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Embryonic diapause
Embryonic diapause
Embryonic diapause
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Animal dormancy

Embryonic diapause[a] (delayed implantation in mammals) is a reproductive strategy used by a number of animal species across different biological classes. In more than 130 types of mammals where this takes place, the process occurs at the blastocyst stage of embryonic development,[1] and is characterized by a dramatic reduction or complete cessation of mitotic activity, arresting most often in the G0 or G1 phase of division.[2]

In placental embryonic diapause, the blastocyst does not immediately implant in the uterus after sexual reproduction has resulted in the zygote, but rather remains in this non-dividing state of dormancy until conditions allow for attachment to the uterine wall to proceed as normal.[3] As a result, the normal gestation period is extended for a species-specific time.[4][5]

Diapause provides a survival advantage to offspring, because birth or emergence of young can be timed to coincide with the most hospitable conditions, regardless of when mating occurs or length of gestation; any such gain in survival rates of progeny confers an evolutionary advantage.

Evolutionary significance

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Organisms which undergo embryonic diapause are able to synchronize the birth of offspring to the most favorable conditions for reproductive success, irrespective of when mating took place.[3] Many different factors can induce embryonic diapause, such as the time of year, temperature, lactation and supply of food.[3]

Embryonic diapause is a relatively widespread phenomenon outside of mammals, with known occurrence in the reproductive cycles of many insects, nematodes, fish, and other non-mammalian vertebrates.[6] It has been observed in approximately 130 mammalian species,[7] which is less than two percent of all species of mammals.[8] These include certain pinnipeds,[9] rodents, bears, armadillos, mustelids (e.g. weasels and badgers), and marsupials (e.g. kangaroos). Some groups only have one species that undergoes embryonic diapause, such as the roe deer in the order Artiodactyla.[5][10]

Experimental induction of embryonic discontinuous development within species which do not spontaneously undergo embryonic diapause in nature has been achieved; reversible developmental arrest was successfully demonstrated. This may be evidence for the evolutionary significance of this phenomenon, with latent capacity for diapause potentially present in a much wider segment of species than known to occur naturally.[8][11]

General mechanism

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Organisms which can stop their cellular division (embryonic diapause) can prevent an embryo from growing. Non-ideal reproductive conditions are what initiate this process, as delaying embryo maturation promotes survival of offspring and the parent.

Placental embryonic diapause in particular is an essential component of developmental progression in these species. This cessation is led by the intentional failure of the blastocyst to implant the uterine wall.[12] Hormones relating to the failed implantation also contribute to the embryonic arrest.[11] Once the embryo exits diapause arrest and resumes regular development, no adverse effects have been observed.[13]

Regulation of the cell cycle as it relates to embryonic diapause has been linked to the dacapo gene in the fruit fly. This gene inhibits the formation of Cyclin E/Cdk2 complexes, which is necessary for DNA synthesis. Another known regulator of the cell cycle, the B cell translocation gene 1 BTG1, has shown upregulation in mouse embryos during diapause, responsible for inhibiting transition from G0/G1 (G0 phase, G1 phase). Inversely, other studies have demonstrated that common regulators of the cell cycle lack involvement, such as P53, within the placental model of embryonic diapause.[2] While molecular regulation that activates dormant blastocysts has been characterized, little is known regarding entry into diapause, as well as any conditions that enable a blastocyst to remain dormant.

Types

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There are two distinct forms of embryonic diapause, characterized by different conditions of onset. Facultative diapause occurs in response to certain environmental or metabolic stressors, such as drastic changes in temperature, feeding, or lactation.[13] Obligate diapause occurs regularly in the reproductive cycle of the affected species, and is often associated with seasonal changes and photo-period.[13]

Facultative diapause

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Mechanism of facultative embryonic diapause

Facultative diapause is regulated by several factors, including the maternal environment and ovarian competency, the pituitary gland, and metabolic stress and lactation.[2]

With regards to the many other regulators of this form of diapause, in placental mammals, facultative diapause is most often the result of fertilization shortly following the birth of a previous litter, The consequential pups suckling during lactation promotes prolactin to be released. This in turn reduces progesterone secretion from the corpus luteum in a pregnant female. The corpus luteum is a temporary endocrine organ that is formed from the leftover cells from the ovarian follicle in the ovary, once it has released a mature ovum. The main function of the corpus luteum is to secrete progesterone during pregnancy in order to maintain the uterine environment needed. Prolactin acting on the corpus luteum causes the progesterone level to be below optimal concentration and therefore induces embryonic facultative diapause.

