Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.

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Hemostasis is a major problem in surgical procedures and after major trauma. There are few effective methods to stop bleeding without causing secondary damage. We used a self-assembling peptide that establishes a nanofiber barrier to achieve complete hemostasis immediately when applied directly to a wound in the brain, spinal cord, femoral artery, liver, or skin of mammals. This novel therapy stops bleeding without the use of pressure, cauterization, vasoconstriction, coagulation, or cross-linked adhesives. The self-assembling solution is nontoxic and nonimmunogenic, and the breakdown products are amino acids, which are tissue building blocks that can be used to repair the site of injury. Here we report the first use of nanotechnology to achieve complete hemostasis in less than 15 seconds, which could fundamentally change how much blood is needed during surgery of the future.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to rescue developing motoneurons in vivo and in vitro from both naturally occurring and axotomyinduced cell death. To test whether GDNF has trophic effects on adult motoneurons, we used a mouse model of injuryinduced adult motoneuron degeneration. Injuring adult motoneuron axons at the exit point of the nerve from the spinal cord (avulsion) resulted in a 70% loss of motoneurons by 3 weeks following surgery and a complete loss by 6 weeks. Half of the loss was prevented by GDNF treatment. GDNF also induced an increase (hypertrophy) in the size of surviving motoneurons. These data provide strong evidence that the survival of injured adult mammalian motoneurons can be promoted by a known neurotrophic factor, suggesting the potential use of GDNF in therapeutic approaches to adultonset motoneuron diseases such as amyotrophic lateral sclerosis.Factors that promote motoneuron survival have potential as therapeutic agents for the treatment of human neurodegenerative diseases (1). It has been shown that several neurotrophic factors, including brain-derived neurotrophic factor (BDNF) (2-4), insulin-like growth factor (I.GF) (5), ciliary neurotrophic factor (6), and glial cell line-derived neurotrophic factor (GDNF) (7-10), can rescue developing motoneurons from both naturally occurring and axotomy-induced cell death. However, whether these trophic factors also play a role in adult motoneuron survival is not known. Because many motoneuron diseases, such as amyotrophic lateral sclerosis, have a late (i.e., adult) onset, it is important to determine whether neurotrophic factors are effective on injured adult motoneurons.Interactions between motoneurons and their target muscles have been extensively investigated. For example, it is known that transection of axons of motoneurons or removal of their target during embryonic and early postnatal development results in massive motoneuron cell loss, whereas axotomy of adult peripheral nerve induces little if any neuronal death (11)(12)(13)(14)(15)(16)(17)(18)(19). A plausible explanation for this difference is that trophic support derived from mature nonneuronal cells (e.g., Schwann cells) associated with the peripheral nerve maintains the survival of adult motoneurons.A different type of lesion, ventral root avulsion, which involves pulling the root out of the spinal cord, induces the death of virtually all motoneurons in the adult rat and provides a good model to examine the response of adult motoneurons to trophic factors (20,21). The expression of nitric oxide synthase (NOS), an enzyme for synthesis of the free radical nitric oxide (NO), can be induced in adult rat motoneurons following both spinal root avulsion (20,22) and cranial nerve axotomy (23), and it has been suggested that the cell death following these lesions may be induced by oxidative stress and reactive oxygen species such as [20][21][22].Although the target dependency of motoneuron survival is diminished in adult animals (15, 18), adult rat m...

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Human neural stem cells hold great promise for research and therapy in neural disease. We describe the generation of integration-free and expandable human neural progenitor cells (NPCs). We combined an episomal system to deliver reprogramming factors with a chemically defined culture medium to reprogram epithelial-like cells from human urine into NPCs (hUiNPCs). These transgene-free hUiNPCs can self-renew and can differentiate into multiple functional neuronal subtypes and glial cells in vitro. Although functional in vivo analysis is still needed, we report that the cells survive and differentiate upon transplant into newborn rat brain.

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Self-assembling peptide (SAP) RADA16-I (Ac-(RADA)4-CONH2) has been suffering from a main drawback associated with low pH, which damages cells and host tissues upon direct exposure. In this study, we presented a strategy to prepare nanofiber hydrogels from two designer SAPs at neutral pH. RADA16-I was appended with functional motifs containing cell adhesion peptide RGD and neurite outgrowth peptide IKVAV. The two SAPs were specially designed to have opposite net charges at neutral pH, the combination of which created a nanofiber hydrogel (-IKVAV/-RGD) characterized by significantly higher G' than G″ in a viscoelasticity examination. Circular dichroism, Fourier transform infrared spectroscopy, and Raman measurements were performed to investigate the secondary structure of the designer SAPs, indicating that both the hydrophobic/hydrophilic properties and electrostatic interactions of the functional motifs play an important role in the self-assembling behavior of the designer SAPs. The neural progenitor cells (NPCs)/stem cells (NSCs) fully embedded in the 3D-IKVAV/-RGD nanofiber hydrogel survived, whereas those embedded within the RADA 16-I hydrogel hardly survived. Moreover, the -IKVAV/-RGD nanofiber hydrogel supported NPC/NSC neuron and astrocyte differentiation in a 3D environment without adding extra growth factors. Studies of three nerve injury models, including sciatic nerve defect, intracerebral hemorrhage, and spinal cord transection, indicated that the designer -IKVAV/-RGD nanofiber hydrogel provided a more permissive environment for nerve regeneration than the RADA 16-I hydrogel. Therefore, we reported a new mechanism that might be beneficial for the synthesis of SAPs for in vitro 3D cell culture and nerve regeneration.