![]() ![]() ![]() Along this line, human ESCs and iPSCs can be converted to naïve-like states by several combinations of inhibitors and growth factors (reviewed in Ref. Through inhibition of both GSK3 and MEK signaling pathways in addition to LIF (2iL conditions), mouse ESCs can be maintained serum-free and stably in naïve state pluripotency. However, while mouse ESCs resemble the naïve state of their in vivo counterpart, human ESCs and iPSCs strongly resemble mouse epiblast stem cells (EpiSCs), which are derived from the post-implantation epiblast and reside in primed state pluripotency. ![]() Embryonic stem cells (ESCs) from both mouse and human are derived from the inner cell mass of the pre-implantation epiblast. In vitro, features of naïve (also called ground) and primed state pluripotency are interchangeable through the application (or withdrawal) of small inhibitor molecules and growth factors. The state of pluripotency, in which PSCs reside, has been shown to be crucial for PGC competence (reviewed in Refs. As a first step, primordial germ cells (PGCs) have to be specified from PSCs. However, the capacity and efficiency to produce functional gametes in vitro varies between species necessitating protocol adaption for each species individually. In vitro gametogenesis, the generation of gametes in cell culture from PSCs, has been adapted to several mammalian species (reviewed in Ref. are good candidates because (1) this family includes highly endangered as well as less threatened species, which could serve as surrogates, (2) important advancements have been made in assisted reproductive technology (ART) 6, 7, 8, 9, and (3) iPSCs have already been derived from specimen of the functionally extinct northern white rhinoceros (NWR, Ceratotherium simum cottoni) using standard techniques for reprogramming and maintaining human iPSCs 10, 11. A crucial first step for accomplishing this goal is to gain knowledge on developmental regulation and differentiation mechanisms of PSCs derived from critically endangered species, which fulfill certain prerequisites indicating successful implementation of the proposed modality. In this respect, female somatic cells could in principle be used as a source for induced pluripotent stem cells (iPSCs), which in turn could be differentiated into oocytes in vitro, fertilized and transferred to surrogates of same or related species 4, 5. At the same time, the seminal increase in understanding developmental biology in combination with technological advancements in stem cell biology create innovative opportunities to circumvent the inevitable extinction of diverse species of large mammals. For critically endangered mammals with small population sizes and low genetic diversity, conventional conservation strategies such as habitat protection and captive breeding may not be enough to restore a genetically healthy and self-sustainable population. The world is facing a sixth mass extinction, which is directly and indirectly driven by human activities 1, 2, 3. However, the gained insights into the developmental potential of both primed and naïve-like NWR iPSCs are fundamental for in future PGC-specification in order to rescue the species from extinction using cryopreserved somatic cells. As the conversion process was aided by ectopic BCL2 expression, and we observed integration of reprogramming factors, the NWR iPSCs presented here are unsuitable for gamete production. Furthermore, naïve-like NWR iPSCs displayed increased expression of naïve and PGC marker genes, and a higher integration propensity into developing mouse embryos. Naïve culturing conditions induced a similar expression profile of pluripotency related genes in NWR iPSCs and human ESCs. NWR iPSCs exhibit a broad differentiation potency into the three germ layers and trophoblast, and acquire a naïve-like state of pluripotency, which is pivotal to differentiate PSCs into primordial germ cells (PGCs). To elucidate the regulation of pluripotency and differentiation of NWR PSCs, we generated iPSCs from a deceased NWR female using episomal reprogramming, and observed surprising similarities to human PSCs. To rescue the functionally extinct species, we aim to employ induced pluripotent stem cells (iPSCs) to generate gametes and subsequently embryos in vitro. The northern white rhinoceros (NWR) is probably the earth’s most endangered mammal. ![]()
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