Delphine Monigadon - Academia.edu (original) (raw)

Uploads

Papers by Delphine Monigadon

Background: In intracerebral hemorrhage (ICH), a subtype of stroke, the bloodentry into the brain... more Background: In intracerebral hemorrhage (ICH), a subtype of stroke, the bloodentry into the brain triggers toxicity resulting in a strong loss of neurons andinflammation. Water content is also increases leading to growing intracranial pressure,which worsens neurological outcome. C-Jun N-terminal kinases (JNKs) areactivated in response to stress stimuli. Specific inhibition of JNK by a TAT-coupledpeptide (XG-102) mediates neuroprotection in several models of ischemic stroke.Recently, we have noted that the JNK pathway is also activated in a mouse modelof ICH, raising the question of the efficacy of XG-102 in this model.Method: ICH was induced in the mouse by intrastriatal injection of bacterialcollagenase (0,1U). Three hours later, animals received an i.v. injection of XG-102(100μg/kg). The neuroscore was assessed using a scale (from 0 to 9) based on 3behavioral tests performed daily. Then, mice were sacrificed at 6h, 24h, 48h and 5dafter ICH and histological studies performed.Result...

Somatic Stem Cells, 2012

Treatments for neurodegenerative diseases have little impact on the long-term patient health. How... more Treatments for neurodegenerative diseases have little impact on the long-term patient health. However, cellular transplants of neuroblasts derived from the aborted embryonic brain tissue in animal models of neurodegenerative disorders and in patients have demonstrated survival and functionality in the brain. However, ethical and functional problems due to the use of this fetal tissue stopped most of the clinical trials. Therefore, new cell sources were needed, and scientists focused on neural (NSCs) and mesenchymal stem cells (MSCs). When transplanted in the brain of animals with Parkinson's or Huntington's disease, NSCs and MSCs were able to induce partial functional recovery by promoting neuroprotection and immunomodulation. MSCs are more readily accessible than NSCs due to sources such as the bone marrow. However, MSCs are not capable of differentiating into neurons in vivo where NSCs are. Thus, transplantation of NSCs and MSCs is interesting for brain regenerative medicine. In this chapter, we detail the methods for NSCs and MSCs isolation as well as the transplantation procedures used to treat rodent models of neurodegenerative damage.

Cerebrovascular Diseases, 2010

Background: Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG... more Background: Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG-102 (formerly D- JNKI1) induces strong neuroprotection in ischemic stroke in rodents. We investigated the effect of JNK inhibition in intracerebral hemorrhage (ICH). Methods: Three hours after induction of ICH by intrastriatal collagenase injection in mice, the animals received an intravenous injection of 100 µg/kg of XG-102. The neurological outcome was assessed daily and the mice were sacrificed at 6 h, 1, 2 or 5 days after ICH. Results: XG-102 administration significantly improved the neurological outcome at 1 day (p < 0.01). The lesion volume was significantly decreased after 2 days (29 ± 11 vs. 39 ± 5 mm3 in vehicle-treated animals, p < 0.05). There was also a decreased hemispheric swelling (14 ± 13 vs. 26 ± 9% in vehicle-treated animals, p < 0.05) correlating with increased aquaporin 4 expression. Conclusions: XG-102 attenuates cerebral edema in ICH and functional impairm...

American Journal of Transplantation, 2014

Xenogenic fetal neuroblasts are considered as a potential source of transplantable cells for the ... more Xenogenic fetal neuroblasts are considered as a potential source of transplantable cells for the treatment of neurodegenerative diseases, but immunological barriers limit their use in the clinic. While considerable work has been performed to decipher the role of the cellular immune response in the rejection of intracerebral xenotransplants, there is much still to learn about the humoral reaction. To this end, the IgG response to the transplantation of fetal porcine neural cells (PNC) into the rat brain was analyzed. Rat sera did not contain preformed antibodies against PNC, but elicited anti-porcine IgG was clearly detected in the host blood once the graft was rejected. Only the IgG1 and IgG2a subclasses were up-regulated, suggesting a T-helper 2 immune response. The main target of these elicited IgG antibodies was porcine neurons, as determined by double labeling in vitro and in vivo. Complement and anti-porcine IgG were present in the rejecting grafts, suggesting an active role of the host humoral response in graft rejection. This hypothesis was confirmed by the prolonged survival of fetal porcine neurons in the striatum of immunoglobulin-deficient rats. These data suggest that the prolonged survival of intracerebral xenotransplants relies on the control of both cell-mediated and humoral immune responses.

Cardiovascular Research, 2012

The cardiac interstitium comprises a heterogeneous population of cells relevant to adult heart mu... more The cardiac interstitium comprises a heterogeneous population of cells relevant to adult heart muscle homeostasis. The detailed embryonic origin, quantitative and qualitative composition of cardiac interstitial cells remains unknown. By means of cell lineage tracing technologies, we have mapped the cellular components of the murine developing interstitium from the embryo to postnatal stages. Our results demonstrate that embryonic epicardial-derived cells (EPDC) pioneer the colonization of the interstitial space in the developing heart, displaying a typical transmural patterning across cardiac chamber walls. This study indicates that most EPDC remain at the cardiac interstitium in the form of fibroblastic(-like) cells, dynamically interacting with other non-epicardial-derived cells (e.g. bone marrow-derived cells). Using a variety of in vitro assays, we have characterized subpopulations of EPDC following criteria related to their molecular profile and mobilization properties (cell adhesion; proteolytic activity). From our data we conclude that: 1) EPDC are the first cells that populate the cardiac interstitium, where they home and remain along adulthood; 2) EPDC display a unique proteolytic program from early stages of cardiac development and 3) these cells might be instrumental to the homing of other cell types late in development/postnatal life. In summary, our work provides new information on the biology of cardiac interstitial cells (most specially cardiac fibroblasts), offering clues to understand paracrine and/or autocrine signals, as well as the ECM-related mechanisms (protein deposition and proteolysis), involved in clinically relevant patophysiological phenomena like ventricular remodeling after myocardial infarction.

Background: Intracerebral hemorrhage (ICH) is a subtype of stroke characterized by a haematoma wi... more Background: Intracerebral hemorrhage (ICH) is a subtype of stroke characterized by a haematoma within the brain parenchyma resulting from blood vessel rupture and with a poor outcome. In ICH, the blood entry into the brain triggers toxicity resulting in a substantial loss of neurons and an inflammatory response. At the same time, blood-brain barrier (BBB) disruption increases water content (edema) leading to growing intracranial pressure, which in turn worsens neurological outcome. Although the clinical presentation is similar in ischemic and hemorrhagic stroke, the treatment is different and the stroke type needs to be determined beforehand by imaging which delays the therapy. C-Jun N-terminal kinases (JNKs) are a family of kinases activated in response to stress stimuli and involved in several pathways such as apoptosis. Specific inhibition of JNK by a TAT-coupled peptide (XG-102) mediates strong neuroprotection in several models of ischemic stroke in rodents. Recently, we have ob...

Cerebrovascular Diseases, 2010

Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG-102 (former... more Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG-102 (formerly D- JNKI1) induces strong neuroprotection in ischemic stroke in rodents. We investigated the effect of JNK inhibition in intracerebral hemorrhage (ICH). Three hours after induction of ICH by intrastriatal collagenase injection in mice, the animals received an intravenous injection of 100 microg/kg of XG-102. The neurological outcome was assessed daily and the mice were sacrificed at 6 h, 1, 2 or 5 days after ICH. XG-102 administration significantly improved the neurological outcome at 1 day (p < 0.01). The lesion volume was significantly decreased after 2 days (29 +/- 11 vs. 39 +/- 5 mm(3) in vehicle-treated animals, p < 0.05). There was also a decreased hemispheric swelling (14 +/- 13 vs. 26 +/- 9% in vehicle-treated animals, p < 0.05) correlating with increased aquaporin 4 expression. XG-102 attenuates cerebral edema in ICH and functional impairment at early time points. The...

…, 2010

Cell therapy in the brain is limited by the requirement of high doses of immunosuppressors that h... more Cell therapy in the brain is limited by the requirement of high doses of immunosuppressors that have harmful side effects, and often, it cannot prevent the ultimate rejection of the transplanted cells. Alternative treatments that replace or enable a reduction in the doses of usual immunosuppressors have to be found. In this regard, minocycline shows potential as therapeutic agent. This drug crosses the blood-brain barrier, has good safety records, and exhibits strong antiinflammatory effects. To study the impact of minocycline on the survival of intracerebral transplant, 400,000 porcine fetal neurons were transplanted into the striatum of rats treated daily with minocycline until sacrifice. Graft survival and immunologic reaction were evaluated by immunohistochemistry. In the control groups, all the grafts were rejected at day 63, whereas healthy grafts exhibiting tyrosine hydroxylase neurons were observed in 40% of the treated rats. The low immunoreactivity for ED1 and R73 in treated rats when compared with the control groups suggests that minocycline promotes long-term survival of neuronal xenograft by inhibiting microglial activation and T-cell recruitment. Our present data provide the first evidence of an effect of minocycline on the host immune response after neuronal transplantation into the brain. This observation raises new perspectives concerning the use of minocycline and provides basis for the development of safe and efficient immunosuppressive protocols for intracerebral transplantation.

…, 2011

Transplantation of neural cells provides an interesting form of therapy for certain CNS disorders... more Transplantation of neural cells provides an interesting form of therapy for certain CNS disorders. Although the brain has a special immune status, xenografts of fetal porcine neuroblasts are ultimately rejected after a lag of several weeks. Various strategies have been proposed to prevent this process. These include the design of transgenic pigs whose neurons have an increased immunosuppressive potential. An interesting alternative is provided by the use of neural stem/progenitor cells, which are multipotent cells found in the fetal or adult CNS. These cells are known to be poorly immunogenic. However, pig or rat neural stem/progenitor cells are highly immunosuppressive, as shown by their ability to block the proliferation of activated T lymphocytes. This effect is mediated by cell secreted factor(s), whose nature is discussed.

Experimental …, 2010

Intracerebral xenotransplantation of porcine fetal neuroblasts (pNB) is considered as an alternat... more Intracerebral xenotransplantation of porcine fetal neuroblasts (pNB) is considered as an alternative to human neuroblasts for the treatment of neurodegenerative diseases. However, pNB are systematically rejected, even in an immunoprivileged site such as the brain. Within this context, neural stem/precursor cells (NSPC), which were suggested as exhibiting low immunogenicity, appeared as a useful source of xenogeneic cells. To determine the advantage of using porcine NSPC (pNSPC) in xenotransplantation, pNB and pNSPC were grafted into the striatum of rats without immunosuppression. At day 63, all the pNB were rejected while 40% of the rats transplanted with pNSPC exhibited large and healthy grafts with numerous pNF70positive cells. The absence of inflammation at day 63 and the occasional presence of T cells in pNSPC grafts evoked a weak host immune response which might be partly due to the immunosuppressive properties of the transplanted cells. T cell proliferation assays confirmed such a hypothesis by revealing an inhibitory effect of pNSPC on T cells through a soluble factor. In addition to their immunosuppressive effect, in contrast to pNB, very few pNSPC differentiated into tyrosine hydroxylase-positive neurons but the cells triggered an intense innervation of the striatum by rat dopaminergic fibers coming from the substantia nigra. Further experiments will be required to optimize the use of pNSPC in regenerative medicine but here we show that their immunomodulatory and trophic activities might be of great interest for restorative strategies. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."

