic resonance imaging (MRI) signals that were visible for at least 60days after transplantation. Our data highlight the potential of adult MSC to reduce brain damage under neurodegenerative diseases and indicate the use of nanoparticles in cell tracking, supporting their potential as valuable tools for cell therapy. [Copyright &y& Elsevier]

The level of expression of the neuronal nitric oxide synthase (nNOS) in the retinorecipient layers of rat superior colliculus (SC) was investigated in adult rats after neonatal enucleation using two biochemical methods: (1) measurement of the in vitro specific-activity of NOS by the conversion of [3H]-arginine to [3H]-citrulline and (2) immunochemical analysis by western blotting and densitometry of immunoreactive bands using antibodies that recognise the three prominent isoforms of nNOS, α, β and γ. A total of 20 Lister rats were used in this study. We have shown that the deprivation of the retinocollicular projections at early postnatal ages induces no significant change in the specific-activity of nNOS. We also have shown that the deafferentation does not significantly influence either the total amount of nNOS in the SC superficial layers or the relative contribution ratio of nNOS isoforms. In conclusion, the expression and activity of nNOS in the SC retinorecipient layers was shown not to be dependent on the presence of retinal afferents during development. [Copyright &y& Elsevier]

During development of the cerebellum, radial glial cells guide the migration of granule cell precursors from the external granular cell layer toward the internal granular cell layer. The cellular membranes of migrating neurons and glial fibers organize a specialized migration junction at the site of contact between these cells, and several molecules have been implicated in the control of this glial-guided neuronal migration program. The monoclonal antibody Jones (mAb Jones) recognizes the ganglioside 9-O-acetyl GD3, which is expressed in migratory profiles in the developing and adult CNS. Recently, this ganglioside was suggested to play a role in neuronal migration in cerebellar cultures. In this report, we use antibody perturbation assays to investigate a possible role of 9-O-acetyl GD3 in the neuronal migration program in vivo. The results show that chronic intracerebroventricular administration of mAb Jones arrests neuronal migration in the developing cerebellum of live animals. Proliferating granule cell precursors were labeled with 5-bromo-2'-deoxyuridine (BrdU), and their migratory behavior was analyzed and compared with control groups. Immunoblockage of 9-O-acetyl GD3 arrests 43% of the BrdU-labeled granule precursors in the external granular celllayer. Together with our previous results, this report strongly suggests that the ganglioside 9-O-acetyl GD3 plays a crucial role in the migration of cerebellar granule cells along radial glial fibers in the developing rat cerebellum. [ABSTRACT FROM AUTHOR]