Unlocking the Secrets of Chimpanzee Naive Pluripotent Stem Cells: A Leap Forward in Developmental Biology
Understanding the intricate processes by which cells differentiate during the earliest stages of embryonic development holds immense promise for the fields of regenerative medicine and developmental biology. Pluripotent stem cells (PSCs), celebrated for their ability to give rise to any cell type within the body, have become indispensable instruments in this quest. However, ethical concerns and technical barriers have long impeded detailed studies into human and primate early development, leaving many questions about the nuances of pluripotency unanswered. Recently, a pioneering study out of Japan has shattered these limitations by successfully cultivating naive-type induced pluripotent stem cells derived from chimpanzee somatic cells, marking a transformative milestone for the scientific community.
Naive-type pluripotent stem cells represent a primordial developmental stage preceding the better-known “primed” PSCs. These naive PSCs are characterized by a more open chromatin structure and enhanced differentiation potential, embodying a cellular state reminiscent of the pre-implantation embryo. While naive PSCs derived from humans can uniquely differentiate into both embryonic tissues and extra-embryonic components such as the placenta and yolk sac, their mouse counterparts lack this extended potential, raising critical questions about evolutionary conservation. Does this broadened pluripotency indicate a primate-specific attribute, or is it a hallmark exclusive to humans? The investigation into chimpanzee PSCs sought to provide clarity to this molecular enigma, given the close genetic similarity between chimpanzees and humans.
Led by Associate Professor Hideki Masaki at the newly established Institute of Science Tokyo, the research team embarked on the ambitious challenge of reprogramming chimpanzee somatic cells into naive-type induced pluripotent stem cells. Published in Cell Stem Cell in early 2025, their work not only realized the long-sought culture of chimpanzee naive PSCs but also illustrated the conditions essential for their sustained self-renewal. One groundbreaking aspect of their protocol involved the targeted inhibition of Polycomb Repressive Complex 2 (PRC2), a key epigenetic modulator known to suppress gene expression patterns involved in cell fate determination. The strategic suppression of PRC2 proved critical; without it, naive PSC cultures failed to propagate beyond initial stages despite successful reprogramming efforts.
PRC2 functions as a dynamic regulator of gene accessibility by catalyzing trimethylation of histone H3 on lysine 27 (H3K27me3), a chromatin mark associated with transcriptional repression. By chemically inhibiting PRC2’s enzymatic activity, the researchers maintained an epigenetic landscape conducive to the expression of pluripotency genes and multilineage potential. This revelation underscores the importance of chromatin architecture modulation in stabilizing the naive state. It also suggests a conserved evolutionary role for PRC2 repression dynamics in shaping early embryonic cell potency across higher primates.
Genomic and transcriptomic analyses further revealed that chimpanzee naive PSCs exhibit molecular signatures highly congruent with human naive PSCs. The expression profiles indicated robust activation of core pluripotency networks such as OCT4, NANOG, and SOX2, coupled with markers indicative of early embryonic lineage commitment capability. Crucially, these cells demonstrated the capacity to differentiate into trophectoderm and hypoblast lineages, which are essential extra-embryonic tissues responsible for implantation and nutrient exchange in mammalian embryos. In generating tri-lineage blastoids—3D embryo-like structures encompassing epiblast, trophectoderm, and hypoblast cells—the team fashioned sophisticated models mimicking the earliest stages of development, thus opening unparalleled avenues for comparative embryology.
This successful blastoid formation from chimpanzee naive PSCs represents an unprecedented achievement. Blastoids are artificial constructs that recapitulate the cellular complexity and spatial organization of natural blastocysts, serving as ethically feasible model systems to study early human and non-human primate embryogenesis. The ability to generate these models in chimpanzees paves the way for investigating species-specific regulatory mechanisms governing implantation, lineage specification, and placentation, all of which have remained elusive due to limitations in accessing or ethically experimenting on human embryos.
