- Open Access
Role of Oct4 in the early embryo development
Cell Regenerationvolume 3, Article number: 7 (2014)
Oct4 is a key component of the pluripotency regulatory network, and its reciprocal interaction with Cdx2 has been shown to be a determinant of either the self-renewal of embryonic stem cells (ESCs) or their differentiation into trophoblast. Oct4 of maternal origin is postulated to play critical role in defining totipotency and inducing pluripotency during embryonic development. However, the genetic elimination of maternal Oct4 using a Cre-lox approach in mouse revealed that the establishment of totipotency in maternal Oct4–depleted embryos was not affected, and that these embryos could complete full-term development without any obvious defect. These results indicate that Oct4 is not essential for the initiation of pluripotency, in contrast to its critical role in maintaining pluripotency. This conclusion is further supported by the formation of Oct4-GFP– and Nanog- expressing inner cell masses (ICMs) in embryos with complete inactivation of both maternal and zygotic Oct4 expression and the reprogramming of fibroblasts into fully pluripotent cells by Oct4-deficient oocytes.
Life is like a journey of torch relay. From generation to generation, our bodies vanish at the end of our lives, but the germ cells are passed on to the next generation, ensuring the continuity and prosperity of our species. In comparison with the somatic cells, these germ cells possess many unique properties, of which the expression of Oct4 is the most important as it is required for the survival of primordial germ cells (PGCs) [1, 2]. Oct4 is also expressed specifically in the inner cell mass (ICM) and embryonic stem cells (ESCs), the cells derived from the ICM . Interestingly, Oct4 is expressed in mouse oocytes as a maternal transcript and protein [1, 4–6]. As is typical for most maternal mRNAs, levels of Oct4 mRNA drop dramatically after fertilization . Zygotic Oct4 expression is activated prior to the 8-cell stage, with a significant increase in both mRNA and protein levels [4, 6]. Oct4 expression is abundant and uniform in all cells of the embryo throughout the morula stage. However, as the outer cells of the embryo differentiate into the trophectoderm (TE), Oct4 expression becomes downregulated and restricted to cells of the ICM in the blastocyst [5, 7, 8]. When cells of the primitive endoderm differentiate and migrate away from the ectoderm, their Oct4 protein levels transiently increase . Oct4 expression then becomes downregulated in the primitive endoderm and maintained in the epiblast, concurrently with embryo implantation and gastrulation. Oct4 expression finally becomes restricted to PGCs , which are first specified in the extraembryonic mesoderm at the base of the allantoic bud during gastrulation . PGCs give rise to gametes, which can be fertilized to develop into a new fully functional organism of the next generation and complete one cycle of life (Figure 1).
Oct4, encoded by the gene Pou5f1, is a homeodomain transcription factor of the POU (Pit-Oct-Unc) family. The POU family of transcription factors can activate the expression of their target genes through binding to an octameric sequence motif of an ATGCAAAT consensus sequence. Oct4 protein consists of 3 domains: N-terminal domain, POU domain, and a C-terminal domain. The POU domain consists of two structurally independent subdomains: a 75 amino acid amino-terminal POU-specific (POUS) region and a 60 amino-acid carboxyl-terminal homeodomain (POUHD). Both domains make specific contact with DNA through a helix-turn-helix structure and are connected by a linker of 17 amino acids. Regions outside of the POU domain are not critical for DNA binding and exhibit little sequence conservation. The N-terminal domain (N-domain) is rich in Proline and acidic residues, while the C-terminal domain (C-domain) is rich in Proline, Serine, and Threonine residues. Both the N-domain and the C-domain play an important role in transactivation, but the activity of the C-domain is cell type specific and is regulated through phosphorylation, whereas that of the N-domain is not. The Oct4 POU-domain functions differently by serving as an interaction site for binding by cell type–specific regulatory factors [12, 13]. Oct4 has been deemed to be a critical regulator of cellular pluripotency, as shown by a zygotic Oct4-knockout study . Loss of pluripotency in embryos, observed at the onset of somitogenesis, is coincident with reduction of Oct4 and Nanog expression, and can be rescued by ectopic Oct4 expression . Oct4 can activate its own expression with its transcription factor partner Sox2 through a positive autoregulatory loop in ESCs . Studies on Oct4 interaction protein network have revealed that the Oct4 interactome includes many transcription factors and chromatin-modifying complexes with documented roles in self-renewal and pluripotency, and that acute depletion of Oct4 reduces the binding of Tcfcp2l1, Dax1, and Esrrb to target genes [17–19]. Depletion of Oct4 by siRNA leads to reduced binding of two key components of the bone morphogenetic protein (BMP) and leukemia inhibitory factor (LIF) signaling pathways, Smad1 and STAT3, to their respective targets. This result indicates that Oct4 plays a pivotal role in stabilizing the nucleoprotein complex and establishes a hierarchy of regulatory interactions between Oct4, STAT3, and Smad1 . The core components of the pluripotency circuitry are formed by Oct4, Nanog, and Sox2, and Nanog expression is directly regulated by Oct4 and Sox2 , Sox2 is actually dispensable for the activation of Oct-Sox enhancers, and the forced expression of Oct4 could rescue Sox2-null ESCs . Hence, Oct4 is considered to be the genetic "master switch" in the establishment of totipotency-pluripotency during the life cycle of mammals , and it is presumed to be the most upstream gene in the molecular circuitry of pluripotency .
Maternal Oct4 expression is not critical for developmental competence of the oocyte
All biological processes occurring during the first cell cycle of the embryo rely on maternal factors, which have accumulated during the long growth phase of the germinal vesicle (GV) oocyte , because there is nearly no mRNA synthesis between the end of the mouse oocyte growth phase and the first zygotic cleavage . But during the second cell cycle, there is a burst of transcription—what is known as zygotic genome activation (ZGA) . Mature metaphase II (MII) oocytes have the capacity to reprogram somatic cells into cells of a totipotent state via nuclear transfer (NT) [28, 29]. Therefore, activation of zygotic transcripts mediated by maternal regulatory factors provides the first step in the establishment of totipotency/pluripotency. Oct4 is one of the 27 proven maternal-effect genes and is regarded to be functionally important for zygotic genome activation . Maternal Oct4 is therefore widely accepted to play a role in igniting the establishment of totipotency and induction of pluripotency.
