Effect of Mesenchymal Precursor Cells on the Systemic Inflammatory Response and Endothelial Dysfunction in an Ovine Model of Collagen-Induced Arthritis

Dooley, Laura; Abdalmula, Anwar; Washington, Elizabeth A.; Kaufman, Claire; Tudor, Elizabeth; Ghosh, Peter; Itescu, Silviu; Kimpton, Wayne G.; Bailey, S. R.

doi:10.1371/journal.pone.0124144

Cited by 26 publications

(15 citation statements)

References 78 publications

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“…Arthritic sheep were randomized to intravenous treatment with either 150 million allogeneic MPCs or placebo on day 1 after arthritis induction. 70 The most striking effect of MPC treatment on plasma cytokine levels was in the response of anti-inflammatory IL-10. Plasma levels of IL-10 spiked significantly in sheep treated with MPCs one day after cell treatment with a mean concentration of over 600 ng/mL in the MPC-treated sheep compared with 100 ng/mL in control animals suggesting activation of either a significant number of anti-inflammatory M2 macrophages or polarization of proinflammatory macrophages (M1) into anti-inflammatory macrophages (M2).…”

Section: Mpcs In Advanced Chronic Hfref Patients: Is There Biologic Pmentioning

confidence: 99%

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Borow

Yaroshinsky

Greenberg

et al. 2019

Circulation Research

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Advanced heart failure (HF) is a progressive disease characterized by recurrent hospitalizations and high risk of mortality. Indeed, outcomes in late stages of HF approximate those seen in patients with various aggressive malignancies. Clinical trials assessing beneficial outcomes of new treatments in patients with cancer have used innovative approaches to measure impact on total disease burden or surrogates to assess treatment efficacy. Although most cardiovascular outcomes trials continue to use time-to-first event analyses to assess the primary efficacy end point, such analyses do not adequately reflect the impact of new treatments on the totality of the chronic disease burden. Consequently, patient enrichment and other strategies for ongoing clinical trial design, as well as new statistical methodologies, are important considerations, particularly when studying a population with advanced chronic HF. The DREAM-HF trial (Double-Blind Randomized Assessment of Clinical Events With Allogeneic Mesenchymal Precursor Cells in Advanced Heart Failure) is an ongoing, randomized, sham-controlled phase 3 study of the efficacy and safety of mesenchymal precursor cells as immunotherapy in patients with advanced chronic HF with reduced ejection fraction. Mesenchymal precursor cells have a unique multimodal mechanism of action that is believed to result in polarization of proinflammatory type 1 macrophages in the heart to an anti-inflammatory type 2 macrophage state, inhibition of maladaptive adverse left ventricular remodeling, reversal of cardiac and peripheral endothelial dysfunction, and recovery of deranged vasculature. The objective of DREAM-HF is to confirm earlier phase 2 results and evaluate whether mesenchymal precursor cells will reduce the rate of nonfatal recurrent HF-related major adverse cardiac events while delaying or preventing progression of HF to terminal cardiac events. DREAM-HF is an example of an ongoing contemporary events-driven cardiovascular cell–based immunotherapy study that has utilized the concepts of baseline disease enrichment, prognostic enrichment, and predictive enrichment to improve its efficiency by using accumulating data from within as well as external to the trial. Adaptive enrichment designs and strategies are important components of a rational approach to achieve clinical research objectives in shorter clinical trial timelines and with increased cost-effectiveness without compromising ethical standards or the overall statistical integrity of the study. The DREAM-HF trial also presents an alternative approach to traditional composite time-to-first event primary efficacy end points. Statistical methodologies such as the joint frailty model provide opportunities to expand the scope of events-driven HF with reduced ejection fraction clinical trials to utilize time to recurrent nonfatal HF-related major adverse cardiac events as the primary efficacy end point without compromising the integrity of the statistical analyses for terminal cardiac events. In advanced chronic HF...

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Section: Mpcs In Advanced Chronic Hfref Patients: Is There Biologic Pmentioning

confidence: 99%

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Borow

Yaroshinsky

Greenberg

et al. 2019

Circulation Research

View full text Add to dashboard Cite

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“…The concentration of IL-6, IL-1β, IL-8, IL-10 and TNF-α in lung tissue homogenate and BAL fluid was quantified by in-house ELISAs using methods published previously [ 25 – 27 ]. Positive internal controls were used to ensure that inter- and intra- plate variability was < 10%, and confirm the precision and accuracy of all ELISA assays.…”

Section: Methodsmentioning

confidence: 99%

Inflammation and lung injury in an ovine model of fluid resuscitated endotoxemic shock

et al. 2018

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BackgroundSepsis is a multi-system syndrome that remains the leading cause of mortality and critical illness worldwide, with hemodynamic support being one of the cornerstones of the acute management of sepsis. We used an ovine model of endotoxemic shock to determine if 0.9% saline resuscitation contributes to lung inflammation and injury in acute respiratory distress syndrome, which is a common complication of sepsis, and investigated the potential role of matrix metalloproteinases in this process.MethodsEndotoxemic shock was induced in sheep by administration of an escalating dose of lipopolysaccharide, after which they subsequently received either no fluid bolus resuscitation or a 0.9% saline bolus. Lung tissue, bronchoalveolar fluid (BAL) and plasma were analysed by real-time PCR, ELISA, flow cytometry and immunohistochemical staining to assess inflammatory cells, cytokines, hyaluronan and matrix metalloproteinases.ResultsEndotoxemia was associated with decreased serum albumin and total protein levels, with activated neutrophils, while the glycocalyx glycosaminoglycan hyaluronan was significantly increased in BAL. Quantitative real-time PCR studies showed higher expression of IL-6 and IL-8 with saline resuscitation but no difference in matrix metalloproteinase expression. BAL and tissue homogenate levels of IL-6, IL-8 and IL-1β were elevated.ConclusionsThis data shows that the inflammatory response is enhanced when a host with endotoxemia is resuscitated with saline, with a comparatively higher release of inflammatory cytokines and endothelial/glycocalyx damage, but no change in matrix metalloproteinase levels.

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“…While this plasticity highlights that MPC can directly contribute to tissue and organ repair, the reparative properties of these cells have been ascribed largely to their secretion of paracrine factors that attenuate cell death, promote cell proliferation and stimulate endogenous tissue repair [7][8][9][10][11]. In addition to their reparative properties, other therapeutic benefits of MPC can be attributed to their immuno-modulatory properties, where MPC suppress/regulate immune/inflammatory responses, which underlie various chronic pathologies [12][13][14]. The clinical use of prospectively isolated MPC represents an emerging paradigm for the treatment of various orthopedic [15,16], cardiovascular [17][18][19][20], hematological [10,11,21], and neurological [22,23] indications.…”

Section: Introductionmentioning

confidence: 99%

The Mesenchymal Precursor Cell Marker Antibody STRO-1 Binds to Cell Surface Heat Shock Cognate 70

et al. 2017

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Since its discovery more than 25 years ago, the STRO-1 antibody has played a fundamental role in defining the hierarchical nature of mesenchymal precursor cells (MPC) and their progeny. STRO-1 antibody binding remains a hallmark of immature pluripotent MPC. Despite the significance of STRO-1 in the MPC field, the identity of the antigen has remained elusive. Using a combination of two-dimensional gel electrophoresis, coupled with Western blotting and Tandem mass spectroscopy, we have identified the STRO-1 antigen as heat shock cognate 70 (HSC70;HSPA8). STRO-1 binds to immune-precipitated HSC70 and siRNA-mediated knock down of HSPA8 reduced STRO-1 binding. STRO-1 surface binding does not correlate with HSC70 expression and sequestration of cholesterol reduces STRO-1 surface binding, suggesting that the plasma membrane lipid composition may be an important determinant in the presentation of HSC70 on the cell surface. HSC70 is present on the surface of STRO-1 but not STRO-1 cell lines as assessed by cell surface biotinylation and recombinant HSC70 blocks STRO-1 binding to the cell surface. The STRO-1 epitope on HSC70 was mapped to the ATPase domain using a series of deletion mutants in combination with peptide arrays. Deletion of the first four amino acids of the consensus epitope negated STRO-1 binding. Notably, in addition to HSC70, STRO-1 cross-reacts with heat shock protein 70 (HSP70), however all the clonogenic cell activity is restricted to the STRO-1 /HSP70 fraction. These results provide important insight into the properties that define multipotent MPC and provide the impetus to explore the role of cell surface HSC70 in MPC biology. Stem Cells 2017;35:940-951.

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Effect of Mesenchymal Precursor Cells on the Systemic Inflammatory Response and Endothelial Dysfunction in an Ovine Model of Collagen-Induced Arthritis

Cited by 26 publications

References 78 publications

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure

Inflammation and lung injury in an ovine model of fluid resuscitated endotoxemic shock

The Mesenchymal Precursor Cell Marker Antibody STRO-1 Binds to Cell Surface Heat Shock Cognate 70

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