Each species that undergoes facultative diapause tends to have a specific developmental stage, that is genetically determined, in which this process is initiated. This form of diapause is most well studied in rodents and marsupials[2] but has been identified in many other species, including non-mammals. It is not clear how well the mechanisms studied for the onset, maintenance and release from facultative diapause in the rodent model apply to these other species.

Obligate diapause

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Obligate (adj: by necessity) diapause (a.k.a. seasonal delayed implantation) is a mechanism ensuring the birth of offspring is timed during optimal environmental conditions, to ensure maximal survival.[14][11] The proposed mechanism is to separate conception and parturition (birth) so that each can occur at the most favourable time of year.[11]

Obligate diapause is activated and deactivated by changes to the number of daylight hours within a day (photoperiod) and hence, occurs within specific seasons.[13] While obligate diapause occurs in a variety of species in different groups, there are significant variations in diapause length. Western spotted skunks (Spilogale gracilis) have a diapause of around 200 days while American minks (Neogale vison) only have a diapause of around fourteen days.[13]

Similarly to facultative diapause, a series of hormonal changes arrest the blastocyst development, prior to implantation, preventing continued growth of the embryo. However, in obligate diapause, the blastocyst shall enter into the dormant state in every reproductive season. This means every blastocyst a mother produces shall enter a period of diapause.[13]

Close regulation of obligate diapause is essential for survival of the mother and offspring. Premature diapause can result in forgone growth and breeding opportunities and late diapause can result in death due to adverse conditions.[15]

Prior to the vernal equinox,[b] the photoperiod is less than 12 hours. This increases the production of melatonin in the pineal gland. Due to the inhibitory relationship between melatonin and prolactin, this increase in melatonin decreases prolactin secretion from the pituitary gland. The decrease in prolactin consequently decreases progesterone production in the corpus luteum, preventing development of the blastocyst. This induces embryonic diapause.[13]

After the vernal equinox, the photoperiod is greater than 12 hours. This decreases the production of melatonin in the pineal gland and, therefore, increases the prolactin and progesterone production in the pituitary gland and corpus luteum respectively.[13]

The increase in prolactin induces expression of the gene Odc (ornithine decarboxylase). The Odc gene produces the ODC protein, a rate-limiting enzyme in the production of the polyamine, putrescine, within the uterine environment. The presence of putrescine may indicate a role in inducing the escape of the embryo from obligate diapause.[13]

Embryonic stem cells

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Embryonic stem cells (ESCs) have the potential to allow for further understanding of the mechanisms controlling embryonic diapause.[15] This is because the ESCs and diapausing blastocysts having very similar transcriptome profiles.[15] ESCs are derived from the undifferentiated inner mass cells of blastocysts of an embryo – with the capability of continual proliferation in vitro.[15] ESCs are mostly derived from mouse models, at the point where the ESCs are at optimal efficiency and are able to enter diapause.[3]

Both diapausing blastocysts and ESCs have transcriptome profile similarities, including downregulation of metabolism, biosynthesis and gene expression pathways.[3] These similarities allow for the potential to use ESCs as a cellular model to identify the molecular factors which regulate embryonic diapause.[15]