According to the chromatin organization, growing mouse oocytes could be classified into 2 types: SN (surrounded nucleolus) oocytes, with a ring of chromatin surrounding the nucleolus, and NSN (not surrounded nucleolus) oocytes, with chromatin dispersed throughout the nucleus, i.e., chromatin not surrounding the nucleolus. When they mature into metaphase II (MII) oocytes and are fertilized in vitro, only MIISN oocytes (MII oocytes derived from SN oocytes) are developmentally competent to develop beyond the 2-cell stage, while MIINSN oocytes (MII oocytes derived from NSN oocytes) become arrested at the 2-cell stage . By comparing the transcriptional profiles of these two types of mouse MII oocytes, Zuccotti et al. found that Oct4 was absent in MIINSN oocytes, accounting for the downregulation of Stella, a maternal-effect factor required for the oocyte-to-embryo transition, and the upregulation of 18 Oct4-regulated genes implicated in the activation of adverse biochemical pathways such as oxidative phosphorylation, mitochondrial dysfunction, and apoptosis. Those authors concluded that the downregulation of Oct4 leads to the developmental arrest of MIINSN oocytes and that maternal Oct4 emerges as a key regulator of the molecular events that govern the establishment of the developmental competence of mouse oocytes . Moreover, another study claimed that Oct4 is a critical regulator of the maternal-embryonic transition at the 2-cell stage, as embryos invasively injected with Oct4-antisense morpholino oligonucleotides were found to arrest in various developmental stages prior to the blastocyst stage . A later report from the same group using the same approach also showed developmental arrest between the 2- to 8-cell stages in morpholino-mediated Oct4, Nanog, or Sall4 knockdown, but developmental arrest remained obvious after co-injection of Oct4, Nanog, or Sall4 mRNA . Although such a phenotype contradicts to genetic knockout studies [14, 35, 36], which indicated that homozygous null embryos could develop at least up to the blastocyst stage, the authors ignored the presence of maternal Oct4 protein and assumed that the apparent discrepancy was due to the presence of functional maternal transcript . However, recently, numerous studies found that after genetic removal of maternal Oct4 in oocytes by crossing Oct4flox/flox /ZP3Cre/+female mice with wild-type male mice, these Oct4flox/flox /ZP3Cre/+female mice were found to be fully fertile [37–39]. All offspring had deletion of the maternal Oct4 allele as confirmed by polymerase chain reaction (PCR) genotyping, clearly demonstrating that maternal Oct4 is not critical for the establishment of totipotency-pluripotency . The data in the study also showed the efficient deletion of the maternal Oct4 allele by genotyping of individual oocytes, the depletion of Oct4 mRNA by real-time reverse transcriptase PCR (RT-PCR), and the depletion of Oct4 protein by Western blot .
Oct4-null oocytes can reprogram somatic cells to a pluripotent state
Enucleated oocytes can also reprogram the nuclei of terminally differentiated somatic cells to a totipotent embryonic state after nuclear transplantation [28, 29]. The nuclei can be reprogrammed by the recipient oocytes to express the pluripotent gene Oct4 at a very high efficiency (88.7%) in just 2–3 days  and to give rise to pluripotent cells at an efficiency of up to 20% . This compares favorably with the exciting 4-factor (Oct4, Sox2, Klf4, and c-Myc) technique of generating induced pluripotent stem cells (iPSCs) by Yamanaka and colleagues, which showed activation of internal Oct4 expression after more than 2 weeks, with an efficiency of 0.01–0.1% . A recent study revealed that Oct4 alone could reprogram neural stem cells into pluripotent iPSCs . Could maternal Oct4 in oocytes be essential in the reprogramming of somatic cells to pluripotent status? The answer is no. By conducting NT experiments using maternal Oct4-null oocytes from Oct4flox/flox /ZP3Cre/+female mice, it was found that all cloned embryos expressed pluripotency genes (Oct4 and Nanog) in the ICM and the TE marker gene Cdx2 in the TE by both immunocytochemistry and real-time RT-PCR . Furthermore, ESC lines derived from cloned embryos using Oct4-knockout oocytes demonstrated full pluripotency by generating completely ESC-derived mice through the tetraploid complementation test, the most stringent test for pluripotency . Clearly, the reprogramming engine in oocytes could work effectively to reprogram somatic cells into cells of a pluripotent state without the presence of maternal Oct4.
Reciprocal interaction between Oct4 and Cdx2 is not the initial cause sparking ICM/TE lineage separation
Previous studies have suggested that lineage commitment is controlled by the expression level of Oct4 [14, 44]. Repression of Oct4 expression induced the differentiation of ESCs into TE cells, and a less than two-fold increase in Oct4 expression caused the differentiation of ESCs into cells of primitive endoderm and mesoderm . In the absence of Oct4, embryos could not form an ICM—i.e., the inner cells of morula-stage embryos rather were driven into trophoblast differentiation . Therefore, these results indicated that Oct4 plays a critical role in sustaining stem cell self-renewal and that up- or downregulation of Oct4 expression induces divergent developmental programs, suggesting that Oct4 is the master regulator of pluripotency and that it may also control lineage commitment during early embryonic development . This hypothesis was supported by reports showing that Oct4 and Cdx2 could form a complex that reciprocally repressed their target genes and such an interaction determined the ICM/TE lineage separation in early embryos , while the interaction between Oct4 and the histone H3–specific methyltransferase ESET restricted the extraembryonic trophoblast lineage potential of pluripotent cells . However, the expression of Cdx2 in ESCs was found to be rapidly initiated by Ras activation (i.e., within 24 hours) without previous or simultaneous downregulation of Oct4 expression , while ESCs with reduced Oct4 expression showed robust pluripotency and expressed naïve pluripotency genes, but were deficient in differentiation in the absence of pluripotency culture requisites [48, 49]. On the other hand, Cdx2 deficiency did not interrupt TE-ICM lineage separation [50–52], and zygotic Oct4 expression was shown not to be required for the initial repression of the TE genes Cdx2 and Gata3 in the ICM, indicating that other mechanisms are responsible for restricting the expression of these genes to the TE . Finally, with a conditional knockout system, it was demonstrated that, similar to the reported zygotic Oct4 knockout observation [14, 53], the genetic removal of both maternal and zygotic Oct4 did not prevent ICM-TE lineage separation [37–39], arguing against the notion that maternal Oct4 could partially compensate for the loss of zygotic Oct4 during cell fate specification in the blastocyst . Therefore, the first lineage separation of the ICM-TE is not determined by the reciprocal interaction between Oct4 and Cdx2. More importantly, these studies indicated that maternal Oct4 is not at the root of pluripotency as a determinant of pluripotent cell lineage initiation, contrary to previous assumptions and views [23, 24].
