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

Hartman, Nathaniel W.; Carpentino, Joseph E.; LaMonica, Kristi; Mor, Danielle Emille; Naegele, Janice R.; Grabel, Laura

doi:10.1371/journal.pone.0015856

Cited by 34 publications

(46 citation statements)

References 64 publications

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“…Postmortem immunohistochemical analyses revealed clusters of RFP + cells in the dentate gyrus granule cell layer, the hilus, or the molecular layer (Table 2) and the size of the transplants spanned approximately 500 to 1500 μm along the anterior-posterior axis of the hippocampus. Some transplanted cells migrated into the molecular layer of the dentate gyrus, or upper blade of the granule cell layer in the dentate gyrus (Hartman et al, 2010). However, the majority was located in the hilus and expressed the mature neuronal marker NeuN (87.4 ± 2.6%, n=6) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Differentiation and Functional Incorporation of Embryonic Stem Cell-Derived GABAergic Interneurons in the Dentate Gyrus of Mice with Temporal Lobe Epilepsy

Maisano¹,

Litvina²,

Tagliatela³

et al. 2012

J. Neurosci.

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Cell therapies for neurological disorders require an extensive knowledge of disease-associated neuropathology and procedures for generating neurons for transplantation. In many patients with severe acquired temporal lobe epilepsy (TLE), the dentate gyrus exhibits sclerosis and GABAergic interneuron degeneration. Mounting evidence suggests that therapeutic benefits can be obtained by transplanting fetal GABAergic progenitors into the dentate gyrus in rodents with TLE, but the scarcity of human fetal cells limits applicability in patient populations. By contrast, virtually limitless quantities of neural progenitors can be obtained from embryonic stem (ES) cells. ES cell-based therapies for neurological repair in TLE require evidence that the transplanted neurons integrate functionally and replace cell types that degenerate. To address these issues, we transplanted mouse ES cell-derived neural progenitors (ESNPs) with ventral forebrain identities into the hilus of the dentate gyrus of mice with TLE and evaluated graft differentiation, mossy fiber sprouting, cellular morphology and electrophysiological properties of the transplanted neurons. Additionally we compared electrophysiological properties of the transplanted neurons to endogenous hilar interneurons in mice without TLE. The majority of transplanted ESNPs differentiated into GABAergic interneuron subtypes expressing calcium-binding proteins parvalbumin, calbindin or calretinin. Global suppression of mossy fiber sprouting was not observed, however, ESNP-derived neurons formed dense axonal arborizations in the inner molecular layer and throughout the hilus. Whole-cell hippocampal slice electrophysiological recordings and morphological analyses of the transplanted neurons identified five basic types; most with strong after-hyperpolarizations and smooth or sparsely spiny dendritic morphologies resembling endogenous hippocampal interneurons. Moreover, intracellular recordings of spontaneous excitatory postsynaptic currents indicated that the new cells functionally integrate into epileptic hippocampal circuitry.

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Section: Resultsmentioning

confidence: 99%

Differentiation and Functional Incorporation of Embryonic Stem Cell-Derived GABAergic Interneurons in the Dentate Gyrus of Mice with Temporal Lobe Epilepsy

Maisano¹,

Litvina²,

Tagliatela³

et al. 2012

J. Neurosci.

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“…Adhesion molecules (P- and E- selectin) are up-regulated in response to electrographic seizures at the luminal side of the endothelium forming the BBB [47], chemokines and their receptors (CXCL12 and CXCR4; CCL2 and CCR2) are up-regulated in glia during seizures [17, 55, 56] and regions characterized by a “leaky” BBB have been consistently reported in epileptic brain [57]. An example of a synergism between BBBD and its downstream consequences is vascular endothelial growth factor (VEGF).…”

