Availability of Pre- and Pro-regions of Transgenic GDNF Affects the Ability to Induce Axonal Sprout Growth

Kust, Nadezda; Panteleev, D. Yu.; Мерцалов, И. Б.; Savchenko, Ekaterina; Rybalkina, Ekaterina Yu.; Revishchin, A. V.; Pavlova, Galina

doi:10.1007/s12035-014-8792-8

Cited by 6 publications

(19 citation statements)

References 29 publications

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“…34,35 Past work from our group has shown that a significant fraction of cranially grafted human stem cells ultimately differentiate along glial lineages. 16,17,20,24 36 and protect neurons from transient ischemia induced damage. 37 Other work in different stem cell-based systems has noted various beneficial effects of secreted exosome-derived GDNF.…”

Section: Discussionmentioning

confidence: 99%

Functional equivalence of stem cell and stem cell-derived extracellular vesicle transplantation to repair the irradiated brain

Smith

Giedzinski

Angulo

et al. 2019

Stem Cells Translational Medicine

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Cranial radiotherapy, although beneficial for the treatment of brain tumors, inevitably leads to normal tissue damage that can induce unintended neurocognitive complications that are progressive and debilitating. Ionizing radiation exposure has also been shown to compromise the structural integrity of mature neurons throughout the brain, an effect believed to be at least in part responsible for the deterioration of cognitive health. Past work has shown that cranially transplanted human neural stem cells (hNSCs) or their extracellular vesicles (EVs) afforded long-term beneficial effects on many of these cognitive decrements. To provide additional insight into the potential neuroprotective mechanisms of cell-based regenerative strategies, we have analyzed hippocampal neurons for changes in structural integrity and synaptic remodeling after unilateral and bilateral transplantation of hNSCs or EVs derived from those same cells. Interestingly, hNSCs and EVs similarly afforded protection to host neurons, ameliorating the impact of irradiation on dendritic complexity and spine density for neurons present in both the ipsilateral and contralateral hippocampi 1 month following irradiation and transplantation. These morphometric improvements were accompanied by increased levels of glial cell-derived growth factor and significant attenuation of radiation-induced increases in postsynaptic density protein 95 and activated microglia were found ipsi-and contra-lateral to the transplantation sites of the irradiated hippocampus treated with hNSCs or hNSC-derived EVs. These findings document potent far-reaching neuroprotective effects mediated by grafted stem cells or EVs adjacent and distal to the site of transplantation and support their potential as therapeutic agents to counteract the adverse effects of cranial irradiation.

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Section: Discussionmentioning

confidence: 99%

Functional equivalence of stem cell and stem cell-derived extracellular vesicle transplantation to repair the irradiated brain

Smith

Giedzinski

Angulo

et al. 2019

Stem Cells Translational Medicine

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“…For the control we used construct with pre-pro-GDNF, which were prepared using the primers T3 (F) 5′-ATTAACCCTCACTAAAGGGA-3′ и Gdnf Bam H1 5′-TGGATCCCAGA TACACCACACCTTTTAGCGG-3′. This construct was obtained according to the protocol described elsewhere [ 1 ].…”

Section: Methodsmentioning

confidence: 99%

“…Glial cell line-derived neurotrophic factor (GDNF) promotes the survival and differentiation of neurons and glial cells [ 1 – 3 ]. This GDNF activity can be useful in the treatment of neuronal degeneration and loss of differentiation typical for a number of neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

“…At the same time, the release of the shorter protein encoded by pre-(β)pro-GDNF is largely mediated by secretogranin II and Rab3A-positive vesicles and, thus, bypasses the Golgi apparatus. Kust et al [ 1 ] demonstrated that the deletion of the pre- and pro-regions of the GDNF gene does not affect the transgenic factor release from transfected cells. Moreover, the deletion of both pre- and pro-regions enhances the trophic activity of GDNF.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the deletion of both pre- and pro-regions enhances the trophic activity of GDNF. Spinal ganglia cultured in the presence of medium conditioned by cells transfected with mGDNF demonstrated active growth of β-3-tubulin-positive axons by day 4 of culture [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