How Oct4 is activated in the embryo remains an open question
Oct4 is at the top of the pluripotency regulatory hierarchy in pluripotent cells [20, 21]. It forms a positive feedback loop  and is essential to maintaining pluripotency , but is not required for initiating totipotency/pluripotency in embryos [37–39]. Therefore, understanding how early embryos activate Oct4 expression is key in clarifying the oocyte reprogramming mechanism.
The upstream region of the transcriptional initiation site of the Oct4 gene contains three regulatory elements for gene transcription: the distal enhancer (DE), proximal enhancer (PE), and TATA-less proximal promoter (PP)  as illustrated in Figure 2. The two enhancers exhibit a differential activation pattern according to the developmental stage of the mouse embryo. The DE drives Oct4 expression in the ICM, ESCs, and PGCs, while the PE activates Oct4 expression in epiblast cells. Each enhancer contains multiple potential binding sites for transcription factors that can either activate or repress Oct4 expression. In addition, the methylation of these regions represses Oct4 expression in differentiated cells. Several positive and negative regulators bind to the Oct4 gene to regulate its expression. Of these, members of the orphan nuclear receptor superfamily, which can bind to Sp1 sites  and hormone response elements (HREs) in the PE and PP, are known to influence Oct4 expression. Positive regulators of Oct4 expression include Nr5a2 , SF1 (Steroidogenic Factor-1), and RXR-β (Retinoid X Receptor-β, also known as Nr2b2) [56, 57]. Negative regulators include GCNF (Germ Cell Nuclear Factor) (also known as Nr6a1) , and COUF-TFI/II (Chicken Ovalbumin Upstream promoter-Transcription Factors- I/II), encoded by Nr2f1 and Nr2f2, respectively [59, 60]. The transcription factor TR2 can bind to the HRE of the Oct4 gene to either activate or repress Oct4 expression in P19 embryonal carcinoma (EC) stem cells and regulate the proliferation of the culture, based on whether there is SUMOylation on the Lys-238 of TR2 .
Recent studies have found that certain maternal factors are involved in the regulation of Oct4 expression, providing clues on the mechanism underlying the initiation of totipotency/pluripotency. Cancer-associated factor Tpt1 has been reported to activate the transcription of Oct4 and Nanog in transplanted somatic nuclei in the Xenopus oocyte , but another study failed to replicate this finding upon knockdown of Tpt1 by Small interfering RNA (siRNA) in the mouse embryos . Components of the ATP-dependent BAF chromatin-remodeling complex have been shown to significantly increase reprogramming efficiency when used together with the Yamanaka’s 4 factors . Promyelocytic leukemia (Pml) protein was found to be required for Oct4 gene expression and the maintenance of its open chromatin conformation in stem cells. In proliferating stem cells, Pml-nuclear body, along with the transcription factors TR2, SF1 and Sp1, and the Brg1-dependent chromatin remodeling complex (BRGC), associates with the Oct4 promoter to maintain a nucleosome-free region for gene activity . Studies in search for master genes in the oocyte have revealed a novel oocyte-specific eukaryotic translation initiation factor 4E (Eif4eloo)  and a large number of oocyte-specific genes with yet unknown functions, such as those belonging to the homeodomain transcription factor Obox family . The maternal transcription factor Sall4 binds to the Oct4 DE, and it is regarded to be a transcriptional activator of Oct4 expression based on evidence that reduction in Sall4 mRNA level in blastocysts at merely 50% knockdown efficiency by Sall4 siRNA injection into zygotes led to a 70% reduction in Oct4 expression . Single-cell expression analyses during in vitro cellular reprogramming have confirmed that Sall4 is indeed an upstream activator of Oct4 expression . However, the efficient knockdown of Sall4 by injecting Sall4 siRNA into maternal Oct4-deficient zygotes—to avoid any possible effect of maternal Oct4 as a positive autoregulator—did not lead to any changes in Oct4 expression at the blastocyst stage, arguing against such a role for Sall4 as an upstream activator of Oct4 expression in vivo . Nr5a2 was found to maintain Oct4 expression at the epiblast stage of embryonic development, by binding to the PE and PP regions of Oct4, but to play no evident role in ESC self-renewal . However, Nr5a2 can induce epiblast stem cells into ground state pluripotency, a basal proliferative state that is free of epigenetic restriction , and replace Oct4 in the reprogramming of somatic cells into pluripotent cells . Activation of Zscan4 expression occurs during ZGA, with the gene being expressed in ESCs, whereas reduction in Zscan4 transcript levels by siRNAs delays the progression from the 2-cell to the 4-cell stage, leading to blastocysts that fail to implant or proliferate in blastocyst outgrowth culture . Zscan4 is essential for induction of iPSCs and its ectopic expression can activate early embryonic genes and improve the efficiency of iPSC generation . However, knockdown of Zscan4 in preimplantation embryos by siRNA against all 6 isoforms of Zscan4 (a-f) had no impact on Oct4 expression . A component of an active DNA demethylase, activation-induced cytidine deaminase (AID), was also shown to be required for reprogramming . A genome-scale RNA interference (RNAi) screen in ESCs identified components of the Paf1 complex with strong effects on Oct4 expression, and showed that Paf1C overexpression blocks the differentiation of ESCs and that Paf1C knockdown causes expression changes in ESCs that are similar to those observed with Oct4 or Nanog depletion .
Oct4B expression in oocytes and embryos
After the finding that truncated isoforms of OCT4 are transcribed from the POU5F1 gene in human  and mouse , the originally described OCT4 is designated as OCT4A and the newly found truncated isoforms are variants of an OCT4 version named OCT4B . OCT4B mRNAs encode proteins that have identical POU DNA-binding domains and C-domains but differ in their N-domains (Figure 3). Continued expression of Oct4B after the original Oct4 promoter was removed indicates that Oct4B transcription is regulated by an alternative promoter in the first intron , as presumed by an earlier study . Other isoforms of Oct4B could be produced by alternative splicing or alternative translation initiation [80, 81]. ESC-based complementation assays using ZHBTc4 ESCs, which has endogenous Oct4 inactivated by gene targeting and harbors a tetracycline-repressible Oct4 transgene to support ESC self-renewal , showed that OCT4B cannot rescue the self-renewal ability of ZHBTc4 ESCs in the presence of doxycycline, unlike OCT4A. Electrophonetic mobility shift assay showed that OCT4B does not bind to a probe carrying the OCT4 consensus binding sequence due to the repressive effect of the OCT4B N-domain. Furthermore, overexpression of OCT4B does not activate transcription from OCT4-dependent promoters . However, Oct4B is involved in stress response  and acts as an antiapoptotic factor in cancer cells .
