Although the source of embryonic stem (ES) cells presents ethical concerns, their use may lead to many clinical benefits if differentiated cell types can be derived from them and used to assemble functional organs. In pancreas, insulin is produced and secreted by specialized structures, islets of Langerhans. Diabetes, which affects 16 million people in the United States, results from abnormal function of pancreatic islets. We have generated cells expressing insulin and other pancreatic endocrine hormones from mouse ES cells. The cells self-assemble to form three-dimensional clusters similar in topology to normal pancreatic islets where pancreatic cell types are in close association with neurons. Glucose triggers insulin release from these cell clusters by mechanisms similar to those employed in vivo. When injected into diabetic mice, the insulin-producing cells undergo rapid vascularization and maintain a clustered, islet-like organization.

Background and Purpose— Because fibroblast growth factor 2 is a mitogen for central nervous system stem cells, we explored whether long-term fibroblast growth factor 2 delivery to the brain can improve functional outcome and induce cortical neurogenesis after ischemia. Methods— Rats underwent permanent distal middle cerebral artery occlusion resulting in an ischemic injury limited to the cortex. We used an adeno-associated virus transfection system to induce long-term fibroblast growth factor 2 expression and monitored behavioral and histological changes. Results— Treatment increased the number of proliferating cells and improved motor behavior. Neurogenesis continued throughout 90 days after the ischemia, and the occurrence of newly generated cells with characteristics of neural precursors and immature neurons was most evident 90 days after treatment. Conclusions— Focal cortical ischemia elicits an ongoing neurogenic response that can be enhanced with fibroblast growth factor 2 leading to improved functional outcome.

The derivation of dopamine neurons is one of the best examples of the clinical potential of embryonic stem (ES) cells, but the long-term function of the grafted neurons has not been established. Here, we show that, after transplantation into an animal model, neurons derived from mouse ES cells survived for over 32 weeks, maintained midbrain markers, and had sustained behavioral effects. Microdialysis in grafted animals showed that dopamine (DA) release was induced by depolarization and pharmacological stimulants. Positron emission tomography measured the expression of presynaptic dopamine transporters in the graft and also showed that the number of postsynaptic DA D2 receptors was normalized in the host striatum. These data suggest that ES cell-derived neurons show DA release and reuptake and stimulate appropriate postsynaptic responses for long periods after implantation. This work supports continued interest in ES cells as a source of functional DA neurons. Disclosure of potential conflicts of interest is found at the end of this article.

Damage caused to neural tissue by disease or injury frequently produces a discontinuity in the nervous system. Such damage generates diverse alterations that are commonly permanent, due to the limited regeneration capacity of the adult nervous system, particularly the Central Nervous System (CNS). The cellular reaction to noxious stimulus leads to several events such as the formation of glial and fibrous scars, which inhibit axonal regeneration in both the CNS and the Peripheral Nervous System (PNS). Although in the PNS there is some degree of nerve regeneration, it is common that the growing axons reinnervate incorrect areas, causing mismatches. Providing a permissive substrate for axonal regeneration in combination with delivery systems for the release of molecules, which enhances axonal growth, could increase regeneration and the recovery of functions in the CNS or the PNS. Currently, there are no effective vehicles to supply growth factors or cells to the damaged/diseased nervous system. Hydrogels are polymers that are biodegradable, biocompatible and have the capacity to deliver a large range of molecules in situ. The inclusion of cultured neural cells into hydrogels forming three-dimensional structures allows the formation of synapses and neuronal survival. There is also evidence showing that hydrogels constitute an amenable substrate for axonal growth of endogenous or grafted cells, overcoming the presence of axonal regeneration inhibitory molecules, in both the central and peripheral nervous systems. Recent experiments suggest that hydrogels can carry and deliver several proteins relevant for improving neuronal survival and axonal growth. Although the use of hydrogels is appealing, its effectiveness is still a matter of discussion, and more results are needed to achieve consistent recovery using different parameters. This review also discusses areas of opportunity where hydrogels can be applied, in order to promote axonal regeneration of the nervous system.

The neural crest (NC) is a transient multipotent cell population that originates in the dorsal neural tube. Cells of the NC are highly migratory, as they travel considerable distances through the body to reach their final sites. Derivatives of the NC are neurons and glia of the peripheral nervous system (PNS) and the enteric nervous system as well as non-neural cells. Different signaling pathways triggered by Bone Morphogenetic Proteins (BMPs), Fibroblast Growth Factors (FGFs), Wnt proteins, Notch ligands, retinoic acid (RA), and Receptor Tyrosine Kinases (RTKs) participate in the processes of induction, specification, cell migration and neural differentiation of the NC. A specific set of signaling pathways and transcription factors are initially expressed in the neural plate border and then in the NC cell precursors to the formation of cranial nerves. The molecular mechanisms of control during embryonic development have been gradually elucidated, pointing to an important role of transcriptional regulators when neural differentiation occurs. However, some of these proteins have an important participation in malformations of the cranial portion and their mutation results in aberrant neurogenesis. This review aims to give an overview of the role of cell signaling and of the function of transcription factors involved in the specification of ganglia precursors and neurogenesis to form the NC-derived cranial nerves during organogenesis.