There is now evidence to suggest that bone marrow mesenchymal stem cells (MSCs) not only differentiate into mesodermal cells, but can also adopt the fate of endodermal and ectodermal cell types. In this study, we addressed the hypotheses that human MSCs can differentiate into neural cells when implanted in the brain and restore sensorimotor function after experimental stroke. Purified human MSCs were grafted into the cortex surrounding the area of infarction 1 week after cortical brain ischemia in rats. Two and 6 weeks after transplantation animals were assessed for sensorimotor function and then sacrificed for histological examination. Ischemic rats that received human MSCs exhibited significantly improved functional performance in limb placement test. Histological analyses revealed that transplanted human MSCs expressed markers for astrocytes (GFAP ؉ ), oligodendroglia (GalC ؉ ), and neurons (␤III ؉ , NF160 ؉ , NF200 ؉ , hNSE ؉ , and hNF70 ؉ ). The morphological features of the grafted cells, however, were spherical in nature with few processes. Therefore, it is unlikely that the functional recovery observed by the ischemic rats with human MSC grafts was mediated by the integration of new "neuronal" cells into the circuitry of the host brain. The observed functional improvement might have been mediated by proteins secreted by transplanted hMSCs, which could have upregulated host brain plasticity in response to experimental stroke.

Although Sox1, Sox2, and Sox3 are all part of the Sox-B1 group of transcriptional regulators, only Sox1 appears to play a direct role in neural cell fate determination and differentiation. We find that overexpression of Sox1 but not Sox2 or Sox3 in cultured neural progenitor cells is sufficient to induce neuronal lineage commitment. Sox1 binds directly to the Hes1 promoter and suppresses Hes1 transcription, thus attenuating Notch signaling. Sox1 also binds to beta-catenin and suppresses beta-catenin-mediated TCF/LEF signaling, thus potentially attenuating the wnt signaling pathway. The C-terminus of Sox1 is required for both of these interactions. Sox1 also promotes exit of cells from cell cycle and up-regulates transcription of the proneural bHLH transcription factor neurogenin 1 (ngn1). These observations suggest that Sox1 works through multiple independent pathways to promote neuronal cell fate determination and differentiation.

BackgroundIf a critical nerve is circumferentially involved with tumor, radical surgery intended to cure the cancer must sacrifice the nerve. Loss of critical nerves may lead to serious consequences. In spite of the impressive technical advancements in nerve reconstruction, complete recovery and normalization of nerve function is difficult to achieve. Though irreversible electroporation (IRE) might be a promising choice to treat tumors near or involved critical nerve, the pathophysiology of the nerve after IRE treatment has not be clearly defined.MethodsWe applied IRE directly to a rat sciatic nerve to study the long term effects of IRE on the nerve. A sequence of 10 square pulses of 3800 V/cm, each 100 µs long was applied directly to rat sciatic nerves. In each animal of group I (IRE) the procedure was applied to produce a treated length of about 10 mm. In each animal of group II (Control) the electrodes were only applied directly on the sciatic nerve for the same time. Electrophysiological, histological, and functional studies were performed on immediately after and 3 days, 1 week, 3, 5, 7 and 10 weeks following surgery.FindingsElectrophysiological, histological, and functional results show the nerve treated with IRE can attain full recovery after 7 weeks.ConclusionThis finding is indicative of the preservation of nerve involving malignant tumors with respect to the application of IRE pulses to ablate tumors completely. In summary, IRE may be a promising treatment tool for any tumor involving nerves.

Improved spread of transduction in the central nervous system (CNS) was achieved from intravenous administration of adeno-associated virus serotype-9 (AAV9) to neonatal rats. Spinal lower motor neuron transduction efficiency was estimated to be 78% using the highest vector dose tested at a 12-week interval. The widespread expression could aid studying diseases that affect both the spinal cord and brain, such as amyotrophic lateral sclerosis (ALS). The protein most relevant to neuropathology in ALS is transactive response DNA-binding protein 43 (TDP-43). When expressed in rats, human wild-type TDP-43 rapidly produced symptoms germane to ALS including paralysis of the hindlimbs and muscle wasting, and mortality over 4 weeks that did not occur in controls. The hindlimb atrophy and weakness was evidenced by assessments of rotarod, rearing, overall locomotion, muscle mass, and histology. The muscle wasting suggested denervation, but there was only 14% loss of motor neurons in the TDP-43 rats. Tissues were negative for ubiquitinated, cytoplasmic TDP-43 pathology, suggesting that altering TDP-43's nuclear function was sufficient to cause the disease state. Other relevant pathology in the rats included microgliosis and degenerating neuronal perikarya positive for phospho-neurofilament. The expression pattern encompassed the distribution of neuropathology of ALS, and could provide a rapid, relevant screening assay for TDP-43 variants and other disease-related proteins.

We have previously demonstrated that receptors for hematopoietic growth factors, stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) are expressed in the neurons and the neural progenitor cells (NPCs) in adult rat brain, and systemic administration of SCF and G-CSF in the first week after induction of cortical brain ischemia (3 hrs-7d post-ischemia) significantly improve functional outcome, augment NPC proliferation, and reduce infarct volume in rats. The purpose of the present study was to determine whether SCF and G-CSF pass through the blood brain barrier (BBB) in intact rats. The growth factors were labeled with iodine (I 125 ), a radioactive compound. I 125 -SCF and I 125 -G-CSF were intravenously administered, and the concentrations of I 125 -SCF and I 125 -G-CSF in the blood plasma and the brain were determined at 10, 30, 60, and 120 minutes after injection. We observed that both SCF and G-CSF were slowly and continuously, in the same rate, transported from the blood stream to the brain. In addition, both immunofluorescent staining and western blots showed that receptors for SCF and G-CSF were expressed in the capillaries of adult rat brain, suggesting that SCF and G-CSF entry to the brain may be mediated via receptor-mediated transport, one of the endogenous transports in the BBB. These data indicate that both SCF and G-CSF were able to pass through the BBB in intact animals. This observation will help in further exploring the physiological role of peripheral SCF and G-CSF in the brain and therapeutic possibility to chronic stroke.