Recent advances in understanding context-dependent mechanisms controlling neurotrophin signaling and function

Bothwell, Mark

doi:10.12688/f1000research.19174.1

Cited by 32 publications

(26 citation statements)

References 58 publications

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“…Similar outcomes of the enhanced neurotrophic potential of hADSC in response to HPL-conditioning were reported recently in a co-culture in vitro model with chicken embryonic DRG [51]. Whether such factors could be internalized by cells during culture [52] and potentially released or influencing hADSC gene/protein expression will be a matter of further in vitro studies of our group, together with in vivo applications.…”

Section: Discussionsupporting

confidence: 78%

Human platelet lysate as a potential clinical-translatable supplement to support the neurotrophic properties of human adipose-derived stem cells

et al. 2020

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Background The autologous nerve graft, despite its donor site morbidity and unpredictable functional recovery, continues to be the gold standard in peripheral nerve repair. Rodent research studies have shown promising results with cell transplantation of human adipose-derived stem cells (hADSC) in a bioengineered conduit, as an alternative strategy for nerve regeneration. To achieve meaningful clinical translation, cell therapy must comply with biosafety. Cell extraction and expansion methods that use animal-derived products, including enzymatic adipose tissue dissociation and the use of fetal bovine serum (FBS) as a culture medium supplement, have the potential for transmission of zoonotic infectious and immunogenicity. Human-platelet-lysate (hPL) serum has been used in recent years in human cell expansion, showing reliability in clinical applications. Methods We investigated whether hADSC can be routinely isolated and cultured in a completely xenogeneic-free way (using hPL culture medium supplement and avoiding collagenase digestion) without altering their physiology and stem properties. Outcomes in terms of stem marker expression (CD105, CD90, CD73) and the osteocyte/adipocyte differentiation capacity were compared with classical collagenase digestion and FBS-supplemented hADSC expansion. Results We found no significant differences between the two examined extraction and culture protocols in terms of cluster differentiation (CD) marker expression and stem cell plasticity, while hADSC in hPL showed a significantly higher proliferation rate when compared with the usual FBS-added medium. Considering the important key growth factors (particularly brain-derived growth factor (BDNF)) present in hPL, we investigated a possible neurogenic commitment of hADSC when cultured with hPL. Interestingly, hADSC cultured in hPL showed a statistically higher secretion of neurotrophic factors BDNF, glial cell-derived growth factor (GDNF), and nerve-derived growth factor (NFG) than FBS-cultured cells. When cocultured in the presence of primary neurons, hADSC which had been grown under hPL supplementation, showed significantly enhanced neurotrophic properties. Conclusions The hPL-supplement medium could improve cell proliferation and neurotropism while maintaining stable cell properties, showing effectiveness in clinical translation and significant potential in peripheral nerve research.

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Section: Discussionsupporting

confidence: 78%

Human platelet lysate as a potential clinical-translatable supplement to support the neurotrophic properties of human adipose-derived stem cells

et al. 2020

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“…Furthermore, the evolutionarily-conserved molecular mechanisms we investigated in the context of synaptogenesis, such as TrkB and sensorin signaling, MAPK activation, and CREB-dependent transcription, are known to be engaged during learning-related synaptic plasticity in the same and other systems 3,4,25,26,32,34,35,39 . While clear similarities between the two programs of plasticity have been previously described [7][8][9][10] and were suggested by our present findings (e.g., activation of MAPK and of TrkB and sensorin signaling), our results also revealed differences in the valence of transcriptional effects (e.g., C/EBP downregulation vs. upregulation in learning). Taken together with previous research in Aplysia, the present study reveals novel molecular mechanisms of plasticity that could represent points of contact between developmental synapse formation and experience-dependent synaptic restructuring.…”

Section: Discussionsupporting

confidence: 82%

“…BDNF, one of the mammalian TrkB ligand orthologs, has been shown to act in an autocrine manner to stabilize cyclic AMP-dependent axon initiation and growth 28 . Interestingly, BDNF can act through TrkB receptors to promote neural development and synaptic strengthening, and through the p75NTR receptor to promote neuronal death and synaptic depression 10 . Moreover, reports from the mammalian and invertebrate literature have shown that the same growth factor can both promote and inhibit synaptogenesis by signaling through distinct receptors and inducing different downstream signaling [44][45][46][47] .…”

Section: Discussionmentioning

confidence: 99%

Specificity of synapse formation in Aplysia: paracrine and autocrine signaling regulates bidirectional molecular interactions between sensory and non-target motor neurons