See also

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Notes

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Embryonic diapause

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Embryonic diapause is a reversible, temporary or slowing of early embryonic development, typically at the stage, characterized by minimal , reduced , and delayed implantation in the , allowing embryos to remain viable for extended periods without detriment upon resumption. This phenomenon occurs in over 130 mammalian across diverse orders, including Rodentia (e.g., mice), (e.g., and bears), Artiodactyla (e.g., ), and Marsupialia (e.g., tammar ), and is phylogenetically conserved, as demonstrated by the induction of diapause in non-naturally diapausing like sheep when exposed to appropriate uterine environments. It manifests as either obligate (mandatory, often seasonal, as in , lasting 4-5 months) or facultative (induced by factors like or stress, as in mice), enabling synchronization of birth with favorable environmental conditions to enhance offspring survival. Molecularly, diapause involves hormonal regulation by , progesterone, and , alongside growth factors such as EGF, VEGF, and LIF, with uterine secretions and embryo-uterine signaling maintaining low proliferation (e.g., G1/G0 ) and specific gene expression patterns, including downregulation of PCNA and upregulation of BTG1. Recent findings in reveal that developmental progression, such as formation via SOX17 and FOXA2 markers, continues slowly during diapause, contrasting with more complete arrests in other , and proliferation accelerates fivefold upon reactivation. Evolutionarily, this strategy likely arose independently multiple times to adapt to ecological pressures like scarcity or photoperiod changes. While direct evidence is lacking, embryonic diapause may occur in humans, potentially influenced by stress or endocannabinoids like , with implications for understanding implantation delays and assisted reproductive technologies.

Biological Basis

Definition and Stages

Embryonic diapause is a temporary arrest in the development of the early , typically occurring at the stage, which enables survival and reproduction under adverse environmental conditions. This phenomenon is observed primarily in over 130 mammalian species but also in certain non-mammalian vertebrates, such as teleost fish (e.g., ) and reptiles (e.g., and ), as well as in some invertebrates like . In mammals, the remains free-floating in the without implanting, conserving resources until conditions improve. The concept of embryonic diapause was first described in 1854 by Theodor Bischoff, who observed delayed implantation in the roe deer (Capreolus capreolus), where fertilization occurs in summer but implantation is postponed until winter, ensuring spring births. This discovery, building on earlier observations by Ziegler in 1843, was later confirmed in the early 20th century through experimental studies, and subsequent research has identified the trait in diverse taxa across invertebrates, fish, and mammals. Unlike organismal dormancy forms such as estivation (summer torpor to endure heat and drought) or hibernation (winter torpor to survive cold and food scarcity), embryonic diapause specifically halts pre-implantation embryonic development at the cellular level, without affecting the adult organism's activity. The process unfolds in distinct stages following fertilization. Initially, the develops into a within days, characterized by a fluid-filled cavity and an . Entry into then occurs, marked by metabolic quiescence, greatly reduced , and reduced , allowing the to persist without implantation. The maintenance phase follows, a period of that can last from a few days to several months, depending on environmental cues and species-specific adaptations. Reactivation concludes the , triggered by favorable signals, leading to resumed proliferation, increased , and uterine implantation to initiate . Hormonal changes, such as shifts in progesterone levels, briefly influence transitions between these stages.

Physiological Characteristics

Embryonic diapause involves a profound metabolic slowdown in the embryo, marked by reduced oxygen consumption, , and ATP production, which sustains only essential basal functions while minimizing expenditure. This metabolic depression facilitates a shift to quiescence with negligible cellular proliferation, as cells arrest primarily in the G0/ of the . In species like mice, uptake in blastocysts drops significantly during this state, supporting long-term survival without implantation. Recent research in reveals that, unlike the more complete developmental arrest in species such as mice, some progression continues slowly during , including endoderm formation marked by SOX17 and FOXA2 expression. Upon reactivation, proliferation accelerates approximately fivefold. At the cellular level, the maintains a compact size, typically ranging from 100 to 200 μm in diameter with around 100-130 cells in such as mice, ensuring the trophectoderm and retain full viability. There is no notable increase in , and protein and synthesis persist at low levels to preserve cellular integrity without progression through the . In marsupials like the tammar wallaby, the embryo halts at approximately 100 cells, with minimal mitotic activity confined to specific lineages if any occurs. Structurally, the remains intact in many species, such as carnivores and , acting as a barrier to prevent premature implantation and allowing the to remain unattached. In , the often hatches from the zona during yet continues to float freely within the uterine lumen, avoiding adhesion to the . This free-floating state, combined with encapsulation in some cases like seals, supports without developmental advancement. The duration of embryonic diapause exhibits considerable variability across , lasting from as short as 4-10 days in facultative cases among to up to 11 months in the tammar wallaby or several months in seals, during which the embryo accrues no detectable aging or genetic damage. In mice, viability is maintained for up to 10-36 days, after which prolonged diapause may reduce implantation success. This temporal flexibility enables synchronization with optimal environmental conditions for post-diapause development.

