TGF-β isoform signaling regulates secondary transition and mesenchymal-induced endocrine development in the embryonic mouse pancreas

Tulachan, Sidhartha; Tei, Eri; Hembree, Mark; Crisera, Christopher A.; Prasadan, Krishna; Koizumi, Masayuki; Shah, Sohail R.; Guo, Ping; Böttinger, Erwin P.; Gittes, George K.

doi:10.1016/j.ydbio.2007.02.033

Cited by 53 publications

(57 citation statements)

References 29 publications

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“…Among the many cytokines related to pancreatic endocrine cell differentiation [Larsson, 1998], TGF-b1 is considered to be related to a variety of biological processes, including growth, differentiation, morphogenesis, development, angiogenesis, and apoptosis [Miralles et al, 1998;Tulachan et al, 2007]. However, the mechanisms underlying the effects on pancreatic duct cell proliferation and transdifferentiation are currently poorly understood, and this is particularly true in human tissues.…”

Section: Discussionmentioning

confidence: 99%

“…In our protein work, we were noted marked changes in the expression of a variety of structural proteins following TGF-b1 treatment. Those proteins belonged to the actin family (myosin heavy chain, ACTB, villin2, Bub1, dynactin) and the cytokeratin family [Tulachan et al, 2007] (Tables Ia and Ib). Gamma actin, tubulin, and mutant beta-actin were identified by mass spectrometry, although the ratio was below two times that of the controls.…”

Section: Discussionmentioning

confidence: 99%

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Transforming growth factor‐β induces epithelial to mesenchymal transition and suppresses the proliferation and transdifferentiation of cultured human pancreatic duct cells

Shin

Hong

Lee

et al. 2011

J of Cellular Biochemistry

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Pancreatic duct cells are considered a potential source of β-cell regeneration, and transforming growth factor-β (TGF-β) has been suggested to perform an important role in these processes, but the underlying mechanism of the signal pathways, especially in humans, remains poorly understood. To evaluate the role of TGF-β1, pancreatic duct cells were isolated from three brain-dead organ donors. Pancreatic cell clusters harvested after islet isolation were dispersed to single cells and cultured in monolayers, then treated with TGF-β1. We analyzed the characteristics of the cultured cells, the TGF-β1 intracellular signaling pathway, the proliferation, and transdifferentiation rates of the duct cells. We also evaluated the genes and protein expression patterns after TGF-β1 treatment. After TGF-β1 treatment, typical morphologic changes representative of EMT were observed and Erk1/2, JNK, and AKT phosphorylation, Ras downstream effectors, were increased. β cell-specific transcription factors including PDX-1, Beta2/NeuroD, Ist-1, and NGN3 were markedly suppressed and the rate of transdifferentiation into β cells was also suppressed. Genomic and proteomic analyses suggested that TGF-β1 induces marked changes in a variety of structural genes and proteins associated with EMT. In conclusion, TGF-β1 induces EMT in cultured human pancreatic duct cells, but suppresses its proliferation and transdifferentiation into β cells. Our results are the first report of TGF-β1 effects for EMT and ductal cell transdifferentiation and proliferation at the protein level in human pancreatic duct cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transforming growth factor‐β induces epithelial to mesenchymal transition and suppresses the proliferation and transdifferentiation of cultured human pancreatic duct cells

Shin

Hong

Lee

et al. 2011

J of Cellular Biochemistry

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“…Additionally, DNT␤RII mice exhibit increased endocrine precursors and proliferating endocrine cells, with an abnormal accumulation of endocrine cells around the developing ducts of mid-late stage embryonic pancreas (16). Transgenic mice expressing TGF-␤1 in ␤-cells exhibit abnormal small islet cell clusters without formation of normal adult islets although the overall islet cell mass is not significantly diminished (17).…”

mentioning

confidence: 99%

Transforming Growth Factor-β/Smad3 Signaling Regulates Insulin Gene Transcription and Pancreatic Islet β-Cell Function