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Effects of striatal transplantation of cells transfected with GDNF gene without pre- and pro-regions in mouse model of Parkinson’s disease

et al. 2016

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BackgroundPreviously, we have shown that transgenic cells bearing the GDNF gene with deleted pre- and pro-regions (mGDNF) can release transgenic GDNF. The medium conditioned by transgenic cells with mGDNF induced axonal growth in rat embryonic spinal ganglion in vitro. Here we demonstrate a neurotrophic effect of mGDNF on PC12 cells in vitro as well as its neuroprotective effect on dopaminergic neurons in the substantia nigra pars compacta in vivo as indicated by improved motor coordination and sleep-wakefulness cycle in the MPTP mouse model of Parkinson’s disease.ResultsHEK293 cells were transfected with a vector encoding an isoform of the human GDNF gene with deleted pre- and pro-regions (mGDNF). This factor in the medium conditioned by the transfected cells was shown to induce axonal growth in PC12 cells. The early Parkinson’s disease model was established by injection of the dopaminergic pro-neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into C57Bl/6 mice. Transgenic HEK293/mGDNF/GFP cells were transplanted into the striatum (caudate-putamen) of experimental mice. The sleep-wakefulness cycle was studied by continuous EEG and motor activity monitoring 1 and 2 weeks after MPTP injection. After the experiment, the motor coordination of experimental animals was evaluated in the rotarod test, and dopaminergic neurons in the substantia nigra pars compacta were counted in cross-sections of the midbrain. MPTP administration lowered the number of tyrosine hydroxylase immunopositive cells in the substantia nigra pars compacta, decreased motor coordination, and increased the total wake time during the dark period. The transplantation of HEK293/mGDNF cells into the caudate-putamen 3 days prior to MPTP injection smoothed these effects, while the control transplantation of HEK293 cells showed no notable impact.ConclusionsTransplantation of transgenic cells with the GDNF gene lacking the pre- and pro-sequences can protect dopaminergic neurons in the mouse midbrain from the subsequent administration of the pro-neurotoxin MPTP, which is confirmed by polysomnographic, behavioral and histochemical data. Hence it is released from transfected cells and preserves the differentiation activity and neuroprotective properties.

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Neuroinductive properties of mGDNF depend on the producer, E. Coli or human cells

et al. 2021

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The glial cell line‐derived neurotrophic factor (GDNF) is involved in the survival of dopaminergic neurons. Besides, GDNF can also induce axonal growth and creation of new functional synapses. GDNF potential is promising for translation to treat diseases associated with neuronal death: neurodegenerative disorders, ischemic stroke, and cerebral or spinal cord damages. Unproductive clinical trials of GDNF for Parkinson’s disease treatment have induced to study this failure. A reason could be due to irrelevant producer cells that cannot perform the required post-translational modifications. The biological activity of recombinant mGDNF produced by E. coli have been compared with mGDNF produced by human cells HEK293. mGDNF variants were tested with PC12 cells, rat embryonic spinal ganglion cells, and SH-SY5Y human neuroblastoma cells in vitro as well as with a mouse model of the Parkinson’s disease in vivo. Both in vitro and in vivo the best neuro-inductive ability belongs to mGDNF produced by HEK293 cells. Keywords: GDNF, neural differentiation, bacterial and mammalian expression systems, cell cultures, model of Parkinson’s disease.

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Availability of Pre- and Pro-regions of Transgenic GDNF Affects the Ability to Induce Axonal Sprout Growth

Cited by 6 publications

References 29 publications

Functional equivalence of stem cell and stem cell-derived extracellular vesicle transplantation to repair the irradiated brain

Functional equivalence of stem cell and stem cell-derived extracellular vesicle transplantation to repair the irradiated brain

Effects of striatal transplantation of cells transfected with GDNF gene without pre- and pro-regions in mouse model of Parkinson’s disease

Neuroinductive properties of mGDNF depend on the producer, E. Coli or human cells

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