On the other hand, Oct4 expression in the adult has been reported in hematopoietic and mesenchymal stem cells [84–95], as well as progenitor cells from various somatic tissues including pancreatic islets , kidney [97, 98], peripheral blood [89, 99, 100], endometrium of the uterus [101, 102], thyroid , lung , brain [105, 106], liver , and skin [108–111]. The wide expression of Oct4 in normal tissues suggests that Oct4 may not only be crucial for the maintenance of pluripotency in embryonic cells, but also play an important role in the self-renewal of somatic stem cells and in maintenance of tissue homeostasis. As these studies did not distinguish the Oct4 isoforms, it is likely they actually detected Oct4B. A later study that conditionally deleted Oct4 from somatic cells in vivo found that Oct4 is dispensable for both the self-renewal and maintenance of somatic stem cells in the adult mammal . Oct4 gene ablation in the intestinal epithelium, bone marrow (hematopoietic and mesenchymal lineages), hair follicle, brain, and liver revealed no abnormalities in homeostasis or regenerative capacity . Like many other publications claiming Oct4 expression in somatic stem cells, this study also noted low level of expression but that was regarded as false detection of Oct4 due to the noise of the detection methods, expression of pseudogenes, and expression of other POU-domain family members . These conclusions are now in question. In our lab, the same Oct4floxed mice were used, in which two LoxP motifs had been inserted that span the proximal promoter and the Oct4A-unique first exon . As the other 4 exons shared by Oct4B were not mutated, it is still possible that Oct4 B can still be transcribed using an alternative promoter. After efficiently removing the floxed sequence of Oct4 in oocytes by crossing the Oct4flox/flox mice with ZP3Cre transgenic mice, indeed, the expression of only Oct4B (not Oct4A) was detected at low levels by RT-PCR in the mutated oocytes and preimplantation embryos, which was confirmed by sequencing. Another recent report used a different Oct4floxed mouse line to delete the entire Oct4 POU domain and C-domain, yet the authors of that study also observed full-term development of maternal Oct4–null embryos and TE/ICM lineage separation, as well as Nanog activation in maternal and zygotic Oct4–null embryos . Taken together, these studies confirmed that (1) maternal Oct4 is indeed not essential for the establishment of totipotency. (2) The low levels of Oct4B expression could not rescue Oct4A-null embryos to maintain pluripotency in vivo [37, 38]. The precise function of Oct4B in embryos and somatic stem cells remains to be clarified.
As summarized in Figure 4, new pieces of evidence clearly indicate that Oct4 is not the master regulator responsible for initiating totipotency-pluripotency in oocytes, and that maternal and zygotic Oct4–null blastocysts maintain the ability to activate Nanog and Oct4-GFP expression, indicating that unknown pathways other than the Oct4-centered pluripotency-regulating network are active in embryos and function upstream of Oct4 in driving pluripotency. However, to date no factors have proven to be essential for Oct4 activation in the preimplantation embryos. Further studies are required to elucidate how oocytes activate the pluripotent genes Oct4 and Nanog on top of the Oct4/Sox2 autoregulatory loop in an effort to understand the establishment of totipotency in zygotes and in transplanted somatic cells.
Inner cell mass
Embryonic stem cells
Primordial germ cells
Bone morphogenetic protein
Leukemia inhibitory factor
Zygotic genome activation
Not surrounded nucleolus
Polymerase chain reaction
Reverse transcriptase PCR
Induced pluripotent stem cells
Hormone response elements
Retinoid X Receptor-Beta
Germ Cell Nuclear Factor
Chicken Ovalbumin Upstream promoter-Transcription Factors- I/II
Brg1-dependent chromatin remodeling complex
Oocyte-specific eukaryotic translation initiation factor 4E
Activation-induced cytidine deaminase
Small interfering RNA
Days post coitum
days post partum.
Scholer HR, Hatzopoulos AK, Balling R, Suzuki N, Gruss P: A family of octamer-specific proteins present during mouse embryogenesis: evidence for germline-specific expression of an Oct factor. EMBO J 1989, 8: 2543–2550.
Kehler J, Tolkunova E, Koschorz B, Pesce M, Gentile L, Boiani M, Lomeli H, Nagy A, McLaughlin KJ, Scholer HR, Tomilin A: Oct4 is required for primordial germ cell survival. EMBO Rep 2004, 5: 1078–1083. 10.1038/sj.embor.7400279
Pesce M, Scholer HR: Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 2001, 19: 271–278. 10.1634/stemcells.19-4-271
Palmieri SL, Peter W, Hess H, Scholer HR: Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. Dev Biol 1994, 166: 259–267. 10.1006/dbio.1994.1312
Rosner MH, Vigano MA, Ozato K, Timmons PM, Poirier F, Rigby PW, Staudt LM: A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo. Nature 1990, 345: 686–692. 10.1038/345686a0
Yeom YI, Ha HS, Balling R, Scholer HR, Artzt K: Structure, expression and chromosomal location of the Oct-4 gene. Mech Dev 1991, 35: 171–179. 10.1016/0925-4773(91)90016-Y
Okamoto K, Okazawa H, Okuda A, Sakai M, Muramatsu M, Hamada H: A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 1990, 60: 461–472. 10.1016/0092-8674(90)90597-8
Scholer HR, Dressler GR, Balling R, Rohdewohld H, Gruss P: Oct-4: a germline-specific transcription factor mapping to the mouse t-complex. Embo J 1990, 9: 2185–2195.
Yeom YI, Fuhrmann G, Ovitt CE, Brehm A, Ohbo K, Gross M, Hubner K, Scholer HR: Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 1996, 122: 881–894.
Scholer HR, Balling R, Hatzopoulos AK, Suzuki N, Gruss P: Octamer binding proteins confer transcriptional activity in early mouse embryogenesis. Embo J 1989, 8: 2551–2557.
