Quantitative and phenotypic analysis of mesenchymal stromal cell graft survival and recognition by microglia and astrocytes in mouse brain

Vocht, Nathalie De; Lin, Dan; Praet, Jelle; Hoornaert, Chloé; Reekmans, Kristien; Blon, Debbie Le; Daans, Jasmijn; Pauwels, Patrick; Goossens, Herman; Hens, Niel; Berneman, Zwi N.; Linden, Annemie Van der; Ponsaerts, Peter

doi:10.1016/j.imbio.2012.08.266

Cited by 35 publications

(56 citation statements)

References 37 publications

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“…Previous studies have proposed that reactive astrocytes form scar-like barriers surrounding the grafted MSCs, which sequesters them from immune effector cells, or that astrocytes infiltrating the graft may provide cellular and structural support for graft survival (Coyne et al 2006;De Vocht et al 2013a;De Vocht et al 2013b;Praet et al 2012). Our data demonstrated the induction of VEGFR-3 protein, but not its ligand, in reactive astrocytes at the graft site.…”

Section: Discussionsupporting

confidence: 49%

“…Altogether, it is likely that the neuroinflammatory response in engrafted brain tissue is not induced by MSCs secreting VEGF-C but is rather a phenomenon secondary to cell death observed after allogeneic or xenogeneic stem cell transplantation into the CNS (De Vocht et al 2013a). Previous studies have suggested that even autologous MSC grafts as well as allo-or xenogeneic stem cell grafts in the rat brain can trigger robust microglial activation and severe astrogliosis (Camp et al 2009;Tambuyzer et al 2009;Bergwerf et al 2011;De Vocht et al 2013a;De Vocht et al 2013b). In addition, Khoo et al (2011) reported that the glial reaction after transplantation of human MSCs into the rat brain occurs in the presence of cyclosporine immunosuppression, indicating that it is not specific to the transplanted cells.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, only a limited number of stem cells can be stably engrafted into the brain (Bergwerf et al 2011;De Vocht et al 2013a;De Vocht et al 2013b;Praet et al 2012;Reekmans et al 2012;Tambuyzer et al 2009). These data suggest the interaction between cellular grafts and the microenvironment of the host brain, especially the glia, is important for graft survival.…”

Section: Introductionmentioning

confidence: 99%

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Expression of Vascular Endothelial Growth Factor-C (VEGF-C) and Its Receptor (VEGFR-3) in the Glial Reaction Elicited by Human Mesenchymal Stem Cell Engraftment in the Normal Rat Brain

Shin

Riew

Park

et al. 2014

J Histochem Cytochem.

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To determine whether vascular endothelial growth factor-C (VEGF-C) and its receptor (VEGFR-3) are involved in the glial reaction elicited by transplanted mesenchymal stem cells (MSCs), we examined the cellular localization of VEGF-C and VEGFR-3 proteins in the striatum of adult normal rats that received bone marrow-derived human MSCs. The MSC grafts were infiltrated with activated microglia/macrophages and astrocytes over a 2-week period post-transplantation, which appeared to parallel the loss of transplanted MSCs. VEGF-C/VEGFR-3 was expressed in activated microglia/macrophages recruited to the graft site, where the induction of VEGF-C protein was rather late compared with that of its receptor. VEGF-C protein was absent or very weak on day 3, whereas VEGFR-3 immunoreactivity was evident within the first three days. Furthermore, within three days, VEGF-C could be detected in the brain macrophages localized immediately adjacent to the needle track. At the same time, almost all the brain macrophages in both regions expressed VEGFR-3. Reactive astrocytes at the graft site expressed VEGFR-3, but not VEGF-C. These data demonstrated the characteristic time- and cell-dependent expression patterns for VEGF-C and VEGFR-3 within the engrafted brain tissue, suggesting that they may contribute to neuroinflammation in MSC transplantation, possibly through the recruitment and/or activation of microglia/macrophages and astrogliosis.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of Vascular Endothelial Growth Factor-C (VEGF-C) and Its Receptor (VEGFR-3) in the Glial Reaction Elicited by Human Mesenchymal Stem Cell Engraftment in the Normal Rat Brain

Shin

Riew

Park

et al. 2014

J Histochem Cytochem.

