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.

Generation of salivary glands derived from pluripotent stem cells via conditional blastocyst complementation

“…Together, our study has demonstrated the Foxa2 lineage as a critical lineage for salivary gland primordial formation and for generating fully matured, whole salivary glands via CBC, which will serve as a crucial experimental basis for future interspecies blastocyst complementation using human iPSC 43–45 .…”

Generation of human-pig chimeric renal organoids using iPSC technology

“…1a). For the reaggregation medium and the maturation medium during chimeric kidney organoid formation, we selected previously employed media for differentiation and maturation of NPCs, specifically "NPC_Re-agg" medium for the reaggregation medium, and "NPC_Mat" medium and "KR5_Mat" medium [15,16] for the maturation medium [26][27][28][29] (Fig. 1a).…”

“…Interspecies chimeric organogenesis by injecting human iPSC-derived cells into developing organs of interspecies animals is envisioned as a promising approach to address these challenges in organ production [15,16]. Indeed, in our previous studies, we achieved the creation of heterologous, including human, chimeric kidneys by utilizing the prenatal kidney development environment of a different species [16,17].…”

Chimeric Livers: Interspecies Blastocyst Complementation and Xenotransplantation for End-Stage Liver Disease

“…[73][74][75][76] When compared to other contemporary methods for organ regeneration, such as the previously discussed implementation of PHH transplantation for ESLD, blastocyst complementation has the benefit of requiring remarkably few PSCs, and most of the inductive cues required for hepatogenesis are already present within the developing blastocyst. [77][78][79] In reference to blastocyst complementation for hepatogenesis, genetic modification of the recipient species' blastocysts occurs such that key gene(s), such as the aforementioned Hhex, required for hepatogenesis and liver bud development are knocked out, and subsequently complemented with a microinjection of PSCs from the donor species -often ESCs or iPSCs (Figure 2). Following this, the complemented blastocysts are then directly implanted into the uterus of a pseudo-pregnant animal of the recipient species.…”

“…Nevertheless, as previously discussed, the chimeric liver, regardless of whether patient-derived cells were used for complementation, still receives much of its vascular development from recipient-derived cells and therefore, immunosuppressive therapy may still be required for proper function of the chimeric organ. 77 It is also pertinent to discuss the potential that chimeric livers have for the treatment of ESLD outside of xenotransplantation. As example, innovative drugs and therapies could be applied to human-pig chimeric livers to assess efficacy before clinical studies.…”