Mesenchymal Stem Cells Regulate Blood-Brain Barrier Integrity Through TIMP3 Release After Traumatic Brain Injury

Menge, Tyler; Zhao, Yuhai; Zhao, Jing; Wataha, Kathryn; Gerber, M.; Jian-hu, Zhang; Letourneau, Phillip A.; Redell, John B.; Шен, Ли; Wang, Jing; Peng, Zhalong; Xue, Hasen; Kozar, Rosemary A.; Cox, Charles S.; Khakoo, Aarif Y.; Holcomb, John B.; Dash, Pramod K.; Pati, Shibani

doi:10.1126/scitranslmed.3004660

Cited by 138 publications

(127 citation statements)

References 30 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…22 In swine, plasma resuscitation versus crystalloid decreases the contusion volume in a model of severe traumatic brain injury, while in mice, tissue inhibitor of metalloproteinases-3 (TIMP3) and mesenchymal stem cells have the same effect. [23][24][25] Why does plasma reverse the systemic EC defect associated with injury? We are not sure.…”

mentioning

confidence: 99%

Optimal trauma resuscitation with plasma as the primary resuscitative fluid: the surgeon's perspective

Holcomb¹,

2013

Self Cite

View full text Add to dashboard Cite

Over the past century, blood banking and transfusion practices have moved from whole blood therapy to components. In trauma patients, the shift to component therapy was achieved without clinically validating which patients needed which blood products. Over the past 4 decades, this lack of clinical validation has led to uncertainty on how to optimally use blood products and has likely resulted in both overuse and underuse in injured patients. However, recent data from both US military operations and civilian trauma centers have shown a survival advantage with a balanced transfusion ratio of RBCs, plasma, and platelets. This has been extended to include the prehospital arena, where thawed plasma, RBCs, and antifibrinolytics are becoming more widely used. The Texas Trauma Institute in Houston has followed this progression by putting RBCs and thawed plasma in the emergency department and liquid plasma and RBCs on helicopters, transfusing platelets earlier, and using thromboelastogram-guided approaches. These changes have not only resulted in improved outcomes, but have also decreased inflammatory complications, operations, and overall use of blood products. In addition, studies have shown that resuscitating with plasma (instead of crystalloid) repairs the "endotheliopathy of trauma," or the systemic endothelial injury and dysfunction that lead to coagulation disturbances and inflammation. Data from the Trauma Outcomes Group, the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, and the ongoing Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial represent a decade-long effort to programmatically determine optimal resuscitation practices, balancing risk versus benefits. With injury as the leading cause of death in patients age 1 to 44 years and hemorrhage the leading cause of potentially preventable death in this group, high-quality data must be obtained to provide superior care to the civilian and combat injured.

show abstract

“…We visualized the signals using enhanced chemiluminescence (ECL Prime; GE Healthcare Bio-Sciences, Pittsburgh, PA, USA) before exposure to autoradiographic film (Phenix, Candler, NC, USA). We detected pro-MMP-2, cleaved-MMP-2, MMP-8, MMP-13, TIMP-1, TIMP-2, TIMP-3, TIMP-4, β-actin, and vinculin bands at 72,64,53,54,26,24,26,25,42, and 117 kDa, respectively. Omission of the primary antibodies eliminated the chemiluminescent signals, thereby establishing the specificity of the primary antibodies to detect the specific protein bands.…”

Section: Western Immunoblotmentioning

confidence: 95%

Ischemic-Reperfusion Injury Increases Matrix Metalloproteinases and Tissue Metalloproteinase Inhibitors in Fetal Sheep Brain

Chen¹,

Patra²,

Sadowska³

et al. 2018

Dev Neurosci

View full text Add to dashboard Cite

Hypoxic-ischemic brain injury is a leading cause of neurodevelopmental morbidities in preterm and full-term infants. Blood-brain barrier dysfunction represents an important component of perinatal hypoxic-ischemic brain injury. The extracellular matrix (ECM) is a vital component of the blood-brain barrier. Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are important ECM components. They contribute to brain development, blood-brain barrier maintenance, and to regenerative and repair processes after hypoxic-ischemic brain injury. We hypothesized that ischemia at different durations of reperfusion affects the ECM protein composition of MMPs and TIMPs in the cerebral cortex of fetal sheep. Cerebral cortical samples were snap-frozen from sham control fetuses at 127 days of gestation and from fetuses after exposure to 30-min carotid occlusion and 4-, 24-, and 48-h of reperfusion. Protein expression of MMP-2, -8, -9, and -13 and TIMP-1, -2, -3, and -4 was measured by Western immunoblotting along with the gelatinolytic activity of MMP-2 and MMP-9 by zymography. The expression of MMP-8 was increased (Kruskal-Wallis, p = 0.04) in fetuses 48 h after ischemia. In contrast, changes were not observed in the protein expression of MMP-2, -9, or -13. The gelatinolytic activity of pro-MMP-2 was increased (ANOVA, p = 0.02, Tukey HSD, p = 0.05) 24 h after ischemia. TIMP-1 and -3 expression levels were also higher (TIMP-1, ANOVA, p = 0.003, Tukey HSD, p = 0.01; TIMP-3, ANOVA, p = 0.006, Tukey HSD, p = 0.01) 24 h after ischemia compared with both the sham controls and with fetuses exposed to 4 h of reperfusion. The changes in the expression of TIMP-1, -2, and -3 correlated with the changes in the MMP-8 and -13 protein expression. We speculate that regulation of MMP-8, MMP-13, and TIMPs contributes to ECM remodeling after is chemic-reperfusion injury in the fetal brain.

show abstract

Mesenchymal Stem Cells Regulate Blood-Brain Barrier Integrity Through TIMP3 Release After Traumatic Brain Injury

Cited by 138 publications

References 30 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

Optimal trauma resuscitation with plasma as the primary resuscitative fluid: the surgeon's perspective

Ischemic-Reperfusion Injury Increases Matrix Metalloproteinases and Tissue Metalloproteinase Inhibitors in Fetal Sheep Brain

Contact Info

Product

Resources

About