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“…Impressively, as few as 10 Fluc-labelled cells could be visualized in vivo, suggesting that bioluminescent tools are amenable to monitoring patient tumour growth and therapeutic responses in surrogate hosts. Similar cell tracking experiments have been performed using immune cells, [49,50] stem cells, [51–55] and even pathogens. [31,45,56,57]…”

Section: Introductionmentioning

confidence: 80%

Bioluminescence: a versatile technique for imaging cellular and molecular features

2014

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Bioluminescence is a ubiquitous imaging modality for visualizing biological processes in vivo. This technique employs visible light and interfaces readily with most cell and tissue types, making it a versatile technology for preclinical studies. Here we review basic bioluminescence imaging principles, along with applications of the technology that are relevant to the medicinal chemistry community. These include noninvasive cell tracking experiments, analyses of protein function, and methods to visualize small molecule metabolites. In each section, we also discuss how bioluminescent tools have revealed insights into experimental therapies and aided drug discovery. Last, we highlight the development of new bioluminescent tools that will enable more sensitive and multi-component imaging experiments and, thus, expand our broader understanding of living systems.

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“…In our preceding studies regarding mMSC and mEF grafting in the CNS of immune-competent mice, we noted that mMSC and mEF grafts became highly infiltrated by microglia (at week 2 postgrafting, up to 50-80% of cells within the graft site are microglia) and surrounded by microglia and astrocytes (4,5,10,21). From the representative Iba1/eGFP, S100b/eGFP, and GFAP/eGFP images provided in Figure 2A, it is clear that mFMSC grafts, too, become highly infiltrated by microglia and surrounded by both microglia and astrocytes.…”

Section: Quantitative Analysis Of Glial Cell Responses Following Mfmsmentioning

confidence: 98%

Distinct In Vitro Properties of Embryonic and Extraembryonic Fibroblast-Like Cells are Reflected in their in Vivo Behavior following Grafting in the Adult Mouse Brain

et al. 2015

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Although intracerebral transplantation of various fibroblast(-like) cell populations has been shown feasible, little is known about the actual in vivo remodeling of these cellular grafts and their environment. In this study, we aimed to compare the in vitro and in vivo behavior of two phenotypically similar-but developmentally distinctfibroblast-like cell populations, namely, mouse embryonic fibroblasts (mEFs) and mouse fetal membrane-derived stromal cells (mFMSCs). While both mEFs and mFMSCs are readily able to reduce TNF-a secretion by LPS/IFN-gactivated BV-2 microglia, mFMSCs and mEFs display strikingly opposite behavior with regard to VEGF production under normal and inflammatory conditions. Whereas mFMSCs downregulate VEGF production upon coculture with LPS/IFN-g-activated BV-2 microglia, mEFs upregulate VEGF production in the presence of LPS/ IFN-g-activated BV-2 microglia. Subsequently, in vivo grafting of mFMSCs and mEFs revealed no difference in microglial and astroglial responses toward the cellular grafts. However, mFMSC grafts displayed a lower degree of neoangiogenesis compared to mEF grafts, thereby potentially explaining the lower cell number able to survive in mFMSC grafts. In summary, our results suggest that physiological differences between fibroblast-like cell populations might lie at the basis of variations in histopathological and/or clinical outcome following cell grafting in mouse brain.

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Quantitative and phenotypic analysis of mesenchymal stromal cell graft survival and recognition by microglia and astrocytes in mouse brain

Cited by 35 publications

References 37 publications

Expression of Vascular Endothelial Growth Factor-C (VEGF-C) and Its Receptor (VEGFR-3) in the Glial Reaction Elicited by Human Mesenchymal Stem Cell Engraftment in the Normal Rat Brain

Expression of Vascular Endothelial Growth Factor-C (VEGF-C) and Its Receptor (VEGFR-3) in the Glial Reaction Elicited by Human Mesenchymal Stem Cell Engraftment in the Normal Rat Brain

Bioluminescence: a versatile technique for imaging cellular and molecular features

Distinct In Vitro Properties of Embryonic and Extraembryonic Fibroblast-Like Cells are Reflected in their in Vivo Behavior following Grafting in the Adult Mouse Brain

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