scholarly journals Intrastriatal Ventral Mesencephalic Xenografts of Porcine Tissue in Rats: Immune Responses and Functional Effects

2000 ◽  
Vol 9 (2) ◽  
pp. 261-272 ◽  
Author(s):  
Lena C. Larsson ◽  
Kimberly A. Czech ◽  
Patrik Brundin ◽  
Håkan Widner
Keyword(s):  
Immune Responses ◽  
Graft Survival ◽  
Functional Recovery ◽  
Dopaminergic Neurons ◽  
Immunosuppressive Treatment ◽  
Neural Tissue ◽  
Scar Tissue ◽  
Rat Striatum ◽  
Intracerebral Transplantation ◽  
Ventral Mesencephalic

Transplantation of neural tissue from other species has the potential to improve function in patients with neurodegenerative disorders. We investigated the functional effects of embryonic porcine dopaminergic neurons transplanted in a rat model of Parkinson's disease and the immune responses to the grafts in immunosuppressed and nonimmunosuppressed hosts. Twenty-three rats with unilateral 6-hydroxydopamine lesions received dissociated, 27-day-old embryonic porcine ventral mesencephalic tissue in the right striatum. Eighteen rats received cyclosporine (10 mg/kg, IP, daily) during the whole period of 14 weeks, in combination with prednisolone (20 mg/kg, IP, daily) the first 4 days. Five rats served as nonimmunosuppressed controls. All rats were tested for amphetamine-induced rotational behavior at 3-week intervals. Two immunosuppressed rats were excluded due to severe side effects of the treatment. Functional recovery was seen in 9 of 16 immunosuppressed rats at 12 weeks. Six animals remained functionally recovered at 14 weeks and contained an average of 5750 ± 1450 (SEM) dopaminergic neurons. Between 9 and 14 weeks, three immunosuppressed rats rejected their grafts, based on rotation scores and immunohistochemical demonstration of cell infiltrates. One additional immunosuppressed rat showed evidence of ongoing rejection at 14 weeks. The striata in animals with ongoing or recent rejection contained large numbers of CD4- and CD8-positive lymphocytes, NK cells, macrophages, and microglia cells, whereas scar tissue was found in rats with grafts rejected at earlier time points (n = 11). Embryonic porcine ventral mesencephalic tissue matures in the adult rat striatum, reinnervates the host brain, and restores behavioral defects. Immunosuppressive treatment was necessary for long-term graft survival and functional recovery, but did not sufficiently protect from rejection mechanisms. Porcine neural tissue is an interesting alternative to embryonic human tissue for intracerebral transplantation in neurodegenerative diseases. However, to achieve stable graft survival in discordant xenogeneic combinations, an appropriate immunosuppressive treatment or donor tissue modifications are needed.

Differential Dissection of the Rat E16 Ventral Mesencephalon and Survival and Reinnervation of the 6-Ohda-Lesioned Striatum by a Subset of Aldehyde Dehydrogenase-Positive th Neurons

1997 ◽  
Vol 6 (3) ◽  
pp. 239-248 ◽  
Author(s):  
Nadia S.K. Haque ◽  
Celeste J. Leblanc ◽  
Ole Isacson
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Functional Recovery ◽  
Dopaminergic Neurons ◽  
Histological Evaluation ◽  
Ventral Mesencephalon ◽  
Th Cells ◽  
Immunohistochemical Markers ◽  
Normal Projection ◽  
Ventral Mesencephalic ◽  
Projection Pattern

The retinoic acid-generating enzyme, aldehyde dehydrogenase (AHD), is expressed in a subpopulation of dopaminergic neurons found in the substantia nigra. Using AHD and tyrosine hydroxylase (TH) as immunohistochemical markers, we determined whether differential dissection of the embryonic (E16) ventral mesencephalon (VM) into its lateral and medial portions contributed equally to the number of TH cells surviving transplantation, if grafted AHD/TH neurons reinnervate the host striatum according to their normal projection patterns, and examined the functional recovery caused by the implanted cells as assessed by amphetamine-induced rotation in a 6-OHDA-lesioned model of Parkinson's disease. The embryonic tissue was transplanted as solid pieces injected via a 20-gauge lumbar puncture needle into the center of the deafferented striatum. Groups received either one complete ventral mesencephalic piece (VM), two medial pieces of ventral mesencephalic tissue (MVM), or two lateral pieces of ventral mesencephalic tissue (LVM). Both VM and MVM groups showed a significant decrease in amphetamine-induced rotation over time and, there was no difference in the degree of reduction observed between the two groups. Histological evaluation of the transplants revealed a much larger total number of surviving TH cells in grafts from the VM and MVM groups compared to the LVM group. Surviving AHD/TH neurons were found in all groups. Whereas TH staining of the transplanted striatum displayed a halo of graft-derived fibers all around the transplant and integration of these fibers into the host neuropil, AHD staining showed a preferential reinnervation of the dorsolateral striatum corresponding to the normal projection pattern of AHD/TH neurons. In summary, selective dissection of the embryonic ventral mesencephalon is possible, functional recovery as assessed by amphetamineinduced rotation in animals transplanted with MVM is similar to that seen in animals grafted with VM, and AHD/TH neurons have a selective reinnervation pattern in the PD transplantation paradigm. These findings may have implications for the grafting of fetal mesencephalic tissue in PD patients.

