Roles of activin family in pancreatic development and homeostasis

Wiater, Ezra; Vale, Wylie

doi:10.1016/j.mce.2012.02.015

Cited by 22 publications

(12 citation statements)

References 89 publications

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“…An additional parallel between Sox4 and pancreatic development emerged when we examined the requirement of Smad4 for Sox4 expression. Although Smads 2 and 3 play a key role in the development and patterning of the foregut and pancreas (Wiater and Vale, 2012), Smad4 is dispensable for normal pancreas development (Bardeesy et al, 2006). Notably, Sox4 induction by TGF-β was Smad4-independent in all Smad4-mutant mouse lines that we tested (Figure 4A,B and data not shown).…”

Section: Resultsmentioning

confidence: 99%

TGF-β Tumor Suppression through a Lethal EMT

David

Huang

Chen

et al. 2016

Cell

530

456

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TGF-β signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-β mediator Smad4. We show that TGF-β induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-β sensitive PDA cells, EMT becomes lethal by converting TGF-β-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-β. TGF-β-induced Sox4 is thus geared to bolster progenitor identity, while simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-β tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.

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Section: Resultsmentioning

confidence: 99%

TGF-β Tumor Suppression through a Lethal EMT

David

Huang

Chen

et al. 2016

Cell

530

456

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“…We have not addressed whether this effect of Wnt3A was due to increased proliferation, decreased cell death, decreased migration of cells from aggregates (and into the medium and subsequently aspirated on daily feeding), or a combination of these. Wnt signaling has been shown to promote proliferation of PPs in the developing mouse pancreas [25], and activin family signaling has been implicated in pancreas specification [26], although because of the complexity of these pathways, the particular ligands used in vivo are not well established. Others have used relatively low concentrations of activin A similarly in their hESC-to-pancreatic cell differentiation protocols [10].…”

Section: Discussionmentioning

confidence: 99%

Insulin-Producing Endocrine Cells Differentiated In Vitro From Human Embryonic Stem Cells Function in Macroencapsulation Devices In Vivo

Agulnick

Ambruzs

Moorman

et al. 2015

Stem Cells Translational Medicine

226

161

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The PEC-01 cell population, differentiated from human embryonic stem cells (hESCs), contains pancreatic progenitors (PPs) that, when loaded into macroencapsulation devices (to produce the VC-01 candidate product) and transplanted into mice, can mature into glucose-responsive insulin-secreting cells and other pancreatic endocrine cells involved in glucose metabolism. We modified the protocol for making PEC-01 cells such that 73%-80% of the cell population consisted of PDX1-positive (PDX1 + ) and NKX6.1 + PPs. The PPs were further differentiated to islet-like cells (ICs) that reproducibly contained 73%-89% endocrine cells, of which approximately 40%-50% expressed insulin. A large fraction of these insulin-positive cells were single hormone-positive and expressed the transcription factors PDX1 and NKX6.1. To preclude a significant contribution of progenitors to the in vivo function of ICs, we used a simple enrichment process to remove remaining PPs, yielding aggregates that contained 93%-98% endocrine cells and 1%-3% progenitors. Enriched ICs, when encapsulated and implanted into mice, functioned similarly to the VC-01 candidate product, demonstrating conclusively that in vitro-produced hESC-derived insulin-producing cells can mature and function in vivo in devices. A scaled version of our suspension culture was used, and the endocrine aggregates could be cryopreserved and retain functionality. Although ICs expressed multiple important b cell genes, the cells contained relatively low levels of several maturity-associated markers. Correlating with this, the time to function of ICs was similar to PEC-01 cells, indicating that ICs required cell-autonomous maturation after delivery in vivo, which would occur concurrently with graft integration into the host. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1214-1222 SIGNIFICANCEType 1 diabetes (T1D) affects approximately 1.25 million people in the U.S. alone and is deadly if not managed with insulin injections. This paper describes the production of insulin-producing cells in vitro and a new protocol for producing the cells, representing another potential cell source for a diabetes cell therapy. These cells can be loaded into a protective device that is implanted under the skin. The device is designed to protect the cells from immune rejection by the implant recipient. The implant can engraft and respond to glucose by secreting insulin, thus potentially replacing the b cells lost in patients with T1D.

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“…In humans, activin A levels in serum correlate with fasting glucose, fasting insulin, and glycosylated hemoglobin levels (Wu et al 2013). Loss-and gainof-function transgenic mouse models for activins, activin receptors, FSTL-3, and Smads have contributed to our understanding of activin signaling in pancreas development and the proliferation, differentiation and function of islet cells (reviewed in Wiater and Vale 2012). Transgenic expression of a dominant negative ActRIIB or a constitutively active ALK-4 receptor in the pancreas results in islet hypoplasia with reduced insulin secretion and reduced glucose tolerance (Yamaoka et al 1998).…”

Section: Activin Signaling In Glucose Homeostasismentioning

confidence: 99%

Activins and Inhibins: Roles in Development, Physiology, and Disease

Namwanje

Brown

2016

Cold Spring Harb Perspect Biol

214

175

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Since their original discovery as regulators of follicle-stimulating hormone (FSH) secretion and erythropoiesis, the TGF-β family members activin and inhibin have been shown to participate in a variety of biological processes, from the earliest stages of embryonic development to highly specialized functions in terminally differentiated cells and tissues. Herein, we present the history, structures, signaling mechanisms, regulation, and biological processes in which activins and inhibins participate, including several recently discovered biological activities and functional antagonists. The potential therapeutic relevance of these advances is also discussed.

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Roles of activin family in pancreatic development and homeostasis

Cited by 22 publications

References 89 publications

TGF-β Tumor Suppression through a Lethal EMT

TGF-β Tumor Suppression through a Lethal EMT

Insulin-Producing Endocrine Cells Differentiated In Vitro From Human Embryonic Stem Cells Function in Macroencapsulation Devices In Vivo

Activins and Inhibins: Roles in Development, Physiology, and Disease

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