Hyaluronan Tetrasaccharide Exerts Neuroprotective Effect and Promotes Functional Recovery After Acute Spinal Cord Injury in Rats

Wang, Jun; Wang, Xiaofang; Wei, Jie; Wang, Manyi

doi:10.1007/s11064-014-1470-4

Cited by 11 publications

(7 citation statements)

References 37 publications

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“…Null mutation of WWOX/Wwox gene causes severe neural diseases and early death in humans and animals [22, 34]. HA protects neurons from traumatic brain injuries [64], and this could be related with HA-mediated disappearance of Hyal-2, which reduces the WWOX/Smad4 signaling. During embryonic development, murine WWOX is overexpressed in the cardiac cells and endothelia of blood vessels [63].…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed

et al. 2016

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Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

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Section: Discussionmentioning

confidence: 99%

Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed

et al. 2016

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“…Additional evidence supporting the possibility that hyaluronidase-generated HA products could influence nervous system repair comes from studies utilizing HA oligosaccharides. For example, an HA tetrasaccharide was reported to improve functional recovery following spinal cord injury, possibly by inducing the expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in astrocytes within the injury environment [ 59 ]. HA tetrasaccharides can also promote axonal outgrowth and promote peripheral nerve regeneration [ 60 ].…”

Section: Endogenous Hyaluronidases Influence Cns Repairmentioning

confidence: 99%

Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases

Sherman

Matsumoto

et al. 2015

International Journal of Cell Biology

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The glycosaminoglycan hyaluronan (HA), a component of the extracellular matrix, has been implicated in regulating neural differentiation, survival, proliferation, migration, and cell signaling in the mammalian central nervous system (CNS). HA is found throughout the CNS as a constituent of proteoglycans, especially within perineuronal nets that have been implicated in regulating neuronal activity. HA is also found in the white matter where it is diffusely distributed around astrocytes and oligodendrocytes. Insults to the CNS lead to long-term elevation of HA within damaged tissues, which is linked at least in part to increased transcription of HA synthases. HA accumulation is often accompanied by elevated expression of at least some transmembrane HA receptors including CD44. Hyaluronidases that digest high molecular weight HA into smaller fragments are also elevated following CNS insults and can generate HA digestion products that have unique biological activities. A number of studies, for example, suggest that both the removal of high molecular weight HA and the accumulation of hyaluronidase-generated HA digestion products can impact CNS injuries through mechanisms that include the regulation of progenitor cell differentiation and proliferation. These studies, reviewed here, suggest that targeting HA synthesis, catabolism, and signaling are all potential strategies to promote CNS repair.

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“…TLR4 has also been shown to play an important role in nervous system inflammation after insults such as trauma and ischemia through observations that pharmacological inhibition of TLR4 improves outcomes after these events [ 163 , 172 , 173 ]. Interestingly, HA tetrasaccharides can improve outcomes after spinal cord injury in a CD44 and TLR4 dependent manner [ 174 ], and also protect hippocampal neurons during ischemia through the inhibition of TLR2 signaling [ 175 ].…”

Section: Multiple Ha Receptors Respond To Ha In the Developing Mamentioning

confidence: 99%

Diverse Roles for Hyaluronan and Hyaluronan Receptors in the Developing and Adult Nervous System

Peters

Sherman

2020

IJMS

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Hyaluronic acid (HA) plays a vital role in the extracellular matrix of neural tissues. Originally thought to hydrate tissues and provide mechanical support, it is now clear that HA is also a complex signaling molecule that can regulate cell processes in the developing and adult nervous systems. Signaling properties are determined by molecular weight, bound proteins, and signal transduction through specific receptors. HA signaling regulates processes such as proliferation, differentiation, migration, and process extension in a variety of cell types including neural stem cells, neurons, astrocytes, microglia, and oligodendrocyte progenitors. The synthesis and catabolism of HA and the expression of HA receptors are altered in disease and influence neuroinflammation and disease pathogenesis. This review discusses the roles of HA, its synthesis and breakdown, as well as receptor expression in neurodevelopment, nervous system function and disease.

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Hyaluronan Tetrasaccharide Exerts Neuroprotective Effect and Promotes Functional Recovery After Acute Spinal Cord Injury in Rats

Cited by 11 publications

References 37 publications

Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed

Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed

Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases

Diverse Roles for Hyaluronan and Hyaluronan Receptors in the Developing and Adult Nervous System

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