Expert Review of Cardiovascular Therapy, 2012

Background: In intracerebral hemorrhage (ICH), a subtype of stroke, the bloodentry into the brain... more Background: In intracerebral hemorrhage (ICH), a subtype of stroke, the bloodentry into the brain triggers toxicity resulting in a strong loss of neurons andinflammation. Water content is also increases leading to growing intracranial pressure,which worsens neurological outcome. C-Jun N-terminal kinases (JNKs) areactivated in response to stress stimuli. Specific inhibition of JNK by a TAT-coupledpeptide (XG-102) mediates neuroprotection in several models of ischemic stroke.Recently, we have noted that the JNK pathway is also activated in a mouse modelof ICH, raising the question of the efficacy of XG-102 in this model.Method: ICH was induced in the mouse by intrastriatal injection of bacterialcollagenase (0,1U). Three hours later, animals received an i.v. injection of XG-102(100μg/kg). The neuroscore was assessed using a scale (from 0 to 9) based on 3behavioral tests performed daily. Then, mice were sacrificed at 6h, 24h, 48h and 5dafter ICH and histological studies performed.Result...

Somatic Stem Cells, 2012

Treatments for neurodegenerative diseases have little impact on the long-term patient health. How... more Treatments for neurodegenerative diseases have little impact on the long-term patient health. However, cellular transplants of neuroblasts derived from the aborted embryonic brain tissue in animal models of neurodegenerative disorders and in patients have demonstrated survival and functionality in the brain. However, ethical and functional problems due to the use of this fetal tissue stopped most of the clinical trials. Therefore, new cell sources were needed, and scientists focused on neural (NSCs) and mesenchymal stem cells (MSCs). When transplanted in the brain of animals with Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s or Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease, NSCs and MSCs were able to induce partial functional recovery by promoting neuroprotection and immunomodulation. MSCs are more readily accessible than NSCs due to sources such as the bone marrow. However, MSCs are not capable of differentiating into neurons in vivo where NSCs are. Thus, transplantation of NSCs and MSCs is interesting for brain regenerative medicine. In this chapter, we detail the methods for NSCs and MSCs isolation as well as the transplantation procedures used to treat rodent models of neurodegenerative damage.

Cerebrovascular Diseases, 2010

Background: Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG... more Background: Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG-102 (formerly D- JNKI1) induces strong neuroprotection in ischemic stroke in rodents. We investigated the effect of JNK inhibition in intracerebral hemorrhage (ICH). Methods: Three hours after induction of ICH by intrastriatal collagenase injection in mice, the animals received an intravenous injection of 100 µg/kg of XG-102. The neurological outcome was assessed daily and the mice were sacrificed at 6 h, 1, 2 or 5 days after ICH. Results: XG-102 administration significantly improved the neurological outcome at 1 day (p < 0.01). The lesion volume was significantly decreased after 2 days (29 ± 11 vs. 39 ± 5 mm3 in vehicle-treated animals, p < 0.05). There was also a decreased hemispheric swelling (14 ± 13 vs. 26 ± 9% in vehicle-treated animals, p < 0.05) correlating with increased aquaporin 4 expression. Conclusions: XG-102 attenuates cerebral edema in ICH and functional impairm...

American Journal of Transplantation, 2014

Xenogenic fetal neuroblasts are considered as a potential source of transplantable cells for the ... more Xenogenic fetal neuroblasts are considered as a potential source of transplantable cells for the treatment of neurodegenerative diseases, but immunological barriers limit their use in the clinic. While considerable work has been performed to decipher the role of the cellular immune response in the rejection of intracerebral xenotransplants, there is much still to learn about the humoral reaction. To this end, the IgG response to the transplantation of fetal porcine neural cells (PNC) into the rat brain was analyzed. Rat sera did not contain preformed antibodies against PNC, but elicited anti-porcine IgG was clearly detected in the host blood once the graft was rejected. Only the IgG1 and IgG2a subclasses were up-regulated, suggesting a T-helper 2 immune response. The main target of these elicited IgG antibodies was porcine neurons, as determined by double labeling in vitro and in vivo. Complement and anti-porcine IgG were present in the rejecting grafts, suggesting an active role of the host humoral response in graft rejection. This hypothesis was confirmed by the prolonged survival of fetal porcine neurons in the striatum of immunoglobulin-deficient rats. These data suggest that the prolonged survival of intracerebral xenotransplants relies on the control of both cell-mediated and humoral immune responses.

Cardiovascular Research, 2012

The cardiac interstitium comprises a heterogeneous population of cells relevant to adult heart mu... more The cardiac interstitium comprises a heterogeneous population of cells relevant to adult heart muscle homeostasis. The detailed embryonic origin, quantitative and qualitative composition of cardiac interstitial cells remains unknown. By means of cell lineage tracing technologies, we have mapped the cellular components of the murine developing interstitium from the embryo to postnatal stages. Our results demonstrate that embryonic epicardial-derived cells (EPDC) pioneer the colonization of the interstitial space in the developing heart, displaying a typical transmural patterning across cardiac chamber walls. This study indicates that most EPDC remain at the cardiac interstitium in the form of fibroblastic(-like) cells, dynamically interacting with other non-epicardial-derived cells (e.g. bone marrow-derived cells). Using a variety of in vitro assays, we have characterized subpopulations of EPDC following criteria related to their molecular profile and mobilization properties (cell adhesion; proteolytic activity). From our data we conclude that: 1) EPDC are the first cells that populate the cardiac interstitium, where they home and remain along adulthood; 2) EPDC display a unique proteolytic program from early stages of cardiac development and 3) these cells might be instrumental to the homing of other cell types late in development/postnatal life. In summary, our work provides new information on the biology of cardiac interstitial cells (most specially cardiac fibroblasts), offering clues to understand paracrine and/or autocrine signals, as well as the ECM-related mechanisms (protein deposition and proteolysis), involved in clinically relevant patophysiological phenomena like ventricular remodeling after myocardial infarction.

Background: Intracerebral hemorrhage (ICH) is a subtype of stroke characterized by a haematoma wi... more Background: Intracerebral hemorrhage (ICH) is a subtype of stroke characterized by a haematoma within the brain parenchyma resulting from blood vessel rupture and with a poor outcome. In ICH, the blood entry into the brain triggers toxicity resulting in a substantial loss of neurons and an inflammatory response. At the same time, blood-brain barrier (BBB) disruption increases water content (edema) leading to growing intracranial pressure, which in turn worsens neurological outcome. Although the clinical presentation is similar in ischemic and hemorrhagic stroke, the treatment is different and the stroke type needs to be determined beforehand by imaging which delays the therapy. C-Jun N-terminal kinases (JNKs) are a family of kinases activated in response to stress stimuli and involved in several pathways such as apoptosis. Specific inhibition of JNK by a TAT-coupled peptide (XG-102) mediates strong neuroprotection in several models of ischemic stroke in rodents. Recently, we have ob...

Cerebrovascular Diseases, 2010

Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG-102 (former... more Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG-102 (formerly D- JNKI1) induces strong neuroprotection in ischemic stroke in rodents. We investigated the effect of JNK inhibition in intracerebral hemorrhage (ICH). Three hours after induction of ICH by intrastriatal collagenase injection in mice, the animals received an intravenous injection of 100 microg/kg of XG-102. The neurological outcome was assessed daily and the mice were sacrificed at 6 h, 1, 2 or 5 days after ICH. XG-102 administration significantly improved the neurological outcome at 1 day (p < 0.01). The lesion volume was significantly decreased after 2 days (29 +/- 11 vs. 39 +/- 5 mm(3) in vehicle-treated animals, p < 0.05). There was also a decreased hemispheric swelling (14 +/- 13 vs. 26 +/- 9% in vehicle-treated animals, p < 0.05) correlating with increased aquaporin 4 expression. XG-102 attenuates cerebral edema in ICH and functional impairment at early time points. The...