Another significant technical advancement in the study was the development of a feeder-free culture system for chimpanzee naive PSCs. Conventionally, PSC cultures require the presence of feeder layers—usually mouse embryonic fibroblasts—to provide essential extracellular matrix components and paracrine signals facilitating cell growth and maintenance. However, such animal-derived feeder systems introduce complexity and potential contamination risks for translational applications in regenerative medicine. By leveraging PRC2 inhibitors, the research team circumvented the necessity of feeder cells, creating a defined culture environment that sustains naive PSC self-renewal over prolonged periods. This advance holds tremendous potential for generating clinically relevant stem cell lines free from xenogeneic influences.
The implications of these findings extend beyond laboratory methodology. The demonstration that chimpanzee naive PSCs share an expanded pluripotency capacity with humans provides compelling evidence for evolutionary conservation of early developmental features among great apes. This evolutionary insight allows researchers to better understand the molecular underpinnings that distinguish human development and disease susceptibility from other primates. Moreover, by refining blastoid technologies across species, the scientific community gains powerful tools to dissect embryogenesis, congenital disorders, and reproductive failures at a previously unapproachable resolution.
Importantly, this chimpanzee model offers a unique proxy for testing hypotheses related to human development, circumventing ethical limitations while preserving physiological relevance. The model can facilitate investigations into epigenetic reprogramming, lineage fate decisions, and species-specific developmental timing, equipping researchers with a comparative system to unravel the complexities of pluripotency regulation. Furthermore, insights gleaned from chimpanzee PSC biology might inform strategies to optimize human stem cell therapies, enhancing their safety and efficacy.
As the field looks forward, the long-term culturing system without feeders and the blastoid models usher in exciting possibilities. They could accelerate drug screening for reproductive health, serve as platforms to study viral infections during early pregnancy, and help elucidate mechanisms of early embryonic loss. Additionally, the refined control over epigenetic modulators like PRC2 may inspire novel interventions targeting chromatin remodeling pathways to promote tissue regeneration or counteract degenerative diseases.
Institute of Science Tokyo’s establishment in late 2024 marks a timely moment for these innovations. The institute, formed via the merger of Tokyo Medical and Dental University and Tokyo Institute of Technology, is dedicated to pushing scientific boundaries to improve human wellbeing. Under this new institutional umbrella, the team led by Masaki is poised to expand investigations into primate development, bringing together expertise from diverse disciplines and leveraging cutting-edge technologies.
In summary, this breakthrough study not only resolves a key question about the conservation of naive pluripotent states across closely related species but also delivers transformative experimental platforms with wide-ranging biomedical applications. By forging the first cultures of chimpanzee naive PSCs, enabling their self-renewal via PRC2 inhibition, and generating blastoid models in a feeder-free context, the research catapults the scientific community toward a deeper, more precise understanding of mammalian embryology. This work heralds a future where the mysteries of early life and species evolution are decoded with unprecedented clarity and where regenerative medicine’s promise moves closer to clinical reality.
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Subject of Research: Not applicable
Article Title: Inhibition of PRC2 enables self-renewal of blastoid-competent naive pluripotent stem cells from chimpanzee
News Publication Date: 26-Feb-2025
Web References: http://dx.doi.org/10.1016/j.stem.2025.02.002
References: Published in Cell Stem Cell, February 26, 2025
Image Credits: Institute of Science Tokyo
Keywords: Nonhuman primates, Animal research, Somatic cells, Tissue cultures, Stem cell research, Cultural evolution, Human development, Animal science, Social research, Animal models
Tags: breakthroughs in regenerative therapiescellular state of pre-implantation embryochimpanzee pluripotent stem cellsdevelopmental biology advancementsdifferentiation potential of stem cellsearly embryonic developmentethical concerns in stem cell researchevolutionary conservation in stem cellsinduced pluripotent stem cellsnaive pluripotent stem cellsprimate stem cell studiesregenerative medicine research