Biomedical subjects

Michel Modo

Publications and source records attributed to Michel Modo.

8 recordsLinked to original sources

PubMed2007

The in vitro effects of a bimodal contrast agent on cellular functions and relaxometry.

The in vivo monitoring of cell survival and migration will be essential to the translation of cell-based therapies from the laboratory to clinical studies. The pre-labeling of cells with magnetic resonance imaging (MRI) contrast agents renders them visible in vivo for serial cellular imaging. However, little is known about the impact of the presence of these metal particles inside transplanted cells. The use of the bimodal contrast agent GRID made it possible to demonstrate by means of fluorescent microscopy and inductively coupled plasma mass spectrometry (ICP-MS) that, after 16 h of incubation (without the use of a transfection agent), neural stem cells (NSCs) were saturated and no longer incorporated particles. With this maximal uptake, no significant effect on cell viability was observed. However, a significant decrease in proliferation was evident in cells that underwent 24 h of labeling. A significant increase in reactive oxygen species was observed for all GRID labeling, with a very significant increase with 24 h of labeling. GRID labeling did not affect cell motility in comparison with PKH26-labeled NSCs in a glioma-based migration assay and also allowed differentiation into all major cell types of the brain. GRID-labeled cells induced a signal change of 47% on T(2) measurements and allows a detection of cell clusters of approximately 220 cells/microl. Further in vivo testing will be required to ensure that cell labeling with gadolinium-based MRI contrast agents does not impair their ability to repair.

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PubMed2004

Mapping transplanted stem cell migration after a stroke: a serial, in vivo magnetic resonance imaging study.

Preferential migration of stem cells toward the site of a lesion is a highly desirable property of stem cells that allows flexibility in the site of graft implantation in the damaged brain. In rats with unilateral stroke damage, neural stem cells transplanted into the contralateral hemisphere migrate across to the lesioned hemisphere and populate the area around the ischaemic infarct. To date, the migration of neural stem cells in the damaged brain has been mainly inferred from snapshot histological images. In this study, we demonstrate that by pre-labelling neural stem cells with the bimodal contrast agent Gadolinium-RhodamIne Dextran [GRID, detectable by both magnetic resonance imaging (MRI) and fluorescent microscopy], the transhemispheric migration of transplanted neural stem cells contralateral to a stroke lesion can be followed in vivo by serial MRI and corroborated by subsequent histological analyses. Our results indicate that neural stem cells migrated from the injection tract mainly along the corpus callosum within 7 days of transplantation and extensively re-populated the peri-lesion area by 14 days following implantation. In contrast, neural stem cells transplanted into sham controls did not show any substantial migration outside of the injection tract, suggesting that the transcallosal migration observed in the stroke-lesioned animals is due to neural stem cells being attracted by the lesion site. In vivo tracking of the migration of neural stem cells responding to damage will greatly enhance our understanding of optimal transplantation strategies as well as how neural stem cells promote functional and anatomical recovery in neurological disorders.

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PubMed2004

In vivo monitoring of cellular transplants by magnetic resonance imaging and positron emission tomography.

Cellular loss is a common pathological observation in many disease conditions. Recent evidence that these cells can be replaced has generated huge excitement over possible clinical applications. The use of stem or progenitor cells, which can differentiate into site-appropriate phenotypes required to "repair" the damaged tissue, has already demonstrated potential in animal models, but many aspects of this novel treatment strategy require further elucidation. Most importantly, the monitoring of the safety of cellular transplants in patients remains a challenge. Traditional histological methods do not address the dynamic nature of transplant-induced recovery and highlight the necessity of in vivo imaging to probe the survival, migration and functional consequences of transplanted cells. This paper reviews how non-invasive imaging technology can be used to serially assess intact living organisms in order to visualise and monitor cellular transplants.

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PubMed2003

Effects of implantation site of dead stem cells in rats with stroke damage.

Searching for valid control grafts, we assessed the performance of rats subjected to middle cerebral artery occlusion (MCAO) and grafted with freeze-thawed dead stem cells into sites previously used for active grafts (ipsilateral and contralateral striatum and ventricle) on bilateral asymmetry and water maze tests. We expected to find that sham grafted groups had impairments equivalent to those of MCAO-only controls, relative to intact controls. This proved to be the case for contralateral and intraventricular grafts, and for asymmetry in rats with ipsilateral grafts. However, spatial learning was substantially impaired and lesion volume was increased by 55% with ipsilateral dead cell grafts. Exacerbation of stroke effects indicates potential hazards in the use of dead cells for sham grafts.

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PubMed2002

Transplantation of neural stem cells in a rat model of stroke: assessment of short-term graft survival and acute host immunological response.

The use of progenitors and stem cells for neural grafting is promising, as these not only have the potential to be maintained in vitro until use, but may also prove less likely to evoke an immunogenic response in the host, when compared to primary (fetal) grafts. We investigated whether the short-term survival of a grafted conditionally immortalised murine neuroepithelial stem cell line (MHP36) (2 weeks post-implantation, 4 weeks post-ischaemia) is influenced by: (i) immunosuppression (cyclosporin A (CSA) vs. no CSA), (ii) the local (intact vs. lesioned hemisphere), or (iii) global (lesioned vs. sham) brain environment. MHP36 cells were transplanted ipsi- and contralateral to the lesion in rats with middle cerebral artery occlusion (MCAo) or sham controls. Animals were either administered CSA or received no immunosuppressive treatment. A proliferation assay of lymphocytes dissociated from cervical lymph nodes, grading of the survival of the grafted cells, and histological evaluation of the immune response revealed no significant difference between animals treated with or without CSA. There was no difference in survival or immunological response to cells grafted ipsi- or contralateral to the lesion. Although a local upregulation of immunological markers (MHC class I, MHC class II, CD45, CD11b) was detected around the injection site and the ischaemic lesion, these were not specifically upregulated in response to transplanted cells. These results provide evidence for the low immunogenic properties of MHP36 cells during the initial period following implantation, known to be associated with an acute host immune response and ensuing graft rejection.

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PubMed2002

Effects of implantation site of stem cell grafts on behavioral recovery from stroke damage.

BACKGROUND AND PURPOSE: Findings that MHP36 stem cells grafted into intact parenchyma contralateral to the lesion induced by middle cerebral artery occlusion promoted recovery from stroke deficits led us to investigate whether implantation site of stem cells affects the functional efficacy of MHP36 grafts. METHODS: MHP36 cells (200 000/8 microL) were implanted in the left (n=8) or right (n=9) parenchyma or infused into the right ventricle (intraventricular; n=7) 2 to 3 weeks after stroke induced by 60 minutes of intraluminal right middle cerebral artery occlusion. Additionally, intact (n=11) and stroke (n=7) control groups were tested for 14 weeks in bilateral asymmetry, rotation bias, and spatial learning tasks before histological investigation of cell distribution and differentiation. RESULTS: Rats with left and right parenchymal grafts showed reduced bilateral asymmetry but no improvement in spatial learning. Conversely, spatial learning improved in rats with intraventricular grafts, but marked asymmetry persisted. No grafted group showed reduced amphetamine-induced rotation bias or reduced lesion volume relative to stroke controls. In all grafted groups, cells occupied both sides of the brain. A third of cells grafted in the striatum crossed the midline to occupy homologous regions in intact and lesioned hemispheres and differentiated into site-appropriate phenotypes. CONCLUSIONS: After stroke, both the intact and lesioned hemispheres attract grafted stem cells, suggesting repair processes that utilize cells both for local repair and to augment plastic changes in contralateral motor pathways. However, differential effects of parenchymal and intraventricular grafts suggest that different mechanisms are implicated in recovery from cognitive and sensorimotor deficits induced by stroke.

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PubMed2002

Tracking transplanted stem cell migration using bifunctional, contrast agent-enhanced, magnetic resonance imaging.

The ability to track stem cell transplants in the brain by in vivo neuroimaging will undoubtedly aid our understanding of how these cells mediate functional recovery after neural transplantation. One major challenge for the development and refinement of stem cell transplantation is to map the spatial distribution and rate of migration in situ. Here we report a method for tracking transplanted stem cells in the ischemia-damaged rat hippocampus by magnetic resonance imaging (MRI). Before transplantation, stem cells were labeled in vitro either with a novel bifunctional contrast agent, gadolinium rhodamine dextran (GRID), identifiable by both MRI and fluorescence microscopy, or with PKH26, visible exclusively under fluorescence microscopy. At different time points following engraftment, the brains were evaluated by both histology and ex vivo MR imaging. Transplanted stem cells were identified by MRI only if prelabeled with GRID, whereas fluorescence microscopy detected transplanted cells using either label. The distribution of GRID-labeled stem cells identified by MRI corresponded to those detected using fluorescence microscopy. These results demonstrate that GRID-enhanced MRI can reliably identify transplanted stem cells and their migration in the brain.

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PubMedDate not supplied

Cellular MR imaging.

Cellular MR imaging is a young field that aims to visualize targeted cells in living organisms. In order to provide a different signal intensity of the targeted cell, they are either labeled with MR contrast agents in vivo or prelabeled in vitro. Either (ultrasmall) superparamagnetic iron oxide [(U)SPIO] particles or (polymeric) paramagnetic chelates can be used for this purpose. For in vivo cellular labeling, Gd3+- and Mn2+-chelates have mainly been used for targeted hepatobiliary imaging, and (U)SPIO-based cellular imaging has been focused on imaging of macrophage activity. Several of these magnetopharmaceuticals have been FDA-approved or are in late-phase clinical trials. As for prelabeling of cells in vitro, a challenge has been to induce a sufficient uptake of contrast agents into nonphagocytic cells, without affecting normal cellular function. It appears that this issue has now largely been resolved, leading to an active research on monitoring the cellular biodistribution in vivo following transplantation or transfusion of these cells, including cell migration and trafficking. New applications of cellular MR imaging will be directed, for instance, towards our understanding of hematopoietic (immune) cell trafficking and of novel guided (stem) cell-based therapies aimed to be translated to the clinic in the future.

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