Generation of vascular chimerism within donor organs

Shahar Cohen,Dmitry Azarov,Golan Shukrun,Eli Atar,Shirly Partouche,Moshe Israeli,Vered Yahalom,Benny Hovav,Eytan Mor,Avital Wertheimer,Ran Kornowski,Dorit Leshem-Lev,Michael Gurevich,Adi Borovich,Leor Perl,Arnon Wiznitzer,Ana Tobar,Sarit Soffer-Hirschberg,Vladimir Tennak,Hagit Niv-Drori,Chana Weiss,Meora Feinmesser,Vadym Mezhybovsky,Guy Cohen,Eviatar Nesher

doi:10.1038/s41598-021-92823-7

Abstract

Whole organ perfusion decellularization has been proposed as a promising method to generate non-immunogenic organs from allogeneic and xenogeneic donors. However, the ability to recellularize organ scaffolds with multiple patient-specific cells in a spatially controlled manner remains challenging. Here, we propose that replacing donor endothelial cells alone, while keeping the rest of the organ viable and functional, is more technically feasible, and may offer a significant shortcut in the efforts to engineer transplantable organs. Vascular decellularization was achieved ex vivo, under controlled machine perfusion conditions, in various rat and porcine organs, including the kidneys, liver, lungs, heart, aorta, hind limbs, and pancreas. In addition, vascular decellularization of selected organs was performed in situ, within the donor body, achieving better control over the perfusion process. Human placenta-derived endothelial progenitor cells (EPCs) were used as immunologically-acceptable human cells to repopulate the luminal surface of de-endothelialized aorta (in vitro), kidneys, lungs and hind limbs (ex vivo). This study provides evidence that artificially generating vascular chimerism is feasible and could potentially pave the way for crossing the immunological barrier to xenotransplantation, as well as reducing the immunological burden of allogeneic grafts.

Highlights

Whole organ perfusion decellularization has been proposed as a promising method to generate nonimmunogenic organs from allogeneic and xenogeneic donors
We first examined whether the vasculature of donor organs can be decellularized ex vivo, while preserving the remaining organ parenchyma viable and functional
Following the sodium dodecyl sulfate (SDS) treatment organs were washed with saline, and perfusion pressures returned to baseline

Summary

Introduction

Whole organ perfusion decellularization has been proposed as a promising method to generate nonimmunogenic organs from allogeneic and xenogeneic donors. Vascular decellularization was achieved ex vivo, under controlled machine perfusion conditions, in various rat and porcine organs, including the kidneys, liver, lungs, heart, aorta, hind limbs, and pancreas. Graft loss beyond the hyperacute phase still occurs Such a delayed form of acute rejection occurs over period of days to weeks and is characterized by endothelial cell activation and the development of thrombotic microangiopathy, with platelet aggregation and destruction of the m icrovasculature[7,8]. Donor endothelial cells play several key roles in transplant rejection, both as initiators, active participants, and targets of acute cellular- and antibody-mediated r ejection[9].

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Conclusion