Section: Inflammatory Mechanisms Involved In Blood-brain Barrier Disrmentioning

confidence: 99%

Inflammatory pathways of seizure disorders

Marchi

Granata

Janigro

2014

Trends in Neurosciences

204

133

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Epilepsy refers to a cluster of neurological disease characterized by seizures. While many forms of epilepsy have a well-defined immune etiology, in other forms of epilepsy an altered immune response is only suspected. In general, the hypothesis that inflammation contributes to seizures is supported by experimental results. Additionally, antiepileptic maneuvers may act as immunomodulators and anti-inflammatory therapies can treat seizures. Triggers of seizure include a bidirectional communication between the nervous system and organs of immunity. Thus, a crucial cellular interface protecting from immunological seizures is the blood-brain barrier. Here, we summarize recent advances in the understanding and treatment of epileptic seizures which derive from a non-neurocentric viewpoint and suggest key avenues for future research.

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“…NSCs are thought to respond to a variety of extracellular soluble cues, including vascular endothelial growth factor (VEGF), [28c, 29, 32] monocyte chemotactic protein-1 (MCP-1), [33] growth-related oncogene α (GROα), [33a] monocyte chemotactic protein 2 (MCP-2) [33b] and CXCL12, [28a, 28b, 29, 33b, 34] to regulate proper positioning during embryonic development and/or to activate and navigate their migration to injury sites during tissue regeneration. Therefore, the quantitative evaluation of potential NSC chemotaxis in response to these extracellular soluble cues is a critical goal.…”

Section: Discussionmentioning

confidence: 99%

Microfluidic Investigation of BDNF‐Enhanced Neural Stem Cell Chemotaxis in CXCL12 Gradients

Heilshorn

2012

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In vivo studies have suggested that gradients of CXCL12 (aka stromal cell-derived factor 1α) may be a critical guidance cue for neural stem cell (NSC) migration during both brain development and neural tissue regeneration. However, traditional in vitro chemotaxis tools are typically limited by unstable concentration gradients and the inability to decouple cell migration directionality and speed. These limitations have restricted the reproducible and quantitative analysis of neuronal migration, which is a requirement for mechanism-based studies that may guide the development of new therapeutic strategies for neural regeneration. Using a microfluidic gradient generator, we quantified nestin and Sox-2 positive human embryonic NSC chemotaxis within a linear and stable CXCL12 gradient. While untreated NSCs were not able to chemotax within CXCL12 gradients, pre-treatment of the cells with brain-derived neurotrophic factor (BDNF) resulted in significant chemotactic, directional migration. BDNF pre-treatment had no effect on cell migration speed, which averaged about 1 μm min −1 . Quantitative analysis determined that CXCL12 concentrations above 72 ng ml −1 (9.0 nM) are above the minimum activation threshold, while concentrations below 117 ng ml −1 (14.7 nM) are below the saturation threshold. Interestingly, although inhibitor studies with AMD 3100 revealed that CXCL12 chemotaxis requires receptor CXCR4 activation, BDNF pre-treatment was found to have no profound effects on the mRNA levels or surface presentation of CXCR4 or the putative CXCR7 scavenger receptor. The microfluidic study of NSC migration within stable chemokine concentration profiles provided quantitative analysis as well as new insight into the migratory mechanism underlying BDNF-induced chemotaxis towards CXCL12. These data will provide quantitative guidance in the development of new strategies to enhance the homing of endogenous and exogenous NSCs for clinical tissue regeneration therapies.

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

Cited by 34 publications

References 64 publications

Differentiation and Functional Incorporation of Embryonic Stem Cell-Derived GABAergic Interneurons in the Dentate Gyrus of Mice with Temporal Lobe Epilepsy

Differentiation and Functional Incorporation of Embryonic Stem Cell-Derived GABAergic Interneurons in the Dentate Gyrus of Mice with Temporal Lobe Epilepsy

Inflammatory pathways of seizure disorders

Microfluidic Investigation of BDNF‐Enhanced Neural Stem Cell Chemotaxis in CXCL12 Gradients

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