scholarly journals Characterization of Porcine Ventral Mesencephalic Precursor Cells following Long-Term Propagation in 3D Culture

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Pia S. Jensen ◽  
Lise Lyck ◽  
Pia Jensen ◽  
Jens Zimmer ◽  
Morten Meyer
Keyword(s):  
Growth Factor ◽  
Dopaminergic Neurons ◽  
Neural Tissue ◽  
Precursor Cells ◽  
Neural Precursor Cells ◽  
Neural Precursor ◽  
Large Animal ◽  
Ventral Mesencephalic

The potential use of predifferentiated neural precursor cells for treatment of a neurological disorder like Parkinson’s disease combines stem cell research with previous experimental and clinical transplantation of developing dopaminergic neurons. One current obstacle is, however, the lack of ability to generate dopaminergic neurons after long-termin vitropropagation of the cells. The domestic pig is considered a useful nonprimate large animal model in neuroscience, because of a better resemblance of the larger gyrencephalic pig brain to the human brain than the commonly used brains of smaller rodents. In the present study, porcine embryonic (28–30 days), ventral mesencephalic precursor cells were isolated and propagated as free-floating neural tissue spheres in medium containing epidermal growth factor and fibroblast growth factor 2. For passaging, the tissue spheres were cut into quarters, avoiding mechanical or enzymatic dissociation in order to minimize cellular trauma and preserve intercellular contacts. Spheres were propagated for up to 237 days with analysis of cellular content and differentiation at various time points. Our study provides the first demonstration that porcine ventral mesencephalic precursor cells can be long-term propagated as neural tissue spheres, thereby providing an experimental 3Din vitromodel for studies of neural precursor cells, their niche, and differentiation capacity.

Combining Neuroprotective Treatment of Embryonic Nigral Donor Tissue with Mild Hypothermia of the Graft Recipient

2005 ◽  
Vol 14 (5) ◽  
pp. 301-309 ◽  
Author(s):  
Jenny Karlsson ◽  
ÅSa Petersén ◽  
Gunilla Gidö ◽  
Tadeusz Wieloch ◽  
Patrik Brundin
Keyword(s):  
Graft Survival ◽  
Dopaminergic Neurons ◽  
Mild Hypothermia ◽  
Combined Treatment ◽  
Cell Number ◽  
Behavioral Recovery ◽  
Donor Tissue ◽  
Before And After ◽  
Neuroprotective Treatment ◽  
Graft Implantation

Around 80–95% of the immature dopaminergic neurons die when embryonic ventral mesencephalic tissue is transplanted. Cell death occurs both during the preparation of donor tissue and after graft implantation, but the effect of combining successful neuroprotective treatments before and after transplantation has not been extensively investigated. We therefore treated embryonic rat mesencephalic tissue with a combination of the lipid peroxidation inhibitor tirilazad mesylate (3 μM) and the caspase inhibitor Ac.YVAD.cmk (500 μM) and transplanted the tissue into hemiparkinsonian rats kept hypothermic (32–33°C) or normothermic (37°C) during, and 90 min following, graft surgery. Suspension cell number did not differ between untreated or tirilazad/YVAD-treated preparations prior to transplantation. When graft survival was evaluated 6 weeks after implantation, both tirilazad/YVAD pretreatment and mild hypothermia increased the survival of transplanted dopaminergic neurons. Approximately 50–57% of the embryonic dopaminergic neurons survived the dissociation and grafting procedure in rats rendered hypothermic, but there was no significant additive effect on graft survival with a combined treatment. All groups of rats exhibited behavioral recovery in the amphetamine-induced rotation test. There was a significantly enhanced functional capacity of grafts placed in hypothermic as compared to normothermic rats. However, tirilazad/YVAD pretreated implants did not afford greater behavioral improvement than control-treated grafts. Our results suggest that neuroprotective treatments administered prior to and immediately after neural graft implantation may under certain conditions rescue, at least in part, the same subset of dopaminergic neurons. The study also emphasizes the importance of the immediate time after grafting for transplant survival, with relevance both for primary mesencephalic implants and stem cell grafts.

scholarly journals Numbers of Axons in Spared Neural Tissue Bridges But Not Their Widths or Areas Correlate With Functional Recovery in Spinal Cord-Injured Rats

2020 ◽  
Vol 79 (11) ◽  
pp. 1203-1217
Author(s):  
Svenja Rink ◽  
Stoyan Pavlov ◽  
Aliona Wöhler ◽  
Habib Bendella ◽  
Marilena Manthou ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Functional Recovery ◽  
Neural Tissue ◽  
Cord Compression ◽  
Cresyl Violet ◽  
Spinal Cord Tissue ◽  
Class Iii ◽  
Morphological Findings ◽  
Cord Injury ◽  
Magnetic Resonance Imaging Mri

Abstract The relationships between various parameters of tissue damage and subsequent functional recovery after spinal cord injury (SCI) are not well understood. Patients may regain micturition control and walking despite large postinjury medullar cavities. The objective of this study was to establish possible correlations between morphological findings and degree of functional recovery after spinal cord compression at vertebra Th8 in rats. Recovery of motor (Basso, Beattie, Bresnahan, foot-stepping angle, rump-height index, and ladder climbing), sensory (withdrawal latency), and bladder functions was analyzed at 1, 3, 6, 9, and 12 weeks post-SCI. Following perfusion fixation, spinal cord tissue encompassing the injury site was cut in longitudinal frontal sections. Lesion lengths, lesion volumes, and areas of perilesional neural tissue bridges were determined after staining with cresyl violet. The numbers of axons in these bridges were quantified after staining for class III β-tubulin. We found that it was not the area of the spared tissue bridges, which is routinely determined by magnetic resonance imaging (MRI), but the numbers of axons in them that correlated with functional recovery after SCI (Spearman’s ρ > 0.8; p < 0.001). We conclude that prognostic statements based only on MRI measurements should be considered with caution.

scholarly journals B-RAFV600E Inhibitor Dabrafenib Attenuates RIPK3-Mediated Necroptosis and Promotes Functional Recovery after Spinal Cord Injury

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1582 ◽  
Author(s):  
Takehiro Sugaya ◽  
Haruo Kanno ◽  
Michiharu Matsuda ◽  
Kyoichi Handa ◽  
Satoshi Tateda ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Recovery ◽  
Tissue Damage ◽  
Neuroprotective Effect ◽  
Neural Tissue ◽  
Injured Spinal Cord ◽  
Thoracic Spinal Cord ◽  
Thoracic Spinal ◽  
Cord Injury

The receptor-interacting protein kinase 3 (RIPK3) is a key regulator of necroptosis and is involved in various pathologies of human diseases. We previously reported that RIPK3 expression is upregulated in various neural cells at the lesions and necroptosis contributed to secondary neural tissue damage after spinal cord injury (SCI). Interestingly, recent studies have shown that the B-RAFV600E inhibitor dabrafenib has a function to selectively inhibit RIPK3 and prevents necroptosis in various disease models. In the present study, using a mouse model of thoracic spinal cord contusion injury, we demonstrate that dabrafenib administration in the acute phase significantly inhibites RIPK3-mediated necroptosis in the injured spinal cord. The administration of dabrafenib attenuated secondary neural tissue damage, such as demyelination, neuronal loss, and axonal damage, following SCI. Importantly, the neuroprotective effect of dabrafenib dramatically improved the recovery of locomotor and sensory functions after SCI. Furthermore, the electrophysiological assessment of the injured spinal cord objectively confirmed that the functional recovery was enhanced by dabrafenib. These findings suggest that the B-RAFV600E inhibitor dabrafenib attenuates RIPK3-mediated necroptosis to provide a neuroprotective effect and promotes functional recovery after SCI. The administration of dabrafenib may be a novel therapeutic strategy for treating patients with SCI in the future.

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