Non-viral transfer of BDNF and uPA stimulates peripheral nerve regeneration

Karagyaur, Maxim; Dyikanov, Daniyar T.; Макаревич, П.И.; Semina, Ekaterina; Stambolsky, Dmitry; Плеханова, О. С.; Ni, Kalinina; Tkachuk, Vsevolod A.

doi:10.1016/j.biopha.2015.07.002

Cited by 34 publications

(27 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Despite meticulous surgical techniques and non-surgical treatments, fully functional recovery is rarely achieved. Therefore, there is a demand for new approaches to stimulate effective peripheral nerve regeneration after injury [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional Model of Dorsal Root Ganglion Explant as a Method of Studying Neurotrophic Factors in Regenerative Medicine

et al. 2020

View full text Add to dashboard Cite

Neurotrophic factors play a key role in the development, differentiation, and survival of neurons and nerve regeneration. In the present study, we evaluated the effect of certain neurotrophic factors (NGF, BDNF, and GDNF) on axon growth and migration of Nestin-green fluorescent protein (GFP)-positive cells using a 3D model of dorsal root ganglion (DRG) explant culture in Matrigel. Our method generally represents a convenient model for assessing the effects of soluble factors and therapeutic agents on axon growth and nerve regeneration in R&D studies. By analyzing the DRG explants in ex vivo culture for 21 days, one can evaluate the parameters of neurite outgrowth and the rate of cell migration from the DRG explants into the Matrigel. For the current study, we used Nestin-GFP-expressing mice in which neural precursors express Nestin and the green fluorescent protein (GFP) under the same promoter. We revealed that GDNF significantly (two fold) stimulated axon outgrowth (p < 0.05), but not BDNF or NGF. It is well-known that axon growth can be stimulated by activated glial cells that fulfill a trophic function for regenerating nerves. For this reason, we evaluated the number of Nestin-GFP-positive cells that migrated from the DRG into the Matrigel in our 3D ex vivo explant model. We found that NGF and GDNF, but not BDNF, stimulated the migration of Nestin-GFP cells compared to the control (p < 0.05). On the basis of the aforementioned finding, we concluded that GDNF had the greatest stimulating potential for axon regeneration, as it stimulated not only the axon outgrowth, but also glial cell migration. Although NGF significantly stimulated glial cell migration, its effect on axon growth was insufficient for axon regeneration.Biomedicines 2020, 8, 49 2 of 13 (ECM) that surrounds the cells and creates the microenvironment in vivo [6,8]. The lack of the proper cell-cell and cell-matrix contacts results in change of gene and protein expression profiles [9]. These can adversely affect cell morphology, cell cycle progression, cell survival, and intracellular signaling, potentially resulting in false positive or false negative data acquisition [8,10].In 2D culturing systems, the bioavailability of substances is difficult to evaluate [11]. All cells in a monolayer in 2D culturing conditions simultaneously receive the same dose of a tested agent, whereas in vivo there is a gradient of a tested agent that penetrates the matrix and several layers of cells in a tissue [12]. 3D cultures allow for the assessment of the parameters of a gradual diffusion of tested agents through the gel [6,11].Primary neural cell cultures represent a modern challenge in cell biology, as mature neurons do not undergo cell division in vitro, making it complicated to obtain a sufficient number of cells for experiments [13]. Cell survival is usually low, and neural cell cultures from DRG can be maintained for only 5-7 days, provided that soluble factors that increase survival are added [14]. This is one of the complications in result interpretation when...

show abstract

Section: Introductionmentioning

confidence: 99%

Three-Dimensional Model of Dorsal Root Ganglion Explant as a Method of Studying Neurotrophic Factors in Regenerative Medicine

et al. 2020

View full text Add to dashboard Cite

show abstract

“…However, in this study, no correlation was observed between uPA/KLK8 expression and neuronal loss. Other studies have shown that uPA is necessary for synaptic remodeling, repair, and recovery following different kinds of injury . A pronounced decrease in uPA expression following KASE might result in the failure to initiate the appropriate repair mechanisms, leading to a worse behavioral phenotype.…”

