Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation

Mordant, Pierre; Nakajima, Daisuke; Kalaf, R.; Iskender, Ilker; Maahs, Lucas; Behrens, P.; Coutinho, R.; Iyer, R.; Davies, John E.; Cypel, Marcelo; Liu, Mingyao; Waddell, Thomas K.; Keshavjee, Shaf

doi:10.1016/j.healun.2016.04.017

Cited by 88 publications

(101 citation statements)

References 40 publications

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“…In situ topical hypothermia via intrapleural instillation of cold saline slush is effective in preserving DCD lungs before transplant . EVLP perfusate delivery of stem cells, adenosine receptor antagonists, gene therapy, and plasmin have all been shown to be beneficial, as have intrabronchial delivery of surfactant and bronchodilators . Perfusate analysis in this study found elevations of proinflammatory cytokines corresponding to the level of DCD injury, suggesting an opportunity for targeted therapy or, at minimum, an assay for evaluating therapeutic efficacy of other adjunct interventions beyond organ‐level physiologic data.…”

Section: Discussionmentioning

confidence: 65%

“…There is growing experience with various methods of EVLP for preserving and evaluating DBD and DCD lungs, including those from ‘extended‐criteria' donors, which has generated interest in new EVLP‐based methods of allograft evaluation and reconditioning . Allograft evaluation using EVLP is predicated on an understanding of the value of physiologic data collected during EVLP in predicting post‐transplant allograft function.…”

Section: Introductionmentioning

confidence: 99%

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Lung transplant after prolonged ex vivo lung perfusion: predictors of allograft function in swine

et al. 2018

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Portable normothermic EVLP has been evaluated in clinical trials using standard and extended-criteria donor lungs. We describe a swine model of lung transplant following donation after circulatory death using prolonged normothermic EVLP to assess the relationship between EVLP data and acute lung allograft function. Adult swine were anesthetized and heparinized. In the control group (n = 4), lungs were procured, flushed, and transplanted. Treatment swine underwent either standard procurement (n = 3) or agonal hypoxia followed by 1 (n = 4) or 2 hours (H) (n = 4) of ventilated warm ischemia. Lungs were preserved for 24H using normothermic blood-based EVLP then transplanted. Recipients were monitored for 4 H. After 24H of preservation, mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and dynamic compliance (C ) were improved in all EVLP groups. After transplant, EVLP groups showed similar allograft oxygenation. EVLP PVR, mPAP, and lung block weights had significant negative correlations with post-transplant allograft oxygenation. EVLP P:F ratio did not correlate with acute post-transplant allograft function until 24H of preservation. Data measured in the first 8H of EVLP were sufficient for predicting acute post-transplant allograft function. This study provides a benchmark and platform for evaluation of therapies for donor-related allograft injury in injured lungs treated with prolonged normothermic EVLP.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Lung transplant after prolonged ex vivo lung perfusion: predictors of allograft function in swine

et al. 2018

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“…The current study comprises an important component of the preclinical assessment of the benefits and limitations of the HUCPVC cell source cultivated in chemically defined xeno‐ and serum‐free media. Accumulating preclinical evidence supports development of HUCPVCs, cultivated in chemically defined media, as therapeutics that can attenuate acute respiratory response syndrome and reduce inflammation with superior outcomes compared with bone marrow‐derived MSCs . In addition, intramuscularly implanted xeno‐ and serum‐free HUCPVCs persist in situ where they remain metabolically and secretorially active and have delocalized anti‐inflammatory benefits .…”

Section: Discussionmentioning

confidence: 99%

Accumulating Transcriptome Drift Precedes Cell Aging in Human Umbilical Cord-Derived Mesenchymal Stromal Cells Serially Cultured to Replicative Senescence

Wiese

Ruttan

Wood

et al. 2019

Stem Cells Translational Medicine

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In preclinical studies, mesenchymal stromal cells (MSCs) exhibit robust potential for numerous applications. To capitalize on these benefits, cell manufacturing and delivery protocols have been scaled up to facilitate clinical trials without adequately addressing the impact of these processes on cell utility nor inevitable regulatory requirements for consistency. Growing evidence indicates that culture‐aged MSCs, expanded to the limits of replicative exhaustion to generate human doses, are not equivalent to early passage cells, and their use may underpin reportedly underwhelming or inconsistent clinical outcomes. Here, we sought to define the maximum expansion boundaries for human umbilical cord‐derived MSCs, cultured in chemically defined xeno‐ and serum‐free media, that yield consistent cell batches comparable to early passage cells. Two male and two female donor populations, recovered from cryostorage at mean population doubling level (mPDL) 10, were serially cultivated until replicative exhaustion (senescence). At each passage, growth kinetics, cell morphology, and transcriptome profiles were analyzed. All MSC populations displayed comparable growth trajectories through passage 9 (P9; mPDL 45) and variably approached senescence after P10 (mPDL 49). Transcription profiles of 14,500 human genes, generated by microarray, revealed a nonlinear evolution of culture‐adapted MSCs. Significant expression changes occurred only after P5 (mPDL 27) and accumulated rapidly after P9 (mPDL 45), preceding other cell aging metrics. We report that cryobanked umbilical cord‐derived MSCs can be reliably expanded to clinical human doses by P4 (mPDL 23), before significant transcriptome drift, and thus represent a mesenchymal cell source suited for clinical translation of cellular therapies. Stem Cells Translational Medicine 2019;8:945&958

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“…However, many postconditioning therapies have the potential to reverse injury and further improve lung function on EVLP. These include intrabronchial delivery of surfactant and/or ß 2 ‐adrenergic receptor agonists, addition of mesenchymal stem cells or adenosine A2A receptor agonists to the perfusate, and the use of adenoviral vectors for gene therapy .…”

Section: Discussionmentioning

confidence: 99%

An experimental study of the recovery of injured porcine lungs with prolonged normothermic cellularex vivolung perfusion following donation after circulatory death

et al. 2017

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Donation after circulatory death (DCD) is an underused source of donor lungs. Normothermic cellular ex vivo lung perfusion (EVLP) is effective in preserving standard donor lungs but may also be useful in the preservation and assessment of DCD lungs. Using a model of DCD and prolonged EVLP, the effects of donor warm ischemia and postmortem ventilation on graft recovery were evaluated. Adult male swine underwent general anesthesia and heparinization. In the control group (n = 4), cardioplegic arrest was induced and the lungs were procured immediately. In the four treatment groups, a period of agonal hypoxia was followed by either 1 h of warm ischemia with (n = 4) or without (n = 4) ventilation or 2 h of warm ischemia with (n = 4) or without (n = 4) ventilation. All lungs were studied on an EVLP platform for 24 h. Hemodynamic measures, compliance, and oxygenation on EVLP were worse in all DCD lungs compared with controls. Hemodynamics and compliance normalized in all lungs after 24 h of EVLP, but DCD lungs demonstrated impaired oxygenation. Normothermic cellular EVLP is effective in preserving and monitoring of DCD lungs. Early donor postmortem ventilation and timely procurement lead to improved graft function.

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Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation

Cited by 88 publications

References 40 publications

Lung transplant after prolonged ex vivo lung perfusion: predictors of allograft function in swine

Lung transplant after prolonged ex vivo lung perfusion: predictors of allograft function in swine

Accumulating Transcriptome Drift Precedes Cell Aging in Human Umbilical Cord-Derived Mesenchymal Stromal Cells Serially Cultured to Replicative Senescence

An experimental study of the recovery of injured porcine lungs with prolonged normothermic cellularex vivolung perfusion following donation after circulatory death

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