Blastocyst complementation: current progress and future directions in xenogeneic organogenesis

Abstract

The generation of organs derived from pluripotent stem cells can be achieved in vivo through the blastocyst complementation technique. This method is based on the introduction of pluripotent stem cells into organogenesis-disabled pre-implantation embryos, where environmental signals instruct donor cells to colonize the vacant niche and to develop into the missing organ. When applied interspecies, this approach has the potential to produce human organs in genetically engineered livestock, offering a promising solution to the global transplants’ shortage crisis. In this review, we summarize the current progress in blastocyst complementation research and highlight the key challenges that must be addressed to advance this field.

1. Introduction

Organ transplantation is the ultimate treatment for several end-stage organ diseases. However, organ availability is limited. In 2023, approximately 52,000 patients were waiting for an organ transplant in Europe, but only 27,952 transplants were performed [1]. Most of the wait-listed patients face suboptimal health conditions with waiting times ranging from 10 months for a liver transplant to 45 months for a kidney transplant [2]. These patients often require medical procedures that not only compromise their quality of life but also imply a significant economic burden, with the average yearly cost per patient awaiting a kidney transplantation estimated at €40,000 [3]. Artificial organ support like dialysis, artificial liver support systems or left ventricular assist devices are commonly used as a bridge to transplant, in combination with pharmacological treatments.

Nevertheless, these approaches currently offer only partial or temporary alternatives to organ transplantation, and many of these patients often deteriorate further and die while waiting for a suitable organ. On one hand, destination therapy with artificial organs is under study, and for example, mechanical total artificial hearts have been implanted in some cases in patients affected by heart failure who were not eligible for transplant. However, the quality of life for these patients is compromised by the size, biocompatibility and durability of these devices and so far, they only represent a temporary solution to support patient survival until organ transplantation is available [4]. Another approach under study to bridge the gap between organ supply and demand is the xenotransplantation of pig organs genetically modified to avoid graft rejection [5]. In a recent clinical trial of heart xenotransplantation under compassionate use, a pig heart with ten individual gene modifications supported a human patient’s life for 60 days [6]. Despite being a significant step forward, further refinement is needed before this approach becomes a viable option for clinical transplantation. On the other hand, tissue engineering research is engaged in generating transplantable organs in the laboratory. The decellularization-recellularization technique aims to use animals´ organ’s support structure, the extracellular matrix, as a 3D scaffold to be repopulated with human stromal and parenchymal cells. Although promising, this technique remains largely in the experimental phase, with several hurdles yet to be overcome, as reviewed in [7]. Moreover, 3D-printed scaffolds have been used to produce patches of bioartificial tissues. These have been tested for security and effectiveness in many preclinical studies [8] and also a few clinical studies [9], sometimes in combination with bioactive molecules. However, the complexity and size of the human organs have not been reproduced in vitro yet.

In contrast, with the blastocyst complementation (BC) approach, organ generation has been achieved in vivo, by taking advantage of the natural embryonic environment, allowing endogenous processes to guide organ development from exogenous PSCs. In BC, donor PSCs are introduced into an organogenesis-disabled embryo at the pre-implantation stage (early morula or blastocyst) so that during development they can colonize the empty organ niche, receive proper extrinsic signals, and differentiate into the missing organ.