Towards human organ generation using interspecies blastocyst complementation: Challenges and perspectives for therapy

Abstract

Millions of people suffer from end-stage refractory diseases. The ideal treatment option for terminally ill patients is organ transplantation. However, donor organs are in absolute shortage, and sadly, most patients die while waiting for a donor organ. To date, no technology has achieved long-term sustainable patient-derived organ generation. In this regard, emerging technologies of chimeric human organ production via blastocyst complementation (BC) holds great promise. To take human organ generation via BC and transplantation to the next step, we reviewed current emerging organ generation technologies and the associated efficiency of chimera formation in human cells from the standpoint of developmental biology.

Keywords: bioengineering; chimera; human organ generation; human pluripotent stem cell; interspecies blastocyst complementation; swine model; xenotransplantation.

FIGURE 1

Interspecies embryo incompatibilities and barriers in interspecies chimerism: (A) Interspecies zygotes cannot reprogram and fail to develop due to subcellular level incompatibilities (B) Cell competition eliminates less fit (donor) cells donor cells in host blastocyst (C) Stage-matching of donor cells is challenging and unknown factor contribute to apoptosis of donor cells (D) Recipient immune system reacts strongly against graft tissue/organ. Despite long-term immunosuppression, organ failure occurs.

FIGURE 2

Scenarios of organ transplantation derived from various swine models: Schematic: [(A), left] In BC, vacant organ niche formation by a niche-specific transgene depletion through genome editing is essential. [(A), right] Injection of human patient-derived (or MHC-matched human) iPS cells (green) into a blastocyst of a host animal with an organ failure phenotype. [(A), right, and (B)]. (A) Transplantation of human organs by BC is unlikely to fail because most cells are of human origin. Immunosuppression may be necessary if the porcine host origin remains in the graft component. (B) Organs transplanted from human-derived cells created in humanized pigs are assumed to function long-term in recipients with minimal or no immunosuppression because humanized pigs are designed to minimize immune rejection. Using humanized swine as host animals for the BC will work as a safety guard system for immune rejection.