A brief history of clinical xenotransplantation

Cooper, David K.C.; Ekser, Burçin; Tector, A. Joseph

doi:10.1016/j.ijsu.2015.06.060

Cited by 89 publications

(80 citation statements)

References 16 publications

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“…While xenotransfusions have been researched and performed clinically, to the authors’ knowledge, data specifically related to human plasma transfusion into mice recipients has not been reported (19). We believe it is important to study human plasma in rodent models as there are differences in plasma proteins and we are interested in understanding the mechanisms by which plasma is protective to the human endothelium.…”

Section: Discussionmentioning

confidence: 99%

Lack of species-specific difference in pulmonary function when using mouse versus human plasma in a mouse model of hemorrhagic shock

Peng

Pati

Fontaine

et al. 2016

Journal of Trauma and Acute Care Surgery

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Background Clinical studies have demonstrated that the early and empiric use of plasma improves survival after hemorrhagic shock. We have demonstrated in rodent models of hemorrhagic shock that resuscitation with plasma is protective to the lungs compared to lactated Ringers. As our long term objective is to determine the molecular mechanisms that modulate plasma’s protective effects in injured bleeding patients, we have used human plasma in a mouse model of hemorrhagic shock. The goal of the current experiments is to determine if there are significant adverse effects on lung injury when using human versus mouse plasma in an established murine model of hemorrhagic shock and laparotomy. Methods Mice underwent laparotomy and 90 minutes of hemorrhagic shock to a mean arterial pressure of 35±5 mm Hg followed by resuscitation at 1× shed blood using either mouse fresh frozen plasma (FFP), human fresh frozen plasma or human lyophilized plasma. Mean arterial pressure (MAP) was recorded during shock and for the first 30 minutes of resuscitation. After 3 hours, animals were euthanized and lungs collected for analysis. Results There was a significant increase in early MAP when mouse FFP was used to resuscitate animals compared to human FFP or human lyophilized plasma. However in spite of these differences, analysis of the mouse lungs revealed no significant differences in pulmonary histopathology, lung permeability or lung edema between all three plasma groups. Analysis of neutrophil infiltration in the lungs revealed that mouse FFP decreased neutrophil influx as measured by neutrophil staining, however myeloperoxidase immunostaining revealed no significant differences in between groups. Conclusions The study of human plasma in a mouse model of hemorrhagic shock is feasible, but does reveal some differences compared to mouse plasma-based resuscitation in physiologic measures such as MAPs post-resuscitation. Measures of end organ function such as lung injury appear to be comparable in this acute model of hemorrhagic shock and resuscitation.

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Section: Discussionmentioning

confidence: 99%

Lack of species-specific difference in pulmonary function when using mouse versus human plasma in a mouse model of hemorrhagic shock

Peng

Pati

Fontaine

et al. 2016

Journal of Trauma and Acute Care Surgery

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“…The concept of xenotransplantation is not new, and there have been numerous clinical attempts during the past 300 years or more [3]. Clinical blood xenotransfusion was attempted in the 17 th century by Jean Baptiste Denis, corneal xenotransplantation from pig-to-human followed in the early 19 th century, and attempts were made at nonhuman primate (NHP) kidney xenotransplantation in the 1960s by Reemtsma [3,4] and others [5].…”

Section: Introductionmentioning

confidence: 99%

“…Clinical blood xenotransfusion was attempted in the 17 th century by Jean Baptiste Denis, corneal xenotransplantation from pig-to-human followed in the early 19 th century, and attempts were made at nonhuman primate (NHP) kidney xenotransplantation in the 1960s by Reemtsma [3,4] and others [5]. The world experience in pig-to-NHP models of xenotransplantation (until 1997) was reviewed by Lambrigts et al [6], and a comprehensive review regarding progress in pig-to-NHP since then (1998–2013) was published in 2014 [7].…”

Section: Introductionmentioning

confidence: 99%

Xenotransplantation

Ekser

Li²,

Cooper³

2017

Current Opinion in Organ Transplantation

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Purpose of review To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future. Recent findings Starting from early 2000, with the introduction of Gal-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to nonGal antigens continue to be the hurdle to overcome. The production of genetically-engineered pigs was difficult requiring prolonged time. However, advances in gene editing, such as zinc finger nucleases, transcription activator-like effector nucleases, and most recently CRISPR technology made the production of genetically-engineered pigs easier and available to more researchers. Today, the survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation reached >900 days, >400 days, and >600 day, respectively. The availability of multiple-gene pigs (5 or 6 genetic modifications) and/or newer costimulation blockade agents significantly contributed to this success. Now, the field is getting ready for clinical trials with an international consensus. Summary Clinical trials in cellular or solid organ xenotransplantation are getting closer with convincing preclinical data from many centers. The next decade will show us new achievements and additional barriers in clinical xenotransplantation.

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“…The porcine liver has been suggested as a source of hepatocytes for bioartificial liver devices (Nicolas et al 2016) and xenografts for transplantation (Cooper et al 2015); however, these applications are controversial (Wang & Yang, 2012). Nevertheless, there is promising research on decellularized porcine hepatic lobes used for liver bioengineering (Hussein et al 2015) in which porcine tissue scaffolds are supposed to be recellularized by human hepatocytes (Wu et al 2015).…”

Section: Introduction Porcine Liver In Experimental Surgerymentioning

confidence: 99%

Stereological analysis of size and density of hepatocytes in the porcine liver

et al. 2016

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The porcine liver is frequently used as a large animal model for verification of surgical techniques, as well as experimental therapies. Often, a histological evaluation is required that include measurements of the size, nuclearity or density of hepatocytes. Our aims were to assess the mean number-weighted volume of hepatocytes, the numerical density of hepatocytes, and the fraction of binuclear hepatocytes (BnHEP) in the porcine liver, and compare the distribution of these parameters among hepatic lobes and macroscopic regions of interest (ROIs) with different positions related to the liver vasculature. Using disector and nucleator as design-based stereological methods, the morphometry of hepatocytes was quantified in seven healthy piglets. The samples were obtained from all six hepatic lobes and three ROIs (peripheral, paracaval and paraportal) within each lobe. Histological sections (thickness 16 μm) of formalin-fixed paraffin-embedded material were stained with the periodic acid-Schiff reaction to indicate the cell outlines and were assessed in a series of 3-μm-thick optical sections. The mean number-weighted volume of mononuclear hepatocytes (MnHEP) in all samples was 3670 ± 805 μm (mean ± SD). The mean number-weighted volume of BnHEP was 7050 ± 2550 μm . The fraction of BnHEP was 4 ± 2%. The numerical density of all hepatocytes was 146 997 ± 15 738 cells mm of liver parenchyma. The porcine hepatic lobes contained hepatocytes of a comparable size, nuclearity and density. No significant differences were identified between the lobes. The peripheral ROIs of the hepatic lobes contained the largest MnHEP with the smallest numerical density. The distribution of a larger MnHEP was correlated with a larger volume of BnHEP and a smaller numerical density of all hepatocytes. Practical recommendations for designing studies that involve stereological evaluations of the size, nuclearity and density of hepatocytes in porcine liver are provided.

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A brief history of clinical xenotransplantation

Cited by 89 publications

References 16 publications

Lack of species-specific difference in pulmonary function when using mouse versus human plasma in a mouse model of hemorrhagic shock

Lack of species-specific difference in pulmonary function when using mouse versus human plasma in a mouse model of hemorrhagic shock

Xenotransplantation

Stereological analysis of size and density of hepatocytes in the porcine liver

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