Types

Facultative Diapause

Facultative embryonic diapause represents an inducible form of developmental arrest in mammalian embryos, occurring at the stage as a response to environmental stressors rather than a predetermined seasonal pattern. This optional pause allows females to delay implantation and until conditions improve, thereby optimizing by avoiding birth during periods of resource limitation. Unlike fixed cycles, facultative diapause is triggered by immediate external cues, enabling rapid adaptation to fluctuating habitats. Primary triggers include nutrient limitation, often linked to stress in postpartum females. In mice (Mus musculus), mating immediately after parturition leads to suckling-induced elevation, which suppresses function and progesterone secretion, thereby halting embryo development. Other environmental factors, such as short photoperiods or high population densities, can similarly induce in susceptible species by signaling unfavorable conditions for offspring survival. These triggers are mediated hormonally, with playing a key suppressive role during stress. The reversibility of facultative diapause is one of its defining features, allowing embryos to resume development swiftly upon alleviation of the inducing stress. In rodents, reactivation typically occurs within 24-48 hours after nutrient restoration or weaning, triggered by an estrogen surge that promotes uterine receptivity and blastocyst expansion. For instance, experimental induction in mice via ovariectomy followed by progesterone replacement mimics natural stress, and withdrawal of the hormone leads to rapid implantation. This phenomenon has been observed facultatively in over 70 mammalian species, including various rodents and marsupials, and can be experimentally elicited in non-native contexts, such as ovine (sheep) embryos transferred to mouse uteri.

Obligate Diapause

Obligate diapause represents a mandatory, genetically determined arrest of embryonic development that occurs in every gestation cycle of affected species, irrespective of external conditions, primarily to align parturition with optimal seasonal resources and environmental stability. This form of diapause ensures that offspring are born when food availability and maternal condition are favorable, decoupling fertilization from birth over extended periods. Unlike facultative diapause, which responds to immediate stressors, obligate diapause is an inherent reproductive strategy fixed by the species' biology. The onset of obligate diapause is governed by endogenous circannual rhythms, internal biological clocks that synchronize with annual cycles, often initiated shortly after fertilization during the breeding season. For example, in many temperate-zone mammals, spring or summer mating leads to formation followed by immediate entry into , with implantation delayed until the following season. These rhythms are entrained by photoperiod cues via hormonal signals, such as from the , which modulates secretion to maintain the dormant state. The duration of obligate diapause is species-specific and predetermined, ranging from several weeks to nearly a year, after which reactivation is triggered by shifts in photoperiod or endocrine profiles. In ursids like the black bear (Ursus americanus), diapause lasts approximately 6 months, with embryos arresting post-fertilization in early summer and implanting in late fall or winter, coinciding with onset. Reactivation in such species involves rising day lengths in autumn, prompting surges in progesterone and to resume development. Similarly, in mustelids such as the (Neovison vison), the delay is shorter (about 10-30 days) but precisely timed to the vernal for spring births. In pinnipeds like northern fur seals (Callorhinus ursinus), diapause extends 3-4 months, ending with increased during preparation. This reproductive adaptation is widespread among hibernating or high-latitude mammals, occurring in more than 60 species across seven mammalian orders, with notable prevalence in carnivorans including mustelids, ursids, and pinnipeds. These groups, often facing extreme seasonal variability, benefit from the temporal flexibility provides, enhancing survival in unpredictable environments.

