Regulation of in vitro and in vivo differentiation of mouse embryonic stem cells, embryonic germ cells and teratocarcinoma cells by TGFβ family signaling factors

Gordeeva, O. F.; Nikonova, T. M.; Lifantseva, N. V.

doi:10.1134/s1062360409060010

Cited by 8 publications

(5 citation statements)

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“…It is well established that TGFβ is needed to maintain pluripotency in human embryonic stem cell populations [42]. Alterations in TGFβ signaling has been reported in teratocarcinoma development in vitro and in vivo [43] and the mouse teratoma-derived cell line showed increased tumorigenic properties with decreased TGFβ response [44]. While further studies are needed to elucidate the mechanism of teratoma formation, attenuated TGFβ signaling in the granulosa cells or developing follicles could alter the microenvironment of oocytes through paracrine signaling leading to teratoma formation, as seen in a recent publication involving Hedgehog signaling [45].…”

Section: Discussionmentioning

confidence: 99%

Conditional Inactivation of p53 in Mouse Ovarian Surface Epithelium Does Not Alter MIS Driven Smad2-Dominant Negative Epithelium-Lined Inclusion Cysts or Teratomas

et al. 2013

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Epithelial ovarian cancer is the most lethal gynecological malignancy among US women. The etiology of this disease, although poorly understood, may involve the ovarian surface epithelium or the epithelium of the fallopian tube fimbriae as the progenitor cell. Disruptions in the transforming growth factor beta (TGFβ) pathway and p53 are frequently found in chemotherapy-resistant serous ovarian tumors. Transgenic mice expressing a dominant negative form of Smad2 (Smad2DN), a downstream transcription factor of the TGFβ signaling pathway, targeted to tissues of the reproductive tract were created on a FVB background. These mice developed epithelium-lined inclusion cysts, a potential precursor lesion to ovarian cancer, which morphologically resembled oviductal epithelium but exhibited protein expression more closely resembling the ovarian surface epithelium. An additional genetic “hit” of p53 deletion was predicted to result in ovarian tumors. Tissue specific deletion of p53 in the ovaries and oviducts alone was attempted through intrabursal or intraoviductal injection of Cre-recombinase expressing adenovirus (AdCreGFP) into p53 flox/flox mice. Ovarian bursal cysts were detected in some mice 6 months after intrabursal injection. No pathological abnormalities were detected in mice with intraoviductal injections, which may be related to decreased infectivity of the oviductal epithelium with adenovirus as compared to the ovarian surface epithelium. Bitransgenic mice, expressing both the Smad2DN transgene and p53 flox/flox, were then exposed to AdCreGFP in the bursa and oviductal lumen. These mice did not develop any additional phenotypes. Exposure to AdCreGFP is not an effective methodology for conditional deletion of floxed genes in oviductal epithelium and tissue specific promoters should be employed in future mouse models of the disease. In addition, a novel phenotype was observed in mice with high expression of the Smad2DN transgene as validated through qPCR analysis, characterized by teratoma-like lesions implicating Smad signaling in teratoma development.

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Section: Discussionmentioning

confidence: 99%

Conditional Inactivation of p53 in Mouse Ovarian Surface Epithelium Does Not Alter MIS Driven Smad2-Dominant Negative Epithelium-Lined Inclusion Cysts or Teratomas

et al. 2013

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“…The differentiation patterns of ESCs and ECCs in the grafts are very similar to those of their embryoid bodies during spontaneous in vitro differentiation [267]. Nullipotent ECCs form tumors that consist mainly of undifferentiated cells, whereas multipotent ECC lines differentiate into multiple lineages [276].…”

Section: Tgfβ Family Signaling Pathways In Regulation Of Tumorigenicity Of Pluripotent and Teratocarcinoma Stem Cellsmentioning

confidence: 79%

“…The deregulation of pro-mitogenic and pro-differentiation signal balance and intrinsic transcriptional networks impairs ECC differentiation (Figure 2). The self-renewal of both mouse and human ECCs does not require the activity of the LIF/STAT3 pathway, unlike naїve pluripotent stem cells, but depends on serum mitogenic factors, like primed pluripotent stem cells [264][265][266][267]. However, LIF can inhibit the retinoic acid (RA)-induced differentiation to extraembryonic endoderm lineages in OTF9 and P19 mECCs [264,268,269] or potentiate neural induction in P19 mECCs [270,271].…”

