Administration of TSG-6 improves memory after traumatic brain injury in mice

Watanabe, Jun; Shetty, Ashok K.; Hattiangady, Bharathi; Kim, Yon Su; Foraker, Jessica; Nishida, Hidetaka; Prockop, Darwin J.

doi:10.1016/j.nbd.2013.06.017

Cited by 90 publications

(75 citation statements)

References 63 publications

(98 reference statements)

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“…Early intravenous delivery of MSC attenuates injury by regulating inflammation in SCI [43] and traumatic brain injury (TBI) [44][45][46]. Additionally, MSC transplantation can reduce the levels of proinflammatory cytokines, such as TNF-α and IL-1 [11,47], and inhibit NFκB signaling [12,48,49].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Wang

Pei

Liang

et al. 2018

Cell Physiol Biochem

161

119

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Background/Aims: Neurotoxic A1 astrocytes are induced by inflammation after spinal cord injury (SCI), and the inflammation-related Nuclear Factor Kappa B (NFκB) pathway may be related to A1-astrocyte activation. Mesenchymal stem cell (MSC) transplantation is a promising therapy for SCI, where transplanted MSCs exhibit anti-inflammatory effects by downregulating proinflammatory factors, such as Tumor Necrosis Factor (TNF)-α and NFκB. MSC-exosomes (MSC-exo) reportedly mimic the beneficial effects of MSCs. Therefore, in this study, we investigated whether MSCs and MSC-exo exert inhibitory effects on A1 astrocytes and are beneficial for recovery after SCI. Methods: The effects of MSC and MSC-exo on SCIinduced A1 astrocytes, and the potential mechanisms were investigated in vitro and in vivo using immunofluorescence and western blot. In addition, we assessed the histopathology, levels of proinflammatory cytokines and locomotor function to verify the effects of MSC and MSC-exo on SCI rats. Results: MSC or MSC-exo co-culture reduced the proportion of SCIinduced A1 astrocytes. Intravenously-injected MSC or MSC-exo after SCI significantly reduced the proportion of A1 astrocytes, the percentage of p65 positive nuclei in astrocytes, and the percentage of TUNEL-positive cells in the ventral horn. Additionally, we observed decreased lesion area and expression of TNFα, Interleukin (IL)-1α and IL-1β, elevated expression of Myelin Basic Protein (MBP), Synaptophysin (Syn) and Neuronal Nuclei (NeuN), and improved Basso, Beattie & Bresnahan (BBB) scores and inclined-plane-test angle. In vitro assay showed that MSC and MSC-exo reduced SCI-induced A1 astrocytes, probably via inhibiting the nuclear translocation of the NFκB p65. Conclusion: MSC and MSC-exo reduce SCI-induced A1 astrocytes, probably via inhibiting nuclear translocation of NFκB p65, and exert antiinflammatory and neuroprotective effects following SCI, with the therapeutic effect of MSCexo comparable with that of MSCs when applied intravenously.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Wang

Pei

Liang

et al. 2018

Cell Physiol Biochem

161

119

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“…Numerous preclinical studies demonstrate the efficacy of mesenchymal stromal cells in TBI. When infused intravenously, bone marrow derived cells (either allogeneic or autologous) seem to have similar mechanism of action and similar efficacy dampening the innate immune response to injury.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells

et al. 2016

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Background Numerous pre-clinical studies using bone marrow derived cells for the treatment of traumatic brain injury and stroke have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and other functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe TBI demonstrated safety and potentially a CNS structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and potential treatment effect size of structural preservation/inflammatory biomarker mitigation in adults to guide Phase 2 clinical trial design. Methods Adults (aged 18-55) with severe traumatic brain injury (GCS 5-8) and without signs of serious other injury or irreversible brain injury (see Table 1) were evaluated for entry into the trial. A dose escalation format was performed in 25 patients: 5 controls, followed 5 patients in each dosing cohort (6,9,12 ×106 cells/kg body weight), then 5 more controls. Bone marrow harvest, cell processing to isolate the mononuclear fraction, and re-infusion occurred within 48 hours after injury. Patients were monitored for harvest/infusion related hemodynamic changes, infusional toxicity, and adverse events. Outcome measures included MRI based measurements of supratentorial and corpus callosal volumes as well as DTI based measurements of fractional anisotropy and mean diffusivity of the corpus callosum and the corticospinal tract at the level of the brainstem at 1 month and 6 months post-injury. Functional and neurocognitive outcomes were measured and correlated with imaging data. Inflammatory cytokine arrays were measured in the plasma pre-treatment, post-treatment, and at 1 and 6 month follow-up. Results There were no serious adverse events related to harvest/infusion. There was a mild pulmonary toxicity of the highest dose that was not clinically significant. Despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest that correlated with functional outcomes. Key inflammatory cytokines were down-regulated after BMMNC infusion. Conclusions Treatment of severe, adult traumatic brain injury using an intravenously delivered autologous bone marrow mononuclear cell infusion is safe and logistically feasible. There appears to be a treatment signal as evidenced by CNS structural preservation, consistent with previous pediatric trial data. Inflammatory biomarkers are down-regulated after cell infusion. A Phase 2, prospective, randomized trial excluding the highest dose is warranted and can be powered based upon structural outcome variables.

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“…Recently, observations by our group and others identified TSG-6 as being responsible for the beneficial effects of MSCs in the treatment of disease models of the heart (4), cornea (5,19,32), brain (33), lung (34), and pancreas (35). TSG-6 exerts its antiinflammatory actions through multiple mechanisms, one of which is the modulation of myeloid cells into a tolerogenic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

Lee

Jeong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

109

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Intravenously administered mesenchymal stem/stromal cells (MSCs) engraft only transiently in recipients, but confer long-term therapeutic benefits in patients with immune disorders. This suggests that MSCs induce immune tolerance by long-lasting effects on the recipient immune regulatory system. Here, we demonstrate that i.v. infusion of MSCs preconditioned lung monocytes/macrophages toward an immune regulatory phenotype in a TNF-α-stimulated gene/protein (TSG)-6-dependent manner. As a result, mice were protected against subsequent immune challenge in two models of alloand autoimmune ocular inflammation: corneal allotransplantation and experimental autoimmune uveitis (EAU). The monocytes/macrophages primed by MSCs expressed high levels of MHC class II, B220, CD11b, and IL-10, and exhibited T-cell-suppressive activities independently of FoxP3 + regulatory T cells. Adoptive transfer of MSCinduced B220 + CD11b + monocytes/macrophages prevented corneal allograft rejection and EAU. Deletion of monocytes/macrophages abrogated the MSC-induced tolerance. However, MSCs with TSG-6 knockdown did not induce MHC II + B220 + CD11b + cells, and failed to attenuate EAU. Therefore, the results demonstrate a mechanism of the MSC-mediated immune modulation through induction of innate immune tolerance that involves monocytes/macrophages. corneal allotransplantation | experimental autoimmune uveitis | immune tolerance | mesenchymal stem/stromal cell | monocyte/macrophage

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Administration of TSG-6 improves memory after traumatic brain injury in mice

Cited by 90 publications

References 63 publications

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

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