Regulatory Mechanisms

Hormonal Control

Embryonic diapause is primarily regulated by endocrine signals that coordinate maternal and embryonic responses to environmental cues, ensuring developmental arrest at the stage until conditions favor continuation. Key hormones such as progesterone and play central roles in entry and maintenance, while and metabolic factors like insulin/IGF-1 facilitate exit. These hormones act systemically to modulate uterine receptivity and embryonic , integrating with downstream cellular pathways to enforce . Progesterone sustains high circulating levels during , preventing implantation by inducing and maintaining endometrial quiescence, which inhibits uterine and necessary for attachment. In non-diapausing like mice, experimental blockade of progesterone signaling—achieved through ovariectomy prior to the natural surge on embryonic day 3.5, followed by progesterone replacement—artificially induces and prolongs , demonstrating its pivotal role in . Sustained progesterone also suppresses release, further stabilizing the quiescent state across diapausing mammals. Prolactin is crucial for both lactational and seasonal , where its suppression halts embryonic development; in short-day breeders like the , elevated from the inhibits secretion, promoting entry into diapause by reducing activity and progesterone support. Reactivation occurs with a surge, often triggered by lengthening photoperiods, which restores uterine receptivity and initiates implantation. Experimental evidence underscores prolactin's necessity, as receptor expression is upregulated in the during reactivation phases, and disruptions in prolactin signaling prevent exit from dormancy. Estrogen modulates diapause exit by promoting uterine preparation for implantation; a surge in terminates dormancy in mice, counteracting progesterone's effects and stimulating activation. Insulin and insulin-like growth factor-1 (IGF-1) provide metabolic oversight, with pathway suppression—via reduced PI3K/ signaling—enforcing energy conservation during maintenance, while reactivation involves their upregulation to resume growth. Recent studies highlight conserved hormonal mechanisms across diapausing species, integrating environmental cues for synchronized development. These hormonal mechanisms integrate with intracellular arrest to sustain pluripotency without progression.

Molecular and Cellular Pathways

At the cellular level, embryonic diapause enforces a arrest in the , primarily through the upregulation of cyclin-dependent kinase inhibitors p27 and p21, alongside downregulation of s such as . This inhibition prevents progression from to , halting and while maintaining embryo viability. In diapausing blastocysts of species such as mice, , and tammar , elevated p21 and p27 levels suppress activity and ensure metabolic quiescence. Metabolic adaptations during diapause prioritize energy conservation via activation of (AMPK), which senses nutrient scarcity and phosphorylates targets to inhibit anabolic processes. AMPK activation, often triggered by upstream LKB1 signaling under low-energy conditions, directly suppresses mechanistic target of rapamycin () complexes, reducing protein synthesis and to preserve limited resources. This mTOR inhibition is reversible; reintroduction of reactivates , promoting exit from diapause and resumption of proliferation, as observed in embryos. Additionally, stabilization of hypoxia-inducible factor-1α (HIF-1α) supports a shift to glycolytic metabolism in low-oxygen environments, further conserving energy by minimizing oxidative demands. Epigenetic modifications reinforce by altering accessibility and in key embryonic compartments. Changes in patterns, particularly hypermethylation in trophectoderm-specific genes, limit lineage commitment and proliferation under mTOR hypoactivity, contributing to dormancy. Concurrently, histone deacetylation, mediated by increased expression of histone deacetylase-5 (HDAC-5), promotes condensation and transcriptional repression, sustaining cellular quiescence across species like the . These modifications, including reduced H4K16 , create a stable epigenetic landscape that resists developmental progression until environmental cues trigger reversal. Recent post-2020 studies using single-cell RNA sequencing have illuminated diapause-specific transcriptomes, revealing heterogeneous profiles that maintain pluripotency and slow proliferation. In embryos, single-cell of over 80 samples across phases identified upregulated pathways for and , with comparisons to and tammar highlighting conserved signatures like attenuated genes. Emerging evidence also suggests a potential role for sirtuins, NAD+-dependent deacetylases, in extending longevity during by modulating metabolic stress responses and modifications, akin to their function in cellular quiescence and lifespan extension in other models.