Scholer HR, Ruppert S, Suzuki N, Chowdhury K, Gruss P: New type of POU domain in germ line-specific protein Oct-4. Nature 1990, 344: 435–439. 10.1038/344435a0
Campbell PA, Perez-Iratxeta C, Andrade-Navarro MA, Rudnicki MA: Oct4 targets regulatory nodes to modulate stem cell function. Plos One 2007, 2: e553. 10.1371/journal.pone.0000553
Babaie Y, Herwig R, Greber B, Brink TC, Wruck W, Groth D, Lehrach H, Burdon T, Adjaye J: Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells. Stem Cells 2007, 25: 500–510. 10.1634/stemcells.2006-0426
Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Scholer H, Smith A: Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 1998, 95: 379–391. 10.1016/S0092-8674(00)81769-9
Osorno R, Tsakiridis A, Wong F, Cambray N, Economou C, Wilkie R, Blin G, Scotting PJ, Chambers I, Wilson V: The developmental dismantling of pluripotency is reversed by ectopic Oct4 expression. Development 2012, 139: 2288–2298. 10.1242/dev.078071
Okumura-Nakanishi S, Saito M, Niwa H, Ishikawa F: Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. J Biol Chem 2005, 280: 5307–5317.
Ding J, Xu H, Faiola F, Ma'ayan A, Wang J: Oct4 links multiple epigenetic pathways to the pluripotency network. Cell Res 2012, 22: 155–167. 10.1038/cr.2011.179
van den Berg DL, Snoek T, Mullin NP, Yates A, Bezstarosti K, Demmers J, Chambers I, Poot RA: An Oct4-centered protein interaction network in embryonic stem cells. Cell Stem Cell 2010, 6: 369–381. 10.1016/j.stem.2010.02.014
Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH: A protein interaction network for pluripotency of embryonic stem cells. Nature 2006, 444: 364–368. 10.1038/nature05284
Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, Yeo ZX, Narang V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung WK, Clarke ND, Wei CL, Ng HH: Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 2008, 133: 1106–1117. 10.1016/j.cell.2008.04.043
Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P: Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem 2005, 280: 24731–24737. 10.1074/jbc.M502573200
Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K, Okochi H, Okuda A, Matoba R, Sharov AA, Ko MS, Niwa H: Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 2007, 9: 625–635. 10.1038/ncb1589
Pesce M, Anastassiadis K, Scholer HR: Oct-4: lessons of totipotency from embryonic stem cells. Cells Tissues Organs 1999, 165: 144–152. 10.1159/000016694
Jaenisch R, Young R: Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 2008, 132: 567–582. 10.1016/j.cell.2008.01.015
Bachvarova R, De Leon V: Polyadenylated RNA of mouse ova and loss of maternal RNA in early development. Dev Biol 1980, 74: 1–8. 10.1016/0012-1606(80)90048-2
Ram PT, Schultz RM: Reporter gene expression in G2 of the 1-cell mouse embryo. Dev Biol 1993, 156: 552–556. 10.1006/dbio.1993.1101
Schultz RM: Regulation of zygotic gene activation in the mouse. Bioessays 1993, 15: 531–538. 10.1002/bies.950150806
Campbell KH, McWhir J, Ritchie WA, Wilmut I: Sheep cloned by nuclear transfer from a cultured cell line. Nature 1996, 380: 64–66. 10.1038/380064a0
Gurdon JB: Adult frogs derived from the nuclei of single somatic cells. Dev Biol 1962, 4: 256–273. 10.1016/0012-1606(62)90043-X
Li L, Zheng P, Dean J: Maternal control of early mouse development. Development 2010, 137: 859–870. 10.1242/dev.039487
Zuccotti M, Giorgi Rossi P, Martinez A, Garagna S, Forabosco A, Redi CA: Meiotic and developmental competence of mouse antral oocytes. Biol Reprod 1998, 58: 700–704. 10.1095/biolreprod58.3.700
Zuccotti M, Merico V, Sacchi L, Bellone M, Brink TC, Bellazzi R, Stefanelli M, Redi CA, Garagna S, Adjaye J: Maternal Oct-4 is a potential key regulator of the developmental competence of mouse oocytes. BMC Dev Biol 2008, 8: 97. 10.1186/1471-213X-8-97
Foygel K, Choi B, Jun S, Leong DE, Lee A, Wong CC, Zuo E, Eckart M, Reijo Pera RA, Wong WH, Yao MW: A novel and critical role for Oct4 as a regulator of the maternal-embryonic transition. Plos One 2008, 3: e4109. 10.1371/journal.pone.0004109
Tan MH, Au KF, Leong DE, Foygel K, Wong WH, Yao MW: An Oct4-Sall4-Nanog network controls developmental progression in the pre-implantation mouse embryo. Mol Syst Biol 2013, 9: 632.
Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S: The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 2003, 113: 631–642. 10.1016/S0092-8674(03)00393-3
Sakaki-Yumoto M, Kobayashi C, Sato A, Fujimura S, Matsumoto Y, Takasato M, Kodama T, Aburatani H, Asashima M, Yoshida N, Nishinakamura R: The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development. Development 2006, 133: 3005–3013. 10.1242/dev.02457
Wu G, Han D, Gong Y, Sebastiano V, Gentile L, Singhal N, Adachi K, Fischedick G, Ortmeier C, Sinn M, Radstaak M, Tomilin A, Scholer HR: Establishment of totipotency does not depend on Oct4A. Nat Cell Biol 2013, 15: 1089–1097. 10.1038/ncb2816
Frum T, Halbisen MA, Wang C, Amiri H, Robson P, Ralston A: Oct4 Cell-Autonomously Promotes Primitive Endoderm Development in the Mouse Blastocyst. Dev Cell 2013, 25: 610–622. 10.1016/j.devcel.2013.05.004
Le Bin GC, Muñoz-Descalzo S, Kurowski A, Leitch H, Lou X, Mansfield W, Etienne-Dumeau C, Grabole N, Mulas C, Niwa H, Hadjantonakis A-K, Nichols J: Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst. Development 2014, 141: 1001–1010. 10.1242/dev.096875
Boiani M, Eckardt S, Scholer HR, McLaughlin KJ: Oct4 distribution and level in mouse clones: consequences for pluripotency. Genes Dev 2002, 16: 1209–1219. 10.1101/gad.966002
Yang X, Smith SL, Tian XC, Lewin HA, Renard JP, Wakayama T: Nuclear reprogramming of cloned embryos and its implications for therapeutic cloning. Nat Genet 2007, 39: 295–302. 10.1038/ng1973
Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126: 663–676. 10.1016/j.cell.2006.07.024
Kim JB, Sebastiano V, Wu G, Arauzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hubner K, Bernemann C, Ortmeier C, Zenke M, Fleischmann BK, Zaehres H, Scholer HR: Oct4-induced pluripotency in adult neural stem cells. Cell 2009, 136: 411–419. 10.1016/j.cell.2009.01.023
Niwa H, Miyazaki J, Smith AG: Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 2000, 24: 372–376. 10.1038/74199