…, 2010

Cell therapy in the brain is limited by the requirement of high doses of immunosuppressors that h... more Cell therapy in the brain is limited by the requirement of high doses of immunosuppressors that have harmful side effects, and often, it cannot prevent the ultimate rejection of the transplanted cells. Alternative treatments that replace or enable a reduction in the doses of usual immunosuppressors have to be found. In this regard, minocycline shows potential as therapeutic agent. This drug crosses the blood-brain barrier, has good safety records, and exhibits strong antiinflammatory effects. To study the impact of minocycline on the survival of intracerebral transplant, 400,000 porcine fetal neurons were transplanted into the striatum of rats treated daily with minocycline until sacrifice. Graft survival and immunologic reaction were evaluated by immunohistochemistry. In the control groups, all the grafts were rejected at day 63, whereas healthy grafts exhibiting tyrosine hydroxylase neurons were observed in 40% of the treated rats. The low immunoreactivity for ED1 and R73 in treated rats when compared with the control groups suggests that minocycline promotes long-term survival of neuronal xenograft by inhibiting microglial activation and T-cell recruitment. Our present data provide the first evidence of an effect of minocycline on the host immune response after neuronal transplantation into the brain. This observation raises new perspectives concerning the use of minocycline and provides basis for the development of safe and efficient immunosuppressive protocols for intracerebral transplantation.

…, 2011

Transplantation of neural cells provides an interesting form of therapy for certain CNS disorders... more Transplantation of neural cells provides an interesting form of therapy for certain CNS disorders. Although the brain has a special immune status, xenografts of fetal porcine neuroblasts are ultimately rejected after a lag of several weeks. Various strategies have been proposed to prevent this process. These include the design of transgenic pigs whose neurons have an increased immunosuppressive potential. An interesting alternative is provided by the use of neural stem/progenitor cells, which are multipotent cells found in the fetal or adult CNS. These cells are known to be poorly immunogenic. However, pig or rat neural stem/progenitor cells are highly immunosuppressive, as shown by their ability to block the proliferation of activated T lymphocytes. This effect is mediated by cell secreted factor(s), whose nature is discussed.

Experimental …, 2010

Intracerebral xenotransplantation of porcine fetal neuroblasts (pNB) is considered as an alternat... more Intracerebral xenotransplantation of porcine fetal neuroblasts (pNB) is considered as an alternative to human neuroblasts for the treatment of neurodegenerative diseases. However, pNB are systematically rejected, even in an immunoprivileged site such as the brain. Within this context, neural stem/precursor cells (NSPC), which were suggested as exhibiting low immunogenicity, appeared as a useful source of xenogeneic cells. To determine the advantage of using porcine NSPC (pNSPC) in xenotransplantation, pNB and pNSPC were grafted into the striatum of rats without immunosuppression. At day 63, all the pNB were rejected while 40% of the rats transplanted with pNSPC exhibited large and healthy grafts with numerous pNF70positive cells. The absence of inflammation at day 63 and the occasional presence of T cells in pNSPC grafts evoked a weak host immune response which might be partly due to the immunosuppressive properties of the transplanted cells. T cell proliferation assays confirmed such a hypothesis by revealing an inhibitory effect of pNSPC on T cells through a soluble factor. In addition to their immunosuppressive effect, in contrast to pNB, very few pNSPC differentiated into tyrosine hydroxylase-positive neurons but the cells triggered an intense innervation of the striatum by rat dopaminergic fibers coming from the substantia nigra. Further experiments will be required to optimize the use of pNSPC in regenerative medicine but here we show that their immunomodulatory and trophic activities might be of great interest for restorative strategies. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."

Expert Review of Cardiovascular Therapy, 2012