Lin

Lee

Yadav

et al. 2009

Journal of Biological Chemistry

157

155

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Pancreatic islet ␤-cell dysfunction is a signature feature of Type 2 diabetes pathogenesis. Consequently, knowledge of signals that regulate ␤-cell function is of immense clinical relevance. Transforming growth factor (TGF)-␤ signaling plays a critical role in pancreatic development although the role of this pathway in the adult pancreas is obscure. Here, we define an important role of the TGF-␤ pathway in regulation of insulin gene transcription and ␤-cell function. We identify insulin as a TGF-␤ target gene and show that the TGF-␤ signaling effector Smad3 occupies the insulin gene promoter and represses insulin gene transcription. In contrast, Smad3 small interfering RNAs relieve insulin transcriptional repression and enhance insulin levels. Transduction of adenoviral Smad3 into primary human and non-human primate islets suppresses insulin content, whereas, dominant-negative Smad3 enhances insulin levels. Consistent with this, Smad3-deficient mice exhibit moderate hyperinsulinemia and mild hypoglycemia. Moreover, Smad3 deficiency results in improved glucose tolerance and enhanced glucose-stimulated insulin secretion in vivo. In ex vivo perifusion assays, Smad3-deficient islets exhibit improved glucosestimulated insulin release. Interestingly, Smad3-deficient islets harbor an activated insulin-receptor signaling pathway and TGF-␤ signaling regulates expression of genes involved in ␤-cell function. Together, these studies emphasize TGF-␤/Smad3 signaling as an important regulator of insulin gene transcription and ␤-cell function and suggest that components of the TGF-␤ signaling pathway may be dysregulated in diabetes.

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“…Furthermore, hPSCs also offer unique advantages for studying conserved developmental mechanisms. For example, the exact role of TGFβ signaling in pancreatic development has been debated in mice (Harmon et al, 2004;Sanvito et al, 1994;Tei et al, 2005;Tulachan et al, 2007;Wandzioch and Zaret, 2009), potentially owing to the time-sensitive requirement of TGFβ signaling during pancreatic development. Like many other genes and signaling pathways, TGFβ signaling is used repeatedly during embryonic development.…”

Section: Understanding Human Development: Insights Gained From Studyimentioning

confidence: 99%

Human pluripotent stem cells: an emerging model in developmental biology

2013

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SummaryDevelopmental biology has long benefited from studies of classic model organisms. Recently, human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, have emerged as a new model system that offers unique advantages for developmental studies. Here, we discuss how studies of hPSCs can complement classic approaches using model organisms, and how hPSCs can be used to recapitulate aspects of human embryonic development 'in a dish'. We also summarize some of the recently developed genetic tools that greatly facilitate the interrogation of gene function during hPSC differentiation. With the development of high-throughput screening technologies, hPSCs have the potential to revolutionize gene discovery in mammalian development. Key words: Human pluripotent stem cells, Directed differentiation, Gene targeting, High-throughput screening IntroductionHuman pluripotent stem cells (hPSCs), which include human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), can self-renew indefinitely in culture while maintaining the ability to become almost any cell type in the human body (Takahashi et al., 2007;Thomson et al., 1998;Yu et al., 2007). The potential of using hPSCs for cell replacement therapy and disease modeling has been discussed extensively (Wu and Hochedlinger, 2011). This Review focuses on an equally important, yet often overlooked, aspect: using hPSCs to gain insights into human embryonic development. Although this potential has been long recognized (Keller, 2005;Pera and Trounson, 2004), it is only beginning to be realized, owing to advances in both in vitro differentiation approaches and genetic manipulation tools in hPSCs. In this Review, we summarize the latest progress in this nascent, yet rapidly advancing, field and discuss future prospects and potential challenges of using hPSCs for studies of developmental biology. First, the strengths and limitations of classic model organisms are discussed to highlight the need for a new model. Second, we illustrate how hPSCs can be used to recapitulate defined steps of embryogenesis, and we discuss how hPSC-based studies can lead to novel insights into human development. Next, we review new genetic tools that can be applied to interrogate gene function during the in vitro differentiation of hPSCs. Finally, the potential of using hPSCs for discovery-driven research is discussed.This Review focuses primarily on work performed using hPSCs, with occasional references to studies using mouse pluripotent stem cells when comparable studies are not yet available in human cells; work from both hiPSCs and hESCs is discussed, although more examples stem from hESCs, owing to their more-frequent use in differentiation experiments. Nonetheless, because of the high degree of similarity between hESCs and hiPSCs (Yamanaka, 2012), it is likely that the general strategies and most conclusions will apply to both hESCs and hiPSCs. The need for a new model systemA main challenge in biology is to understa...

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TGF-β isoform signaling regulates secondary transition and mesenchymal-induced endocrine development in the embryonic mouse pancreas

Cited by 53 publications

References 29 publications

Transforming growth factor‐β induces epithelial to mesenchymal transition and suppresses the proliferation and transdifferentiation of cultured human pancreatic duct cells

Transforming growth factor‐β induces epithelial to mesenchymal transition and suppresses the proliferation and transdifferentiation of cultured human pancreatic duct cells

Transforming Growth Factor-β/Smad3 Signaling Regulates Insulin Gene Transcription and Pancreatic Islet β-Cell Function

Human pluripotent stem cells: an emerging model in developmental biology

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