Mesenchymal stem cells enhance microglia M2 polarization and attenuate neuroinflammation through TSG-6

Liu, Yi; Zeng, Rong; Wang, Yezhong; Huang, Wenhui; Hu, Bin; Zhu, Guohui; Zhang, Run; Li, Feng; Han, Jianbang; Li, Yongshi

doi:10.1016/j.brainres.2019.146422

Cited by 45 publications

(35 citation statements)

References 27 publications

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“…40 TSG-6 is shown to have various tissue-protective and anti-inflammatory properties and mediates many of the immunomodulatory and beneficial activities of mesenchymal stem/stromal cells. [41][42][43] IL-11 was shown to induce MSCs towards proliferation, migration and attenuation of apoptosis. 44 Overexpression of TGF-β1 in human synovium-derived MSCs enhanced their proliferation and chondrogenic differentiation potentials.…”

Section: Discussionmentioning

confidence: 98%

Comparative analysis of human induced pluripotent stem cell‐derived mesenchymal stem cells and umbilical cord mesenchymal stem cells

Rajasingh

Sigamani

Selvam

et al. 2021

J Cellular Molecular Medi

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Generation of induced pluripotent stem cells (iPSCs) and their differentiation into mesenchymal stem/stromal cells (iMSCs) have created exciting source of cells for autologous therapy. In this study, we have compared the therapeutic potential of iMSCs generated from urinary epithelial (UE) cells with the available umbilical cord MSCs (UC‐MSCs). For this, adult UE cells were treated with the mRNA of pluripotent genes (OCT4, NANOG, SOX2, KLF4, MYC and LIN28) and a cocktail of miRNAs under specific culture conditions for generating iPSCs. Our non‐viral and mRNA‐based treatment regimen demonstrated a high reprogramming efficiency to about 30% at passage 0. These UE‐iPSCs were successfully differentiated further into ectoderm, endoderm and mesoderm lineage of cells. Moreover, these UE‐iPSCs were subsequently differentiated into iMSCs and were compared with the UC‐MSCs. These iMSCs were capable of differentiating into osteocytes, chondrocytes and adipocytes. Our qRT‐PCR and Western blot data showed that the CD73, CD90 and CD105 gene transcripts and proteins were highly expressed in iMSCs and UC‐MSCs but not in other cells. The comparative qRT‐PCR data showed that the iMSCs maintained their MSC characteristics without any chromosomal abnormalities even at later passages (P15), during which the UC‐MSCs started losing their MSC characteristics. Importantly, the wound‐healing property demonstrated through migration assay was superior in iMSCs when compared to the UC‐MSCs. In this study, we have demonstrated an excellent non‐invasive and pain‐free method of obtaining iMSCs for regenerative therapy. These homogeneous autologous highly proliferative iMSCs may provide an alternative source of cells to UC‐MSCs for treating various diseases.

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Section: Discussionmentioning

confidence: 98%

Comparative analysis of human induced pluripotent stem cell‐derived mesenchymal stem cells and umbilical cord mesenchymal stem cells

Rajasingh

Sigamani

Selvam

et al. 2021

J Cellular Molecular Medi

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“…In particular, Mesenchymal stem cells (MSCs) are stem cells found in many adult tissues, including brain, (Appaix, 2014) and can differentiate into neurons (Pavlova et al, 2012;Zeng et al, 2015;Zhao et al, 2015) and glial cells (George et al, 2019) to replace damaged tissues (Dimarino et al, 2013), and thus promoting neuroprotection, regeneration and repair (Qu et al, 2008;Thomi et al, 2019). They have immunomodulatory properties, mitigating the inflammation related to stroke or neurological diseases (Feng et al, 2020;Liu et al, 2019;Salari et al, 2020). Interestingly, both mesenchyme-and immune-related modules display similar topological restructuring.…”

Section: Discussionmentioning

confidence: 99%

LSD induces increased signalling entropy in rats’ prefrontal cortex

Savino

Nichols

2021

Preprint

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Psychedelic drugs are gaining attention from the scientific community as potential new compounds for the treatment of psychiatric diseases such as mood and substance use disorders. The 5-HT2A receptor has been identified as the main molecular target, and early studies pointed to an effect on the expression of neuroplasticity genes. Analysing RNA-seq data from the prefrontal cortex of rats chronically treated with lysergic acid diethylamide (LSD), we describe the psychedelic-induced rewiring of gene co-expression networks, which become less centralized but more complex, with an overall increase in signalling entropy, typical of highly plastic systems. Intriguingly, signalling entropy mirrors, at the molecular level, the increased brain entropy reported through neuroimaging studies in human, suggesting the underlying mechanisms of higher-order phenomena. Moreover, from the analysis of network topology we identify potential transcriptional regulators and imply different cell types in psychedelics' activity.

