Short-Term Withdrawal of Mitogens Prior to Plating Increases Neuronal Differentiation of Human Neural Precursor Cells

Background: Human neural precursor cells (hNPC) are candidates for neural transplantation in a wide range of neurological disorders. Recently, much work has been done to determine how the environment for NPC culture in vitro may alter their plasticity. Epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2) are used to expand NPC; however, it is not clear if continuous exposure to mitogens may abrogate their subsequent differentiation. Here we evaluated if short-term removal of FGF-2 and EGF prior to plating may improve hNPC differentiation into neurons.Principal Findings: We demonstrate that culture of neurospheres in suspension for 2 weeks without EGF-FGF-2 significantly increases neuronal differentiation and neurite extension when compared to cells cultured using standard protocols. in this condition, neurons were preferentially located in the core of the neurospheres instead of the shell. Moreover, after plating, neurons presented radial rather than randomly oriented and longer processes than controls, comprised mostly by neurons with short processes. These changes were followed by alterations in the expression of genes related to cell survival.Conclusions: These results show that EGF and FGF-2 removal affects NPC fate and plasticity. Taking into account that a three dimensional structure is essential for NPC differentiation, here we evaluated, for the first time, the effects of growth factors removal in whole neurospheres rather than in plated cell culture.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Institutos do Milenio de Bioengenharia TecidualUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilUniv Fed Rio de Janeiro, Inst Ciencias Biomed, BR-21941 Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilFAPESP: fellowCNPq: fellowWeb of Scienc

CXCL12-Mediated Guidance of Migrating Embryonic Stem Cell-Derived Neural Progenitors Transplanted into the Hippocampus

Stem cell therapies for neurodegenerative disorders require accurate delivery of the transplanted cells to the sites of damage. Numerous studies have established that fluid injections to the hippocampus can induce lesions in the dentate gyrus (DG) that lead to cell death within the upper blade. Using a mouse model of temporal lobe epilepsy, we previously observed that embryonic stem cell-derived neural progenitors (ESNPs) survive and differentiate within the granule cell layer after stereotaxic delivery to the DG, replacing the endogenous cells of the upper blade. To investigate the mechanisms for ESNP migration and repair in the DG, we examined the role of the chemokine CXCL12 in mice subjected to kainic acid-induced seizures. We now show that ESNPs transplanted into the DG show extensive migration through the upper blade, along the septotemporal axis of the hippocampus. Seizures upregulate CXCL12 and infusion of the CXCR4 antagonist AMD3100 by osmotic minipump attenuated ESNP migration. We also demonstrate that seizures promote the differentiation of transplanted ESNPs toward neuronal rather than astrocyte fates. These findings suggest that ESNPs transplanted into the adult rodent hippocampus migrate in response to cytokine-mediated signals

Conservation of energy-momentum of matter as the basis for the gauge theory of gravitation

According to Yang \& Mills (1954), a {\it conserved} current and a related rigid (`global') symmetry lie at the foundations of gauge theory. When the rigid symmetry is extended to a {\it local} one, a so-called gauge symmetry, a new interaction emerges as gauge potential $A$; its field strength is $F\sim {\rm curl} A$. In gravity, the conservation of the energy-momentum current of matter and the rigid translation symmetry in the Minkowski space of special relativity lie at the foundations of a gravitational gauge theory. If the translation invariance is made local, a gravitational potential $\vartheta$ arises together with its field strength $T\sim {\rm curl}\,\vartheta$. Thereby the Minkowski space deforms into a Weitzenb\"ock space with nonvanishing torsion $T$ but vanishing curvature. The corresponding theory is reviewed and its equivalence to general relativity pointed out. Since translations form a subgroup of the Poincar\'e group, the group of motion of special relativity, one ought to straightforwardly extend the gauging of the translations to the gauging of full Poincar\'e group thereby also including the conservation law of the {\it angular momentum} current. The emerging Poincar\'e gauge (theory of) gravity, starting from the viable Einstein-Cartan theory of 1961, will be shortly reviewed and its prospects for further developments assessed.Comment: 46 pages, 4 figures, minor corrections, references added, contribution to "One Hundred Years of Gauge Theory" edited by S. De Bianchi and C. Kiefe