Alexandrescu

Carew

2020

Sci Rep

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The formation of appropriate neural connections during development is critical for the proper wiring and functioning of the brain. Although considerable research suggests that the specificity of synapse formation is supported by complex intercellular signaling between potential presynaptic and postsynaptic partners, the extracellular factors and the intracellular signal transduction pathways engaged in this process remain largely unknown. Using the sensory-motor neural circuit that contributes to learning in defensive withdrawal reflexes in Aplysia californica, we investigated the molecular processes governing the interactions between sensory neurons and both target and non-target motor neurons during synapse formation in culture. We found that evolutionarilyconserved intercellular and intracellular signaling mechanisms critical for learning-related plasticity are also engaged during synaptogenesis in this in vitro model system. Our results reveal a surprising bidirectional regulation of molecular signaling between sensory neurons and non-target motor neurons. This regulation is mediated by signaling via both paracrine and autocrine diffusible factors that induce differential effects on transcription and on protein expression/activation in sensory neurons and in target and non-target motor neurons. Collectively, our data reveal novel molecular mechanisms that could underlie the repression of inappropriate synapse formation, and suggest mechanistic similarities between developmental and learning-related plasticity. The formation of specific neural connections is critical for the proper development and function of the nervous system. Specificity of synapse formation is supported by complex bidirectional intercellular and intracellular signaling between and within potential pre-and postsynaptic partners 1. The molecules mediating these intercellular exchanges, including growth factors, neuropeptides, neurotransmitters, and cell adhesion molecules, activate intracellular signaling cascades leading to functional and structural changes that promote the formation of functional synapses 1-5. The synaptic proteins supporting the morphological changes that mediate the formation, restructuring, and elimination of synapses have been extensively studied 1,5. However, the extracellular factors and the intracellular signal transduction pathways that regulate the expression of the genes encoding proteins required for appropriate synaptic connectivity remain largely unknown. Over a century ago Santiago Ramón y Cajal proposed that the processes underlying the development of the nervous system and the neural plasticity supporting learning and memory in adulthood share fundamental mechanisms 6. Indeed, in the last two decades, research examining developmental and learning-related plasticity has uncovered a striking degree of overlap between the molecular mechanisms employed by the brain during these different biological processes 1,4,7-10. For example, the members of the neurotrophin family of growth factors were initially character...

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“…Neurotrophin signaling plays an essential role in maintaining neuronal survival and synaptic plasticity as well as learning and memory (Bothwell, 2019). BDNF is predominant among the several neurotrophins in the adult central nervous system.…”

Section: Cell Survival System: the Trkb Signaling Pathwaymentioning

confidence: 99%

“…This mechanism protects neurons from oxidative damage during excitotoxic stimulation with glutamate, an event that frequently encountered in neural injury, stroke, and NDDs ( Ishii and Mann, 2018 ). Moreover, BDNF-TrkB.T1-p75 NTR -Nrf2-mediated neuroprotection is context-dependent ( Bothwell, 2019 ), i.e., it depends on the degree of activation. However, there is no evidence, so far, demonstrating the association of the neuroprotective phytochemicals with this signaling pathway suggesting further investigation.…”

Section: Cross-talk Between Trkb Signaling Pathway and Nrf2-are Antiomentioning

confidence: 99%

Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System

Hannan

Dash

Sohag

et al. 2020

Front. Mol. Neurosci.

129

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Oxidative stress (OS) plays a critical role in the pathophysiology of several brainrelated disorders, including neurodegenerative diseases and ischemic stroke, which are the major causes of dementia. The Nrf2-ARE (nuclear factor erythroid 2-related factor 2/antioxidant responsive element antioxidant) system, the primary cellular defense against OS, plays an essential role in neuroprotection by regulating the expressions of antioxidant molecules and enzymes. However, simultaneous events resulting in the overproduction of reactive oxygen species (ROS) and deregulation of the Nrf2-ARE system damage essential cell components and cause loss of neuron structural and functional integrity. On the other hand, TrkB (tropomyosin-related kinase B) signaling, a classical neurotrophin signaling pathway, regulates neuronal survival and synaptic plasticity, which play pivotal roles in memory and cognition. Also, TrkB signaling, specifically the TrkB/PI3K/Akt (TrkB/phosphatidylinositol 3 kinase/protein kinase B) pathway promotes the activation and nuclear translocation of Nrf2, and thus, confers neuroprotection against OS. However, the TrkB signaling pathway is also known to be downregulated in brain disorders due to lack of neurotrophin support. Therefore, activations of TrkB and the Nrf2-ARE signaling system offer a potential approach to the design of novel therapeutic agents for brain disorders. Here, we briefly overview the development of OS and the association between OS and the pathogenesis of neurodegenerative diseases and brain injury. We propose the cellular antioxidant defense and TrkB signaling-mediated cell survival systems be considered pharmacological targets for the treatment of neurodegenerative diseases, and review the literature on the neuroprotective effects of phytochemicals that can co-activate these neuronal defense systems.

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Recent advances in understanding context-dependent mechanisms controlling neurotrophin signaling and function

Cited by 32 publications

References 58 publications

Human platelet lysate as a potential clinical-translatable supplement to support the neurotrophic properties of human adipose-derived stem cells

Human platelet lysate as a potential clinical-translatable supplement to support the neurotrophic properties of human adipose-derived stem cells

Specificity of synapse formation in Aplysia: paracrine and autocrine signaling regulates bidirectional molecular interactions between sensory and non-target motor neurons

Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System

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