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“…To investigate whether the presence of MSCs in the retinal explant co-culture model could exert immunomodulatory properties and in uence on microglial phenotypes, we analyzed microglial polarization markers through the mRNA expression of type M1 classically activated, namely TNFα, IL1β and IL6, and M2 alternatively activated, namely Arginase 1, IL10, CD163 and TNFAIP6 [15,20]. Our data showed that mRNA expression of M1 phenotype markers TNFα, and IL1β levels were signi cantly lower at DEV 7 in the MSC group compared to the control group (p<0.05 and p<0.001 respectively) ( g 6 A).…”

Section: Mscs Have An Immunomodulatory Effect On Retinal Explantsmentioning

confidence: 99%

“…It allows clearance of debris, restores tissue homeostasis, and promotes tissue repair by inhibiting in ammation through the production of anti-in ammatory, neurotrophic factors and chemokine receptors [14][15][16]18]. Several M2 phenotype markers characterize this M2 state, e.g the enzyme arginase 1 (ARG1), a marker of microglia involved in tissue repair and phagocytosis, the receptor CD163, a marker of microglia implicated in the anti-in ammatory process and healing, IL-10, an anti-in ammatory cytokine used by the M2 subtype to antagonize the pro-in ammatory phase and healing, and TNFα-stimulated gene-6 (TSG-6), which is a key anti-in ammatory factor produced by MSCs [19][20][21][22]. Reducing the proin ammatory M1 phenotype or inducing M2 microglial polarization might represent a potential and promising therapeutic option to treat neuroin ammatory degenerative diseases such as glaucoma [12,[23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Neuroprotective And Immunomodulatory Properties of Mesenchymal Stem Cells in An Ex-vivo Retinal Explant Model

Reboussin¹,

Buffault²,

Brignole‐Baudouin³

et al. 2021

Preprint

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Background: Mesenchymal stem cells (MSCs) have raised considerable hope for the treatment of glaucoma. Their neuroprotective and regenerative potentials are particularly interesting for this degenerative neuropathy in which retinal ganglion cell (RGC) death leads to a progressive loss of visual field and eventually vision. Yet, despite promising results in animal models, no definitive treatment has been developed, and safety concerns have been reported in human trials. Microglial immunomodulation represents a promising therapeutic approach in which MSCs might play a crucial role. In the present study, we investigated the neuroprotective and immunomodulatory properties as well as the safety of MSCs in an ex vivo neuroretina explant model.Methods: Labeled rat bone marrow MSCs were placed in co-culture with rat retinal explants after optic nerve axotomy. We analyzed the neuroprotective effect of MSCs on RGC survival by immunofluorescence using RBPMS, Brn3a and NeuN markers. Gliosis and retinal microglial activation were measured using GFAP, CD68 and ITGAM mRNA quantification and GFAP, CD68 and Iba1 immunofluorescence staining. We also analyzed the mRNA expression of both ‘M1’ or classically activated state inflammatory cytokines (TNFα, IL1β and IL6), and ‘M2’ or alternatively activated state microglial markers (Arginase 1, IL10, CD163, and TNFAIP6).Results: The number of RGCs was significantly higher in retinal explants cocultured with MSCs compared to the control group at Day 7 following optic nerve axotomy. Retinal explants co-cultured with MSCs showed decreased mRNA markers of gliosis and microglial activation, and immunostaining revealed that GFAP, Iba1 and CD68 were limited to the internal layers of the retina compared to controls showing expression of activated microglia throughout the retina. In addition, MSCs inhibited the M1 phenotype of the microglia. However, edema of the explants was observed in the MSC co-culture group, with an increase of fibronectin labelling at the surface of the explant corresponding to an epiretinal membrane-like phenotype. Conclusion: Using an ex vivo model, we demonstrated a neuroprotective and immunomodulatory effect of MSCs on RGCs. Unfortunately, the presence of MSCs also led to explant edema and epiretinal membrane formation, as described in human trials. Using the MSC secretome might offer the beneficial effects of MSCs without their potential adverse effects, through paracrine signaling.

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Mesenchymal stem cells enhance microglia M2 polarization and attenuate neuroinflammation through TSG-6

Cited by 45 publications

References 27 publications

Comparative analysis of human induced pluripotent stem cell‐derived mesenchymal stem cells and umbilical cord mesenchymal stem cells

Comparative analysis of human induced pluripotent stem cell‐derived mesenchymal stem cells and umbilical cord mesenchymal stem cells

LSD induces increased signalling entropy in rats’ prefrontal cortex

Evaluation of Neuroprotective And Immunomodulatory Properties of Mesenchymal Stem Cells in An Ex-vivo Retinal Explant Model

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