Niwa H, Toyooka Y, Shimosato D, Strumpf D, Takahashi K, Yagi R, Rossant J: Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 2005, 123: 917–929. 10.1016/j.cell.2005.08.040
Yuan P, Han J, Guo G, Orlov YL, Huss M, Loh YH, Yaw LP, Robson P, Lim B, Ng HH: Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. Genes Dev 2009, 23: 2507–2520. 10.1101/gad.1831909
Lu CW, Yabuuchi A, Chen L, Viswanathan S, Kim K, Daley GQ: Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos. Nat Genet 2008, 40: 921–926. 10.1038/ng.173
Karwacki-Neisius V, Goke J, Osorno R, Halbritter F, Ng JH, Weisse AY, Wong FC, Gagliardi A, Mullin NP, Festuccia N, Colby D, Tomlinson SR, Ng HH, Chambers I: Reduced oct4 expression directs a robust pluripotent state with distinct signaling activity and increased enhancer occupancy by oct4 and nanog. Cell Stem Cell 2013, 12: 531–545. 10.1016/j.stem.2013.04.023
Radzisheuskaya A, Chia Gle B, dos Santos RL, Theunissen TW, Castro LF, Nichols J, Silva JC: A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages. Nat Cell Biol 2013, 15: 579–590. 10.1038/ncb2742
Blij S, Frum T, Akyol A, Fearon E, Ralston A: Maternal Cdx2 is dispensable for mouse development. Development 2012, 139: 3969–3972. 10.1242/dev.086025
Strumpf D, Mao CA, Yamanaka Y, Ralston A, Chawengsaksophak K, Beck F, Rossant J: Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development 2005, 132: 2093–2102. 10.1242/dev.01801
Wu G, Gentile L, Fuchikami T, Sutter J, Psathaki K, Esteves TC, Arauzo-Bravo MJ, Ortmeier C, Verberk G, Abe K, Scholer HR: Initiation of trophectoderm lineage specification in mouse embryos is independent of Cdx2. Development 2010, 137: 4159–4169. 10.1242/dev.056630
Ralston A, Cox BJ, Nishioka N, Sasaki H, Chea E, Rugg-Gunn P, Guo G, Robson P, Draper JS, Rossant J: Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2. Development 2010, 137: 395–403. 10.1242/dev.038828
Marin M, Karis A, Visser P, Grosveld F, Philipsen S: Transcription factor Sp1 is essential for early embryonic development but dispensable for cell growth and differentiation. Cell 1997, 89: 619–628. 10.1016/S0092-8674(00)80243-3
Gu P, Goodwin B, Chung AC, Xu X, Wheeler DA, Price RR, Galardi C, Peng L, Latour AM, Koller BH, Gossen J, Kliewer SA, Cooney AJ: Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development. Mol Cell Biol 2005, 25: 3492–3505. 10.1128/MCB.25.9.3492-3505.2005
Barnea E, Bergman Y: Synergy of SF1 and RAR in activation of Oct-3/4 promoter. J Biol Chem 2000, 275: 6608–6619. 10.1074/jbc.275.9.6608
Pikarsky E, Sharir H, Ben-Shushan E, Bergman Y: Retinoic acid represses Oct-3/4 gene expression through several retinoic acid-responsive elements located in the promoter-enhancer region. Mol Cell Biol 1994, 14: 1026–1038.
Gu P, LeMenuet D, Chung AC, Mancini M, Wheeler DA, Cooney AJ: Orphan nuclear receptor GCNF is required for the repression of pluripotency genes during retinoic acid-induced embryonic stem cell differentiation. Mol Cell Biol 2005, 25: 8507–8519. 10.1128/MCB.25.19.8507-8519.2005
Ben-Shushan E, Sharir H, Pikarsky E, Bergman Y: A dynamic balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and retinoic acid receptor:retinoid X receptor heterodimers regulates Oct-3/4 expression in embryonal carcinoma cells. Mol Cell Biol 1995, 15: 1034–1048.
Schoorlemmer J, van Puijenbroek A, van Den Eijnden M, Jonk L, Pals C, Kruijer W: Characterization of a negative retinoic acid response element in the murine Oct4 promoter. Mol Cell Biol 1994, 14: 1122–1136.
Park SW, Hu X, Gupta P, Lin YP, Ha SG, Wei LN: SUMOylation of Tr2 orphan receptor involves Pml and fine-tunes Oct4 expression in stem cells. Nat Struct Mol Biol 2007, 14: 68–75. 10.1038/nsmb1185
Ovitt CE, Scholer HR: The molecular biology of Oct-4 in the early mouse embryo. Mol Hum Reprod 1998, 4: 1021–1031. 10.1093/molehr/4.11.1021
Koziol MJ, Garrett N, Gurdon JB: Tpt1 activates transcription of oct4 and nanog in transplanted somatic nuclei. Curr Biol 2007, 17: 801–807. 10.1016/j.cub.2007.03.062
Singhal N, Graumann J, Wu G, Arauzo-Bravo MJ, Han DW, Greber B, Gentile L, Mann M, Scholer HR: Chromatin-Remodeling Components of the BAF Complex Facilitate Reprogramming. Cell 2010, 141: 943–955. 10.1016/j.cell.2010.04.037
Chuang YS, Huang WH, Park SW, Persaud SD, Hung CH, Ho PC, Wei LN: Promyelocytic leukemia protein in retinoic acid-induced chromatin remodeling of Oct4 gene promoter. Stem Cells 2011, 29: 660–669. 10.1002/stem.623
Evsikov AV, Graber JH, Brockman JM, Hampl A, Holbrook AE, Singh P, Eppig JJ, Solter D, Knowles BB: Cracking the egg: molecular dynamics and evolutionary aspects of the transition from the fully grown oocyte to embryo. Genes Dev 2006, 20: 2713–2727. 10.1101/gad.1471006
Rajkovic A, Yan C, Yan W, Klysik M, Matzuk MM: Obox, a family of homeobox genes preferentially expressed in germ cells. Genomics 2002, 79: 711–717. 10.1006/geno.2002.6759
Zhang J, Tam WL, Tong GQ, Wu Q, Chan HY, Soh BS, Lou Y, Yang J, Ma Y, Chai L, Ng HH, Lufkin T, Robson P, Lim B: Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 2006, 8: 1114–1123. 10.1038/ncb1481
Buganim Y, Faddah DA, Cheng AW, Itskovich E, Markoulaki S, Ganz K, Klemm SL, van Oudenaarden A, Jaenisch R: Single-Cell Expression Analyses during Cellular Reprogramming Reveal an Early Stochastic and a Late Hierarchic Phase. Cell 2012, 150: 1209–1222. 10.1016/j.cell.2012.08.023
Guo G, Smith A: A genome-wide screen in EpiSCs identifies Nr5a nuclear receptors as potent inducers of ground state pluripotency. Development 2010, 137: 3185–3192. 10.1242/dev.052753
Heng JC, Feng B, Han J, Jiang J, Kraus P, Ng JH, Orlov YL, Huss M, Yang L, Lufkin T, Lim B, Ng HH: The Nuclear Receptor Nr5a2 Can Replace Oct4 in the Reprogramming of Murine Somatic Cells to Pluripotent Cells. Cell Stem Cell 2010, 6: 167–174. 10.1016/j.stem.2009.12.009
Falco G, Lee SL, Stanghellini I, Bassey UC, Hamatani T, Ko MS: Zscan4: a novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells. Dev Biol 2007, 307: 539–550. 10.1016/j.ydbio.2007.05.003
Hirata T, Amano T, Nakatake Y, Amano M, Piao Y, Hoang HG, Ko MS: Zscan4 transiently reactivates early embryonic genes during the generation of induced pluripotent stem cells. Sci Rep 2012, 2: 208.
Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM: Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 2010, 463: 1042–1047. 10.1038/nature08752
Ding L, Paszkowski-Rogacz M, Nitzsche A, Slabicki MM, Heninger AK, de Vries I, Kittler R, Junqueira M, Shevchenko A, Schulz H, Hubner N, Doss MX, Sachinidis A, Hescheler J, Iacone R, Anastassiadis K, Stewart AF, Pisabarro MT, Caldarelli A, Poser I, Theis M, Buchholz F: A genome-scale RNAi screen for Oct4 modulators defines a role of the Paf1 complex for embryonic stem cell identity. Cell Stem Cell 2009, 4: 403–415. 10.1016/j.stem.2009.03.009
Takeda J, Seino S, Bell GI: Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues. Nucleic Acids Res 1992, 20: 4613–4620. 10.1093/nar/20.17.4613
Mizuno N, Kosaka M: Novel variants of Oct-3/4 gene expressed in mouse somatic cells. J Biol Chem 2008, 283: 30997–31004. 10.1074/jbc.M802992200
Lee J, Kim HK, Rho JY, Han YM, Kim J: The human OCT-4 isoforms differ in their ability to confer self-renewal. J Biol Chem 2006, 281: 33554–33565. 10.1074/jbc.M603937200
Papamichos SI, Lambropoulos AF, Kotoula V: OCT4B expression in PBMNCs suggests the existence of an alternative OCT4 promoter. Genes Chromosomes Cancer 2009, 48: 1112–1114. 10.1002/gcc.20707
Gao Y, Wang X, Han J, Xiao Z, Chen B, Su G, Dai J: The novel OCT4 spliced variant OCT4B1 can generate three protein isoforms by alternative splicing into OCT4B. J Genet Genomics 2010, 37: 461–465. 10.1016/S1673-8527(09)60065-5
Guo CL, Liu L, Jia YD, Zhao XY, Zhou Q, Wang L: A novel variant of Oct3/4 gene in mouse embryonic stem cells. Stem Cell Res 2012, 9: 69–76. 10.1016/j.scr.2012.04.004
Farashahi Yazd E, Rafiee MR, Soleimani M, Tavallaei M, Salmani MK, Mowla SJ: OCT4B1, a novel spliced variant of OCT4, generates a stable truncated protein with a potential role in stress response. Cancer Lett 2011, 309: 170–175. 10.1016/j.canlet.2011.05.027
Asadi MH, Mowla SJ, Fathi F, Aleyasin A, Asadzadeh J, Atlasi Y: OCT4B1, a novel spliced variant of OCT4, is highly expressed in gastric cancer and acts as an antiapoptotic factor. Int J Cancer 2011, 128: 2645–2652. 10.1002/ijc.25643
D'Ippolito G, Diabira S, Howard GA, Menei P, Roos BA, Schiller PC: Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J Cell Sci 2004, 117: 2971–2981. 10.1242/jcs.01103
D'Ippolito G, Diabira S, Howard GA, Roos BA, Schiller PC: Low oxygen tension inhibits osteogenic differentiation and enhances stemness of human MIAMI cells. Bone 2006, 39: 513–522. 10.1016/j.bone.2006.02.061
Goolsby J, Marty MC, Heletz D, Chiappelli J, Tashko G, Yarnell D, Fishman PS, Dhib-Jalbut S, Bever CT Jr, Pessac B, Trisler D: Hematopoietic progenitors express neural genes. Proc Natl Acad Sci USA 2003, 100: 14926–14931. 10.1073/pnas.2434383100
Izadpanah R, Trygg C, Patel B, Kriedt C, Dufour J, Gimble JM, Bunnell BA: Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem 2006, 99: 1285–1297. 10.1002/jcb.20904
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM: Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002, 418: 41–49. 10.1038/nature00870
Johnson J, Bagley J, Skaznik-Wikiel M, Lee HJ, Adams GB, Niikura Y, Tschudy KS, Tilly JC, Cortes ML, Forkert R, Spitzer T, Iacomini J, Scadden DT, Tilly JL: Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 2005, 122: 303–315. 10.1016/j.cell.2005.06.031
Lamoury FM, Croitoru-Lamoury J, Brew BJ: Undifferentiated mouse mesenchymal stem cells spontaneously express neural and stem cell markers Oct-4 and Rex-1. Cytotherapy 2006, 8: 228–242. 10.1080/14653240600735875
Moriscot C, de Fraipont F, Richard MJ, Marchand M, Savatier P, Bosco D, Favrot M, Benhamou PY: Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro. Stem Cells 2005, 23: 594–603. 10.1634/stemcells.2004-0123
Nayernia K, Lee JH, Drusenheimer N, Nolte J, Wulf G, Dressel R, Gromoll J, Engel W: Derivation of male germ cells from bone marrow stem cells. Lab Invest 2006, 86: 654–663. 10.1038/labinvest.3700429
Pallante BA, Duignan I, Okin D, Chin A, Bressan MC, Mikawa T, Edelberg JM: Bone marrow Oct3/4+ cells differentiate into cardiac myocytes via age-dependent paracrine mechanisms. Circ Res 2007, 100: e1-e11. 10.1161/01.RES.0000253487.02398.85
Pochampally RR, Smith JR, Ylostalo J, Prockop DJ: Serum deprivation of human marrow stromal cells (hMSCs) selects for a subpopulation of early progenitor cells with enhanced expression of OCT-4 and other embryonic genes. Blood 2004, 103: 1647–1652. 10.1182/blood-2003-06-1967
Ren H, Cao Y, Zhao Q, Li J, Zhou C, Liao L, Jia M, Zhao Q, Cai H, Han ZC, Yang R, Chen G, Zhao RC: Proliferation and differentiation of bone marrow stromal cells under hypoxic conditions. Biochem Biophys Res Commun 2006, 347: 12–21. 10.1016/j.bbrc.2006.05.169