Evolutionary and Ecological Aspects

Adaptive Significance

Embryonic diapause confers significant survival advantages by allowing embryos to temporarily suspend development in response to adverse environmental conditions, such as extreme cold or seasonal food shortages, thereby avoiding exposure to stressors that could compromise viability. This pause in progression effectively bridges periods of environmental hostility, enabling the to resume growth only when conditions improve. During diapause, metabolic activity is greatly reduced, with cellular proliferation and energy demands minimized to conserve maternal and embryonic resources—metabolic rates can drop substantially, sometimes to levels as low as 1-40% of normal development, facilitating prolonged embryo maintenance without nutritional depletion. A key adaptive role of embryonic diapause lies in reproductive synchronization, decoupling the timing of from parturition to align birth with peaks in resource availability, such as abundant or milder weather, which optimizes conditions for and juvenile rearing. This temporal adjustment enhances overall by increasing the likelihood of survival and growth. Recent studies in show that longer growing seasons advance termination, shifting birth timing earlier to match peaks amid , with an observed 18-day advance in parturition from 1938–1945 to 2020–2022. Facultative diapause, in particular, permits flexible responses to variable cues, while forms ensure predictable alignment in seasonal breeders. Evolutionarily, embryonic diapause is polyphyletic, having arisen independently in over 130 mammalian species across diverse orders, reflecting convergent adaptations to similar ecological pressures rather than a single ancestral trait. Despite this independent evolution, the phenomenon is conserved through shared molecular modules for arrest, such as common signaling pathways that regulate across taxa, underscoring its utility as a versatile survival strategy. Comparatively, diapause extends inter-birth intervals in polyestrous species, allowing females to mate opportunistically while delaying until favorable periods, which prevents overlapping pregnancies that could strain resources. In unpredictable habitats, this mechanism bolsters fitness by mitigating risks from erratic or availability, enabling populations to persist where continuous development would lead to higher embryonic or neonatal mortality.

Species Distribution and Examples

Embryonic diapause has been documented in over 130 mammalian species across nine orders, representing less than 2% of all mammal species, and is predominant in eutherian mammals such as those in the orders , Rodentia, and Chiroptera, with rarer occurrences in metatherian marsupials. It is also observed in select non-mammalian taxa, including certain fish and crustaceans, where it serves as an to environmental extremes like or . In mammals, facultative embryonic diapause occurs in species such as mice, induced by lactation or stress. Obligate embryonic diapause is exemplified by the European roe deer (Capreolus capreolus), where fertilized embryos enter a developmental arrest lasting 4–5 months from late summer to early winter, allowing birth in spring for optimal fawn survival. Obligate diapause also occurs in the American black bear (Ursus americanus), with embryos pausing development for approximately 6 months following mating in early summer, aligning implantation and cub birth with the winter hibernation period to ensure maternal energy conservation. Among marsupials, the tammar wallaby (Macropus eugenii) exhibits one of the longest obligate diapauses, lasting up to 11 months after the preceding lactation ends, enabling synchronized breeding with favorable seasonal conditions. Other notable mammalian cases include various pinnipeds like northern fur seals (Callorhinus ursinus), where diapause of 3–4 months supports Arctic breeding cycles, and some bat species such as the little brown bat (Myotis lucifugus), which delay implantation for 5–6 months to time births with insect abundance. Beyond mammals, embryonic diapause is prominent in annual killifish of the Austrofundulus, such as A. limnaeus, where embryos enter multiple diapause stages during development, surviving up to 8 months of seasonal drought in hydrated cysts buried in mud until rains resume. In , the Artemia franciscana produces encysted embryos that undergo , tolerating extreme , anoxia, and temperature fluctuations for years until rehydration triggers hatching. These examples highlight diapause's role in diverse taxa for enduring predictable environmental hardships.