Section: Discussionmentioning

confidence: 99%

Decreased levels of active uPA and KLK8 assessed by [¹¹¹In]MICA‐401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Thus, our data could support distinct regulation of the two forms of uPA in the SCN, a possibility that requires further exploration. There are reports of uPA involvement in neuronal repair processes, so it is possible that the increased uPA proteolytic activity we observe across time in vitro is in response to the tissue injury (Lahtinen et al ., , ; Lukasiuk et al ., ; Cho et al ., ; Karagyaur et al ., ). Collectively, these results suggest that uPA and tPA proteolytic activity are regulated by distinct mechanisms in the SCN.…”

Section: Discussionmentioning

confidence: 99%

“…uPA also converts plasminogen into plasmin, is inhibited by PAI-1, is expressed in the CNS, and influences a variety of neuronal processes including Schwann cell migration, nerve regeneration, epilepsy, dendritic spine recovery following stroke, and amphetamine and morphine-induced reward (Ploug & Kjeldgaard, 1956;Hayden & Seeds, 1996;Iyer et al, 2014;Wu et al, 2014;Karagyaur et al, 2015). However, much remains unknown about the specific mechanisms of uPA's involvement in modulating neuronal responses (Soleman et al, 2013;Chang et al, 2014;Katic et al, 2014;Lino et al, 2014;Wu et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Urokinase‐type plasminogen activator modulates mammalian circadian clock phase regulation in tissue‐type plasminogen activator knockout mice

Cooper

Rastogi

Krizo

et al. 2017

Eur J of Neuroscience

View full text Add to dashboard Cite

Glutamate phase shifts the circadian clock in the mammalian suprachiasmatic nucleus (SCN) by activating NMDA receptors. Tissue-type plasminogen activator (tPA) gates phase shifts by activating plasmin to generate m(ature) BDNF, which binds TrkB receptors allowing clock phase shifts. Here, we investigate phase shifting in tPA knockout (tPA ; B6.129S2-Plat /J) mice, and identify urokinase-type plasminogen activator (uPA) as an additional circadian clock regulator. Behavioral activity rhythms in tPA mice entrain to a light-dark (LD) cycle and phase shift in response to nocturnal light pulses with no apparent loss in sensitivity. When the LD cycle is inverted, tPA mice take significantly longer to entrain than C57BL/6J wild-type (WT) mice. SCN brain slices from tPA mice exhibit entrained neuronal activity rhythms and phase shift in response to nocturnal glutamate with no change in dose-dependency. Pre-treating slices with the tPA/uPA inhibitor, plasminogen activator inhibitor-1 (PAI-1), inhibits glutamate-induced phase delays in tPA slices. Selective inhibition of uPA with UK122 prevents glutamate-induced phase resetting in tPA but not WT SCN slices. tPA expression is higher at night than the day in WT SCN, while uPA expression remains constant in WT and tPA slices. Casein-plasminogen zymography reveals that neither tPA nor uPA total proteolytic activity is under circadian control in WT or tPA SCN. Finally, tPA SCN tissue has lower mBDNF levels than WT tissue, while UK122 does not affect mBDNF levels in either strain. Together, these results suggest that either tPA or uPA can support photic/glutamatergic phase shifts of the SCN circadian clock, possibly acting through distinct mechanisms.

show abstract

Non-viral transfer of BDNF and uPA stimulates peripheral nerve regeneration

Cited by 34 publications

References 19 publications

Three-Dimensional Model of Dorsal Root Ganglion Explant as a Method of Studying Neurotrophic Factors in Regenerative Medicine

Three-Dimensional Model of Dorsal Root Ganglion Explant as a Method of Studying Neurotrophic Factors in Regenerative Medicine

Decreased levels of active uPA and KLK8 assessed by [¹¹¹In]MICA‐401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy

Urokinase‐type plasminogen activator modulates mammalian circadian clock phase regulation in tissue‐type plasminogen activator knockout mice

Contact Info

Product

Resources

About

Non-viral transfer of BDNF and uPA stimulates peripheral nerve regeneration

Cited by 34 publications

References 19 publications

Three-Dimensional Model of Dorsal Root Ganglion Explant as a Method of Studying Neurotrophic Factors in Regenerative Medicine

Three-Dimensional Model of Dorsal Root Ganglion Explant as a Method of Studying Neurotrophic Factors in Regenerative Medicine

Decreased levels of active uPA and KLK8 assessed by [111In]MICA‐401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy

Urokinase‐type plasminogen activator modulates mammalian circadian clock phase regulation in tissue‐type plasminogen activator knockout mice

Contact Info

Product

Resources

About

Decreased levels of active uPA and KLK8 assessed by [¹¹¹In]MICA‐401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy