12 results on '"Mchugh, Jacalyn"'
Search Results
2. Intermittent Hypoxia and Stem Cell Implants Preserve Breathing Capacity in a Rodent Model of Amyotrophic Lateral Sclerosis
- Author
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Nichols, Nicole L., Gowing, Genevieve, Satriotomo, Irawan, Nashold, Lisa J., Dale, Erica A., Suzuki, Masatoshi, Avalos, Pablo, Mulcrone, Patrick L., McHugh, Jacalyn, Svendsen, Clive N., and Mitchell, Gordon S.
- Published
- 2013
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3. Study of the Murine Allantois by Allantoic Explants
- Author
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Downs, Karen M., Temkin, Roselynn, Gifford, Shannon, and McHugh, Jacalyn
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Allantois -- Growth ,Chorion -- Physiological aspects ,Endothelium -- Physiological aspects ,Placenta -- Physiological aspects ,Smooth muscle -- Physiological aspects ,Biological sciences - Abstract
The murine allantois will become the umbilical artery and vein of the chorioallantoic placenta. In previous studies, growth and differentiation of the allantois had been elucidated in whole embryos. In this study, the extent to which explanted allantoises grow and differentiate outside of the conceptus was investigated. The explant model was then used to elucidate cell and growth factor requirements in allantoic development. Early headfold-stage murine allantoises were explanted directly onto tissue culture plastic or suspended in test tubes. Explanted allantoises vascularized with distal-to-proximal polarity, they exhibited many of the same signaling factors used by the vitelline and cardiovascular systems, and they contained at least three cell types whose identity, gene expression profiles, topographical associations, and behavior resembled those of intact allantoises. DiI labeling further revealed that isolated allantoises grew and vascularized in the absence of significant cell mingling, thereby supporting a model of mesodermal differentiation in the allantois that is position- and possibly age-dependent. Manipulation of allantoic explants by varying growth media demonstrated that the allantoic endothelial cell lineage, like that of other embryonic vasculatures, is responsive to [VEGF.sub.164]. Although [VEGF.sub.164] was required for both survival and proliferation of allantoic angioblasts, it was not sufficient to induce appropriate epithelialization of these cells. Rather, other VEGF isoforms and/or the outer sheath of mesothelium, whose maintenance did not appear to be dependent upon endothelium, may also play important roles. On the basis of these findings, we propose murine allantoic explants as a new tool for shedding light not only on allantoic development, but for elucidating universal mechanisms of blood vessel formation, including vascular supporting cells, either in the intact organism or in existing in vitro systems. [C] 2001 Academic Press Key Words: allantois; angioblasts; chorion; embryos; endothelium; flk1; flt1; immunohistochemistry; in vitro; lacZ; mesenchyme; mesothelium; mouse; placenta; smooth muscle; tie1; tie2; transplantation; vasculogenesis; VCAM1; VEGF.
- Published
- 2001
4. Gonadectomy and dehydroepiandrosterone (DHEA) do not modulate disease progression in the G93A mutant SOD1 rat model of amyotrophic lateral sclerosis.
- Author
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Hayes-Punzo, Antonio, Mulcrone, Patrick, Meyer, Michael, Mchugh, Jacalyn, Svendsen, Clive N., and Suzuki, Masatoshi
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CASTRATION ,DEHYDROEPIANDROSTERONE ,DISEASE progression ,SEX differences (Biology) ,SUPEROXIDE dismutase ,ANIMAL models in research - Abstract
Epidemiological studies have shown a higher incidence of amyotrophic lateral sclerosis (ALS) in men than women. Interestingly, there are clear gender differences in disease onset and progression in rodent models of familial ALS overexpressing mutated human superoxide dismutase-1 (SOD1-G93A). In the present study we sought to determine whether the alterations of serum steroid levels by gonadectomy or chronic treatment of neuroprotective neurosteroids can modulate disease onset and progression in a rat model of ALS (SOD1-G93A transgenic rats). Presymptomatic SOD1-G93A rats were gonadectomized or treated with a neurosteroid dehydroepiandrosterone (DHEA) using silastic tubing implants. Disease onset and progression of the animals were determined by the routine analyses of locomotor testing using the Basso-Beattie-Bresnahan (BBB) score. Although sexual dimorphism was observed in intact and gonadectomized SOD1-G93A rats, there was no significant effect of gonadectomy on disease onset and progression. DHEA treatment did not alter disease progression or survival in SOD1-G93A rats. Our results indicate that gonadal steroids or neurosteroids are not one of the possible modulators for the occurrence or disease progression in a rat model of ALS. Further analysis will be necessary to understand how sexual dimorphism is involved in ALS disease progression. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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5. Direct Muscle Delivery of GDNF With Human Mesenchymal Stem Cells Improves Motor Neuron Survival and Function in a Rat Model of Familial ALS.
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Suzuki, Masatoshi, McHugh, Jacalyn, Tork, Craig, Shelley, Brandon, Hayes, Antonio, Bellantuono, Ilaria, Aebischer, Patrick, and Svendsen, Clive N.
- Subjects
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AMYOTROPHIC lateral sclerosis , *NEURODEGENERATION , *MESENCHYME abnormalities , *INTRAMUSCULAR injections , *STEM cells , *NEUROMUSCULAR diseases , *MOTOR neurons - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which there is a progressive loss of motor neurons and their connections to muscle, leading to paralysis. In order to maintain muscle connections in a rat model of familial ALS (FALS), we performed intramuscular transplantation with human mesenchymal stem cells (hMSCs) used as “Trojan horses” to deliver growth factors to the terminals of motor neurons and to the skeletal muscles. hMSCs engineered to secrete glial cell line–derived neurotrophic factor (hMSC-GDNF) were transplanted bilaterally into three muscle groups. The cells survived within the muscle, released GDNF, and significantly increased the number of neuromuscular connections and motor neuron cell bodies in the spinal cord at mid-stages of the disease. Further, intramuscular transplantation with hMSC-GDNF was found to ameliorate motor neuron loss within the spinal cord where it connects with the limb muscles receiving transplants. While disease onset was similar in all the animals, hMSC-GDNF significantly delayed disease progression, increasing overall lifespan by up to 28 days, which is one of the largest effects on survival noted for this rat model of FALS. This preclinical data provides a novel and practical approach toward ex vivo gene therapy for ALS.Molecular Therapy (2008) 16 12, 2002–2010 doi:10.1038/mt.2008.197 [ABSTRACT FROM AUTHOR]
- Published
- 2008
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6. Sexual dimorphism in disease onset and progression of a rat model of ALS.
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Suzuki, Masatoshi, Tork, Craig, Shelley, Brandon, Mchugh, Jacalyn, Wallace, Kyle, Klein, Sandra M., Lindstrom, Mary J., and Svendsen, Clive N.
- Subjects
SEXUAL dimorphism in animals ,NEURODEGENERATION ,AMYOTROPHIC lateral sclerosis ,MOTOR neuron diseases ,NEUROMUSCULAR diseases ,TRANSGENIC animals ,LABORATORY rats - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing the progressive loss of brain and spinal cord motor neurons. The exact etiology of ALS is still uncertain, but males have consistently been shown to be at a higher risk for the disease than females. Recently, transgenic rats overexpressing mutant forms of the human SOD1 (hSOD1) gene have been established as a valuable disease model of ALS. Here we show that sexual dimorphism in disease onset is also observed in hSOD1G93A transgenic rats. Disease onset was consistently earlier in male than in female hSOD1G93A rats. We also found that hSOD1G93A male rats lost weight more rapidly following disease onset compared to hSOD1G93A females. Furthermore, we tested locomotor function using the Basso-Beattie-Bresnahan (BBB) rating scale and a beam walking test. We found that motor dysfunction started earlier in males than in females but progressed similarly in the two sexes. These results have important implications for future experimentation and therapeutic development using the rat model of ALS. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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7. Investigation into a role for the primitive streak in development of the murine allantois.
- Author
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Downs, Karen M., Hellman, Elissa R., McHugh, Jacalyn, Barrickman, Kathryn, and Inman, Kimberly E.
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ALLANTOIC acid ,MESODERM ,EMBRYOLOGY ,CELL differentiation ,REGENERATION (Biology) ,UMBILICAL cord ,DEVELOPMENTAL biology - Abstract
Despite its importance as the source of one of three major vascular systems in the mammalian conceptus, little is known about the murine allantois, which will become the umbilical cord of the chorio-allantoic placenta. During gastrulation, the allantois grows into the exocoelomic cavity as a mesodermal extension of the posterior primitive streak. On the basis of morphology, gene expression and/or function, three cell types have been identified in the allantois: an outer layer of mesothelial cells, whose distal portion will become transformed into chorio-adhesive cells, and endothelial cells within the core. Formation of endothelium and chorio-adhesive cells begins in the distal region of the allantois, farthest from the streak. Over time, endothelium spreads to the proximal allantoic region, whilst the distal outer layer of presumptive mesothelium gradually acquires vascular cell adhesion molecule (VCAM1) and mediates chorio-allantoic union. Intriguingly, the VCAM1 domain does not extend into the proximal allantoic region. How these three allantoic cell types are established is not known, although contact with the chorion has been discounted. In this study, we have investigated how the allantois differentiates, with the goal of discriminating between extrinsic mechanisms involving the primitive streak and an intrinsic role for the allantois itself. Exploiting previous observations that the streak contributes mesoderm to the allantois throughout the latter's early development, microsurgery was used to remove allantoises at ten developmental stages. Subsequent whole embryo culture of operated conceptuses resulted in the formation of regenerated allantoises at all time points. Aside from being generally shorter than normal, none of the regenerates exhibited abnormal differentiation or inappropriate cell relationships. Rather, all of them resembled intact allantoises by morphological, molecular and functional criteria. Moreover, fate mapping adjacent yolk sac and... [ABSTRACT FROM AUTHOR]
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- 2004
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8. Multiple developmental roles of Ahnak are suggested by localization to sites of placentation and neural plate fusion in the mouse conceptus
- Author
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Downs, Karen M., McHugh, Jacalyn, Copp, Andrew J., and Shtivelman, Emma
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PHOSPHOPROTEINS , *CELL cycle , *MORPHOGENESIS - Abstract
Ahnak is a gigantic (700 kD) phosphoprotein with a unique structure whose expression and cellular localization are dynamically regulated during cell cycle progression. Here, we report that Ahnak is localized to sites of major morphogenesis during mouse placentation and neurulation. Ahnak was found in: (i) derivatives of trophectoderm, including chorionic ectoderm prior to and during union with the ectoplacental cone, presumptive syncytiotrophoblast cells in the chorionic labyrinth, and giant cells at the trophoblast-uterine interface; (ii) the allantois prior to, during, and after union with the chorion; and (iii) the tips of the neural plate during formation of the neural tube. On the basis of these observations, we suggest that Ahnak may play heretofore unrecognized roles in tissue union during normal mouse development. [Copyright &y& Elsevier]
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- 2002
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9. Cervical spinal cord therapeutics delivery: preclinical safety validation of a stabilized microinjection platform.
- Author
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Riley J, Federici T, Park J, Suzuki M, Franz CK, Tork C, McHugh J, Teng Q, Svendsen C, and Boulis NM
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- Animals, Anterior Horn Cells cytology, Anterior Horn Cells physiology, Anterior Horn Cells transplantation, Cell Differentiation physiology, Cell Survival physiology, Cervical Vertebrae anatomy & histology, Cervical Vertebrae surgery, Female, Graft Rejection drug therapy, Graft Rejection prevention & control, Graft Survival physiology, Hematoma, Epidural, Spinal etiology, Hematoma, Epidural, Spinal pathology, Hematoma, Epidural, Spinal physiopathology, Humans, Immunosuppressive Agents therapeutic use, Infusion Pumps, Laminectomy, Microinjections adverse effects, Microinjections methods, Neurogenesis physiology, Postoperative Complications etiology, Postoperative Complications physiopathology, Postoperative Complications prevention & control, Spinal Cord physiology, Stem Cell Transplantation adverse effects, Stem Cell Transplantation methods, Stem Cells physiology, Stereotaxic Techniques, Sus scrofa, Syringes adverse effects, Transplantation, Heterologous adverse effects, Transplantation, Heterologous instrumentation, Transplantation, Heterologous methods, Treatment Outcome, Microinjections instrumentation, Spinal Cord cytology, Spinal Cord surgery, Spinal Cord Diseases surgery, Stem Cell Transplantation instrumentation, Stem Cells cytology, Syringes standards
- Abstract
Objective: The current series represents a preclinical safety validation study for direct parenchymal microinjection of cellular grafts into the ventral horn of the porcine cervical spinal cord., Methods: Twenty-four 30- to 40-kg female Yorkshire farm pigs immunosuppressed with cyclosporine underwent a cervical laminectomy and ventral horn human neural progenitor cell injection. Cell transplantation in groups 1 to 3 (n = 6 pigs each) was undertaken with the intent of assessing the safety of varied injection volumes: 10, 25, and 50 microL injected at 1, 2.5, and 5 microL/min, respectively. Groups 4 and 5 (n = 3 pigs each) received prolonged immunosuppressant pretreatment in an attempt to demonstrate graft viability. The latter was undertaken in an alternate species (mini-pig versus Yorkshire pig)., Results: Neurological morbidity was observed in 1 animal and was attributable to the presence of a resolving epidural hematoma noted at necropsy. Although instances of ventral horn targeting were achieved in all injection groups with a coordinate-based approach, opportunities exist for improvement in accuracy and precision. A relationship between injection volume and graft site cross-sectional area suggested limited reflux. Only animals from group 5 achieved graft survival at a survival end point (t = 1 week)., Conclusion: This series demonstrated the functional safety of targeted ventral horn microinjection despite evidence for graft site immune rejection. Improvements in graft delivery may be augmented with an adapter to improve control of the cannula entry angle, intraoperative imaging, or larger graft volumes. Finally, demonstration of long-term graft viability in future preclinical toxicity studies may require tailored immunosuppressive therapies, an allograft construct, or tailored choice of host species.
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- 2009
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10. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS.
- Author
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Suzuki M, McHugh J, Tork C, Shelley B, Klein SM, Aebischer P, and Svendsen CN
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- Amyotrophic Lateral Sclerosis physiopathology, Animals, Astrocytes cytology, Astrocytes metabolism, Behavior, Animal physiology, Biomarkers metabolism, Cell Movement, Cell Survival physiology, Cells, Cultured, Female, Fetus cytology, Genetic Vectors genetics, Genetic Vectors metabolism, Glial Cell Line-Derived Neurotrophic Factor genetics, Humans, Lentivirus genetics, Lentivirus metabolism, Motor Activity physiology, Motor Neurons cytology, Motor Neurons pathology, Neuromuscular Junction ultrastructure, Rats, Rats, Sprague-Dawley, Spinal Cord cytology, Spinal Cord pathology, Stem Cell Transplantation, Stem Cells cytology, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis pathology, Glial Cell Line-Derived Neurotrophic Factor metabolism, Motor Neurons metabolism, Muscles innervation, Stem Cells physiology
- Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by rapid loss of muscle control and eventual paralysis due to the death of large motor neurons in the brain and spinal cord. Growth factors such as glial cell line derived neurotrophic factor (GDNF) are known to protect motor neurons from damage in a range of models. However, penetrance through the blood brain barrier and delivery to the spinal cord remains a serious challenge. Although there may be a primary dysfunction in the motor neuron itself, there is also increasing evidence that excitotoxicity due to glial dysfunction plays a crucial role in disease progression. Clearly it would be of great interest if wild type glial cells could ameliorate motor neuron loss in these models, perhaps in combination with the release of growth factors such as GDNF., Methodology/principal Findings: Human neural progenitor cells can be expanded in culture for long periods and survive transplantation into the adult rodent central nervous system, in some cases making large numbers of GFAP positive astrocytes. They can also be genetically modified to release GDNF (hNPC(GDNF)) and thus act as long-term 'mini pumps' in specific regions of the rodent and primate brain. In the current study we genetically modified human neural stem cells to release GDNF and transplanted them into the spinal cord of rats over-expressing mutant SOD1 (SOD1(G93A)). Following unilateral transplantation into the spinal cord of SOD1(G93A) rats there was robust cellular migration into degenerating areas, efficient delivery of GDNF and remarkable preservation of motor neurons at early and end stages of the disease within chimeric regions. The progenitors retained immature markers, and those not secreting GDNF had no effect on motor neuron survival. Interestingly, this robust motor neuron survival was not accompanied by continued innervation of muscle end plates and thus resulted in no improvement in ipsilateral limb use., Conclusions/significance: The potential to maintain dying motor neurons by delivering GDNF using neural progenitor cells represents a novel and powerful treatment strategy for ALS. While this approach represents a unique way to prevent motor neuron loss, our data also suggest that additional strategies may also be required for maintenance of neuromuscular connections and full functional recovery. However, simply maintaining motor neurons in patients would be the first step of a therapeutic advance for this devastating and incurable disease, while future strategies focus on the maintenance of the neuromuscular junction.
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- 2007
- Full Text
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11. GDNF delivery using human neural progenitor cells in a rat model of ALS.
- Author
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Klein SM, Behrstock S, McHugh J, Hoffmann K, Wallace K, Suzuki M, Aebischer P, and Svendsen CN
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- Amyotrophic Lateral Sclerosis pathology, Animals, Astrocytes metabolism, Astrocytes pathology, Cell Survival, Cell Transplantation methods, Disease Models, Animal, Glial Cell Line-Derived Neurotrophic Factor, Humans, Motor Neurons cytology, Motor Neurons metabolism, Nerve Growth Factors genetics, Nerve Growth Factors metabolism, Nerve Growth Factors pharmacokinetics, Neurons cytology, Rats, Rats, Mutant Strains, Spinal Cord cytology, Stem Cells cytology, Superoxide Dismutase genetics, Superoxide Dismutase-1, Transplantation, Heterologous methods, Amyotrophic Lateral Sclerosis therapy, Genetic Therapy methods, Nerve Growth Factors administration & dosage, Neurons physiology, Stem Cells physiology
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of spinal cord, brainstem, and cortical motor neurons. In a minority of patients, the disease is caused by mutations in the copper (2+)/zinc (2+) superoxide dismutase 1 (SOD1) gene. Recent evidence suggests that astrocytes are dysfunctional in ALS and may be a critical link in the support of motor neuron health. Furthermore, growth factors, such as glial cell line-derived neurotrophic factor (GDNF), have a high affinity for motor neurons and can prevent their death following various insults, but due to the protein's large size are difficult to directly administer to brain. In this study, human neural progenitor cells (hNPC) isolated from the cortex were expanded in culture and modified using lentivirus to secrete GDNF (hNPC(GDNF)). These cells survived up to 11 weeks following transplantation into the lumbar spinal cord of rats overexpressing the G93A SOD1 mutation (SOD1 (G93A)). Cellular integration into both gray and white matter was observed without adverse behavioral effects. All transplants secreted GDNF within the region of cell survival, but not outside this area. Fibers were seen to upregulate cholinergic markers in response to GDNF, indicating it was physiologically active. We conclude that genetically modified hNPC can survive, integrate, and release GDNF in the spinal cord of SOD1 (G93A) rats. As such, they provide an interesting source of cells for both glial replacement and trophic factor delivery in future human clinical studies.
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- 2005
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12. Multiple developmental roles of Ahnak are suggested by localization to sites of placentation and neural plate fusion in the mouse conceptus.
- Author
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Downs KM, McHugh J, Copp AJ, and Shtivelman E
- Subjects
- Allantois, Animals, Ectoderm metabolism, Female, Gene Expression Regulation, Developmental, Humans, Mice, Pregnancy, Trophoblasts metabolism, Neural Plate, Placentation
- Abstract
Ahnak is a gigantic (700 kD) phosphoprotein with a unique structure whose expression and cellular localization are dynamically regulated during cell cycle progression. Here, we report that Ahnak is localized to sites of major morphogenesis during mouse placentation and neurulation. Ahnak was found in: (i) derivatives of trophectoderm, including chorionic ectoderm prior to and during union with the ectoplacental cone, presumptive syncytiotrophoblast cells in the chorionic labyrinth, and giant cells at the trophoblast-uterine interface; (ii) the allantois prior to, during, and after union with the chorion; and (iii) the tips of the neural plate during formation of the neural tube. On the basis of these observations, we suggest that Ahnak may play heretofore unrecognized roles in tissue union during normal mouse development.
- Published
- 2002
- Full Text
- View/download PDF
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