Research Applications

Embryonic Stem Cells

Embryonic diapause-stage blastocysts provide a unique opportunity for deriving high-quality embryonic stem cells (ESCs) that capture the naive state of pluripotency, characterized by enhanced self-renewal capacity and reduced propensity for spontaneous differentiation. In species exhibiting diapause, such as mice and minks, the epiblast within these arrested blastocysts maintains a ground-state pluripotent identity, with sustained expression of key transcription factors like Nanog and Esrrb, enabling the isolation of ESCs that closely resemble the pre-implantation embryo. This paused state, driven by molecular quiescence pathways such as inhibition, preserves pluripotency without the progression to a primed state, as detailed in related cellular mechanisms. Derivation of ESCs from diapause embryos typically involves isolating the (ICM) and culturing it in defined media that support naive pluripotency, such as 2i/LIF (containing MEK and GSK3 inhibitors plus ). In mice, can be experimentally induced via ovariectomy or anti-estrogenic treatments, followed by ICM explantation onto feeder layers or in serum-free conditions, yielding ESCs with high derivation efficiency even from non-permissive strains. Similarly, in minks, which undergo obligate lasting 1-2 weeks, ES-like cell lines have been established from diapause blastocysts by terminating dormancy with and culturing the ICM in analogous media, demonstrating conserved pluripotency across . For human analogs, in vitro diapause-like states have been induced in naive pluripotent stem cells (hPSCs) or blastoids using like RapaLink-1, allowing derivation of quiescent naive hPSCs that retain developmental potential upon reactivation. These diapause-derived ESCs offer significant advantages, including extended viability—potentially spanning months to years in a quiescent state mimicking natural diapause durations observed in like the tammar wallaby (up to 11 months)—due to reduced metabolic demands and halted cell cycling. Additionally, the quiescent confers resistance to genetic instability by minimizing replication-associated mutations through lowered mitochondrial activity and enhanced mechanisms during . These properties make them particularly valuable for , where stable, long-term propagation supports applications like and disease modeling without the accumulation of aberrations seen in conventional primed ESCs. Key research milestones include the first derivation of naive human ESCs, achieved in 2014 but advanced by 2018 studies optimizing non-transgenic protocols for ground-state hPSCs, with later research linking the naive state to diapause-like quiescence via inhibition. More recently, 2024 investigations have demonstrated inhibition inducing dormancy in human blastoids, revealing conserved responses that enable precise control of developmental timing for studying human embryogenesis.

Assisted Reproductive Technologies

In assisted reproductive technologies (ART), principles of embryonic diapause have been explored to induce artificial dormancy in embryos, mimicking natural pauses to enhance developmental synchrony and implantation outcomes. Researchers have successfully induced a diapause-like state in embryos by modulating the mTOR signaling pathway using such as rapamycin, which halt and metabolism without compromising viability. Upon reactivation, these artificially diapaused embryos demonstrated improved implantation rates compared to non-diapaused controls, attributed to reduced metabolic stress and better uterine . This approach parallels hormonal induction methods but focuses on pharmacological intervention during culture. For applications, artificial holds promise for optimizing frozen storage in IVF, where blastocysts could be paused to extend viability beyond current limits, allowing better assessment of quality before transfer. A 2024 study using blastoids—stem cell-derived models—confirmed that inhibition induces reversible , reducing proliferation while preserving developmental potential, suggesting translational benefits for treatments. Although no large-scale clinical trials were completed as of November 2025, preliminary explorations in models indicate potential advantages for patients with conditions like , where delayed implantation could align readiness with endometrial receptivity, potentially mitigating implantation failures common in such cases. A 2025 study further revealed that oxytocin can induce in , offering insights into hormonal triggers for potential therapeutic modulation in IVF to manage implantation timing. in ART already replicates -like suspension, with thawed achieving live birth rates around 30%, and induction could further elevate these by enabling prolonged, stress-free pauses. In , artificial diapause extension has been proposed to support conservation efforts for through IVF, particularly where natural cycles mismatch timelines. For instance, in rhinoceros conservation programs, IVF has produced viable from southern white rhinos as for the critically endangered northern white rhino, and integrating diapause induction could prolong embryo storage to optimize transfer windows amid logistical challenges like limited . Ethical concerns arise with extended culture, including risks of genetic abnormalities from prolonged and the moral implications of manipulating embryonic timelines in non-human , necessitating guidelines from bodies like the International Union for Conservation of Nature. Such applications build on successful rhino IVF pregnancies achieved in 2023-2024, where diapause could enhance rates in ex situ breeding. Challenges in integrating artificial diapause into ART include regulatory hurdles, as agencies like the FDA and EMA require extensive safety data on and long-term outcomes before approving embryo manipulations. Post-2020 advancements, such as AI models for predicting embryo reactivation timing based on and metabolic profiles of thawed blastocysts, offer tools to mitigate risks but raise additional ethical issues around in selection. These innovations, while promising for scaling ART accessibility, underscore the need for standardized protocols to address incomplete integration in clinical practice and ensure equitable application across species and populations.

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