Section: Tgfβ Family Signaling Pathways Contribute To the Imbalance Of Self-renewal And Differentiation In Embryonal Carcinoma Cellsmentioning

confidence: 99%

“…Additionally, the expression and affinity of TGFβ receptors were found at low levels in undifferentiated F9 and PC-13 ECCs; therefore, there were low responses to these factors in the undifferentiated cells, but these responses increased after RA-induced differentiation [281]. In contrast, Activin receptors Acvr1b and Acvr2b are expressed in both undifferentiated and differentiated P19 and F9 mECCs and Tera-2 hECCs, whereas the expression of Activins and Inhibins greatly varied between these cells [267,282,283].…”

Section: Tgfβ Family Signaling Pathways Contribute To the Imbalance Of Self-renewal And Differentiation In Embryonal Carcinoma Cellsmentioning

confidence: 99%

“…Nullipotent ECCs form tumors that consist mainly of undifferentiated cells, whereas multipotent ECC lines differentiate into multiple lineages [276]. In embryoid bodies and tumors formed by mESCs, mEGCs and F9 mECCs, similar gene expression profiles were revealed for both pluripotency and lineage markers, as well as for TGFβ family factors [267]. Interestingly, during the evolution of the F9 mECC line in vitro, the arising sublines exhibited different potentials for spontaneous and RA-induced differentiation.…”

Section: Tgfβ Family Signaling Pathways In Regulation Of Tumorigenicity Of Pluripotent and Teratocarcinoma Stem Cellsmentioning

confidence: 99%

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TGFβ Family Signaling Pathways in Pluripotent and Teratocarcinoma Stem Cells’ Fate Decisions: Balancing Between Self-Renewal, Differentiation, and Cancer

Gordeeva

2019

Cells

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The transforming growth factor-β (TGFβ) family factors induce pleiotropic effects and are involved in the regulation of most normal and pathological cellular processes. The activity of different branches of the TGFβ family signaling pathways and their interplay with other signaling pathways govern the fine regulation of the self-renewal, differentiation onset and specialization of pluripotent stem cells in various cell derivatives. TGFβ family signaling pathways play a pivotal role in balancing basic cellular processes in pluripotent stem cells and their derivatives, although disturbances in their genome integrity induce the rearrangements of signaling pathways and lead to functional impairments and malignant transformation into cancer stem cells. Therefore, the identification of critical nodes and targets in the regulatory cascades of TGFβ family factors and other signaling pathways, and analysis of the rearrangements of the signal regulatory network during stem cell state transitions and interconversions, are key issues for understanding the fundamental mechanisms of both stem cell biology and cancer initiation and progression, as well as for clinical applications. This review summarizes recent advances in our understanding of TGFβ family functions in naїve and primed pluripotent stem cells and discusses how these pathways are involved in perturbations in the signaling network of malignant teratocarcinoma stem cells with impaired differentiation potential.

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Erratum to: Suppression of malignancy by Smad3 in mouse embryonic stem cell formed teratoma

Chen

Meng

Kwok

et al. 2013

Stem Cell Rev and Rep

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The original version of this article unfortunately contained mistakes. The name of the third author was incorrect and a typological error in the Acknowledgments section was found. The correct information is given below. & Meng Xiaoming should be Xiaoming Meng (as above). & The Acknowledgment should read: "We are grateful to Dennis Lo, Huating Wang, Shuang Zhou and Hao Sun for reagents and helpful discussions. We thank Yu Cai for critical readings of the manuscript and helpful advice."

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Regulation of in vitro and in vivo differentiation of mouse embryonic stem cells, embryonic germ cells and teratocarcinoma cells by TGFβ family signaling factors

Cited by 8 publications

References 39 publications

Conditional Inactivation of p53 in Mouse Ovarian Surface Epithelium Does Not Alter MIS Driven Smad2-Dominant Negative Epithelium-Lined Inclusion Cysts or Teratomas

Conditional Inactivation of p53 in Mouse Ovarian Surface Epithelium Does Not Alter MIS Driven Smad2-Dominant Negative Epithelium-Lined Inclusion Cysts or Teratomas

TGFβ Family Signaling Pathways in Pluripotent and Teratocarcinoma Stem Cells’ Fate Decisions: Balancing Between Self-Renewal, Differentiation, and Cancer

Erratum to: Suppression of malignancy by Smad3 in mouse embryonic stem cell formed teratoma

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