Running the full human developmental clock in interspecies chimeras using alternative human stem cells with expanded embryonic potential

Abstract

Human pluripotent stem cells (hPSCs) can generate specialized cell lineages that have great potential for regenerative therapies and disease modeling. However, the developmental stage of the lineages generated from conventional hPSC cultures in vitro are embryonic in phenotype, and may not possess the cellular maturity necessary for corrective regenerative function in vivo in adult recipients. Here, we present the scientific evidence for how adult human tissues could generate human–animal interspecific chimeras to solve this problem. First, we review the phenotypes of the embryonic lineages differentiated from conventional hPSC in vitro and through organoid technologies and compare their functional relevance to the tissues generated during normal human in utero fetal and adult development. We hypothesize that the developmental incongruence of embryo-stage hPSC-differentiated cells transplanted into a recipient adult host niche is an important mechanism ultimately limiting their utility in cell therapies and adult disease modeling. We propose that this developmental obstacle can be overcome with optimized interspecies chimeras that permit the generation of adult-staged, patient-specific whole organs within animal hosts with human-compatible gestational time-frames. We suggest that achieving this goal may ultimately have to await the derivation of alternative, primitive totipotent-like stem cells with improved embryonic chimera capacities. We review the scientific challenges of deriving alternative human stem cell states with expanded embryonic potential, outline a path forward for conducting this emerging research with appropriate ethical and regulatory oversight, and defend the case of why current federal funding restrictions on this important category of biomedical research should be liberalized.

Nature of epigenetic aging from a single-cell perspective

“…1a). Similar life-course staging can be applied to humans [37][38][39] . Development, especially early development, is known to be a tightly regulated, programmed process, even if molecular aging already exists there 40 .…”

Generation of human-pig chimeric renal organoids using iPSC technology

“…2d). This suggests that, not only cell survival rates but also the regulation of differentiation direction, as well as the synchronization of developmental stages between mice and humans as previously discussed[39,40], may be important factors for chimera formation. Further research, considering differences among animal species, is anticipated to shed more light on this matter.…”

In Vivo CaV3 Channel Inhibition Promotes Maturation of Glucose-Dependent Ca2+ Signaling in Human iPSC-Islets

“…During normal in vivo development, β cell Ca V 3 channels ontogenetically change under the strict control of complex developmental clocks that result from the integration of genetically encoded programs with intrinsic and extrinsic cues [ 15 , 24 , 25 , 26 , 44 , 45 , 46 , 47 ]. This ontogenetic event is species-dependent [ 12 , 13 , 15 , 24 , 25 , 26 ].…”