Wang R, Li J, Yashpal N: Phenotypic analysis of c-Kit expression in epithelial monolayers derived from postnatal rat pancreatic islets. J Endocrinol 2004, 182: 113–122. 10.1677/joe.0.1820113
Sagrinati C, Netti GS, Mazzinghi B, Lazzeri E, Liotta F, Frosali F, Ronconi E, Meini C, Gacci M, Squecco R, Carini M, Gesualdo L, Francini F, Maggi E, Annunziato F, Lasagni L, Serio M, Romagnani S, Romagnani P: Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys. J Am Soc Nephrol 2006, 17: 2443–2456. 10.1681/ASN.2006010089
Gupta S, Verfaillie C, Chmielewski D, Kren S, Eidman K, Connaire J, Heremans Y, Lund T, Blackstad M, Jiang Y, Luttun A, Rosenberg ME: Isolation and characterization of kidney-derived stem cells. J Am Soc Nephrol 2006, 17: 3028–3040. 10.1681/ASN.2006030275
Romagnani P, Annunziato F, Liotta F, Lazzeri E, Mazzinghi B, Frosali F, Cosmi L, Maggi L, Lasagni L, Scheffold A, Kruger M, Dimmeler S, Marra F, Gensini G, Maggi E, Romagnani S: CD14 + CD34low cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors. Circ Res 2005, 97: 314–322. 10.1161/01.RES.0000177670.72216.9b
Tondreau T, Meuleman N, Delforge A, Dejeneffe M, Leroy R, Massy M, Mortier C, Bron D, Lagneaux L: Mesenchymal stem cells derived from CD133-positive cells in mobilized peripheral blood and cord blood: proliferation, Oct4 expression, and plasticity. Stem Cells 2005, 23: 1105–1112. 10.1634/stemcells.2004-0330
Cervello I, Martinez-Conejero JA, Horcajadas JA, Pellicer A, Simon C: Identification, characterization and co-localization of label-retaining cell population in mouse endometrium with typical undifferentiated markers. Hum Reprod 2007, 22: 45–51.
Matthai C, Horvat R, Noe M, Nagele F, Radjabi A, van Trotsenburg M, Huber J, Kolbus A: Oct-4 expression in human endometrium. Mol Hum Reprod 2006, 12: 7–10. 10.1093/molehr/gah254
Thomas T, Nowka K, Lan L, Derwahl M: Expression of endoderm stem cell markers: evidence for the presence of adult stem cells in human thyroid glands. Thyroid 2006, 16: 537–544. 10.1089/thy.2006.16.537
Ling TY, Kuo MD, Li CL, Yu AL, Huang YH, Wu TJ, Lin YC, Chen SH, Yu J: Identification of pulmonary Oct-4+ stem/progenitor cells and demonstration of their susceptibility to SARS coronavirus (SARS-CoV) infection in vitro. Proc Natl Acad Sci USA 2006, 103: 9530–9535. 10.1073/pnas.0510232103
Okuda T, Tagawa K, Qi ML, Hoshio M, Ueda H, Kawano H, Kanazawa I, Muramatsu M, Okazawa H: Oct-3/4 repression accelerates differentiation of neural progenitor cells in vitro and in vivo. Brain Res Mol Brain Res 2004, 132: 18–30. 10.1016/j.molbrainres.2004.08.021
Davis SF, Hood J, Thomas A, Bunnell BA: Isolation of adult rhesus neural stem and progenitor cells and differentiation into immature oligodendrocytes. Stem Cells Dev 2006, 15: 191–199. 10.1089/scd.2006.15.191
Beltrami AP, Cesselli D, Bergamin N, Marcon P, Rigo S, Puppato E, D'Aurizio F, Verardo R, Piazza S, Pignatelli A, Poz A, Baccarani U, Damiani D, Fanin R, Mariuzzi L, Finato N, Masolini P, Burelli S, Belluzzi O, Schneider C, Beltrami CA: Multipotent cells can be generated in vitro from several adult human organs (heart, liver, and bone marrow). Blood 2007, 110: 3438–3446. 10.1182/blood-2006-11-055566
Dyce PW, Zhu H, Craig J, Li J: Stem cells with multilineage potential derived from porcine skin. Biochem Biophys Res Commun 2004, 316: 651–658. 10.1016/j.bbrc.2004.02.093
Dyce PW, Wen L, Li J: In vitro germline potential of stem cells derived from fetal porcine skin. Nat Cell Biol 2006, 8: 384–390. 10.1038/ncb1388
Kues WA, Petersen B, Mysegades W, Carnwath JW, Niemann H: Isolation of murine and porcine fetal stem cells from somatic tissue. Biol Reprod 2005, 72: 1020–1028.
Yu H, Fang D, Kumar SM, Li L, Nguyen TK, Acs G, Herlyn M, Xu X: Isolation of a novel population of multipotent adult stem cells from human hair follicles. Am J Pathol 2006, 168: 1879–1888. 10.2353/ajpath.2006.051170
Lengner CJ, Camargo FD, Hochedlinger K, Welstead GG, Zaidi S, Gokhale S, Scholer HR, Tomilin A, Jaenisch R: Oct4 expression is not required for mouse somatic stem cell self-renewal. Cell Stem Cell 2007, 1: 403–415. 10.1016/j.stem.2007.07.020
This research was supported by the Max Planck Society, DFG grant SI 1695/1-2 (SPP1356) and NIH grant R01HD059946-01 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. We thank Areti Malapetsas for final editing.
The authors declare that they have no competing interests.
GW drafted the manuscript. HRS and GW outlined, edited and revised the manuscript and all authors read and approved the final manuscript.