Functional Relevance of Activin A in the Intestinal Epithelium

Dignaß, Axel; Jung, Susan; Harder-D'heureuse, Johanna; Wiedenmann, B.

doi:10.1080/003655202760230900

Cited by 27 publications

(24 citation statements)

References 24 publications

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“…As activin A reduces LEC sprouting but not LEC proliferation (data not shown), we suggest that activin A decreases LEC motility. This effect appears to be cell type-specific, as activin A increases migration in most cell types tested, e.g., mast cell (Funaba et al, 2003), epithelial cells (Dignass et al, 2002), and smooth muscle cells (Riedy et al, 1999). In addition, in our experiments, activin A increased the migration of melanoma cells in vitro, and this also holds true for other malignant cell types, such as, e.g., prostate carcinoma (Kang et al, 2009).…”

Section: Discussionsupporting

confidence: 52%

Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model

Heinz

Niederleithner

Puujalka

et al. 2015

Journal of Investigative Dermatology

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Melanoma spreads primarily to the sentinel lymph nodes, and its risk correlates with lymphangiogenesis, which is mainly driven by vascular endothelial growth factor (VEGF)-C. However, anti-lymphangiogenic factors are poorly characterized. We have shown in a melanoma model that Wnt1 reduces lymphangiogenesis by reducing VEGF-C expression. Screening this model for additional potentially anti-lymphangiogenic factors identified increased activin A expression and reduced expression of the antagonist, follistatin (FST), in Wnt1(+) cells. Activin A is known to reduce blood vessel formation, but the effects on lymphangiogenesis are unknown. Here we show that human primary melanoma expresses significantly higher levels of activin A and lower levels of FST compared with nevi and melanoma metastasis. Using our mouse model with melanoma cells overexpressing Wnt1, FST, Wnt1/FST, or the inhibin βA subunit (INHBA, resulting in activin A expression), we found both activin A and Wnt1 to reduce lymphangiogenesis. Whereas Wnt1 also reduced metastasis, this was not seen with activin A. In vitro, activin A phosphorylated SMAD2 in both melanoma and lymphatic endothelium but, although it reduced sprouting of lymphatic endothelium, it enhanced the migration of melanoma cells. In conclusion, activin A is an anti-lymphangiogenic factor, but because of its pleiotropic effects on cell mobility it appears not suitable as a pharmacological target.

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Section: Discussionsupporting

confidence: 52%

Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model

Heinz

Niederleithner

Puujalka

et al. 2015

Journal of Investigative Dermatology

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“…In addition, it has to be considered that these factors and also various non-peptide factors may act in an additive or even synergistic fashion which may potentiate their single effects. Notably, in addition to TGF-β the TGF-β family member Activin A has been identified to also inhibit epithelial cell proliferation, thus providing an additional mechanism to counterbalance the effects of proliferative factors present within the intestinal mucosa and to inhibit unrestrained cell growth [59,60] .…”

Section: The Role Of Regulatory Peptides For Intestinal Epithelial Womentioning

confidence: 99%

Epithelial restitution and wound healing in inflammatory bowel disease

Sturm¹,

Dignaß²

2008

WJG

288

260

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disorders including inflammatory bowel diseases and require constant repair of the epithelium. Enhancement of intestinal repair mechanisms by regulatory peptides or other modulatory factors may provide future approaches for the treatment of diseases that are characterized by injuries of the epithelial surface. THE MUCOSAL DEFENSE SYSTEMThe surface of the digestive tract is covered by epithelial cells that constitute an efficient physical barrier between the dietary and enteric flora pathogens found in the intestinal lumen and the individuum, but also allows an exchange between nutrients and the systemic circulation [1] . The epithelial defense mechanism can be categorized into three key components: pre-epithelial, epithelial and post-epithelial, the latter is represented by the lamina propria [2] . The pre-epithelial mucus barrier is composed of mucin associated with other proteins and lipids and forms a continuous gel into which a bicarbonate-rich fluid is secreted, maintaining a neutralizing pH at the epithelial surface. Phosphatidylcholine is the predominant surface bioactive phospholipid found within the gastrointestinal tract [3] . Intestinal epithelial cells secrete mucins and glycocalyx, which contain membrane-anchored negatively charged mucin-like glycoproteins and hydrophobic phospholipids [4] . The tight adherence of mucin to the apical surfaces of epithelia is owed to the existence of the specific complex between mucin oligosaccharides and the mucin binding protein of the apical mucosal membrane [5] . AbstractInflammatory bowel disease is characterized by a chronic inflammation of the intestinal mucosa. The mucosal epithelium of the alimentary tract constitutes a key element of the mucosal barrier to a broad spectrum of deleterious substances present within the intestinal lumen including bacterial microorganisms, various dietary factors, gastrointestinal secretory products and drugs. In addition, this mucosal barrier can be disturbed in the course of various intestinal disorders including inflammatory bowel diseases. Fortunately, the integrity of the gastrointestinal surface epithelium is rapidly reestablished even after extensive destruction. Rapid resealing of the epithelial barrier following injuries is accomplished by a process termed epithelial restitution, followed by more delayed mechanisms of epithelial wound healing including increased epithelial cell proliferation and epithelial cell differentiation. Restitution of the intestinal surface epithelium is modulated by a range of highly divergent factors among them a broad spectrum of structurally distinct regulatory peptides, variously described as growth factors or cytokines. S e ve ra l re g u l a t or y pe pt ide fac t or s ac t from t he basolateral site of the epithelial surface and enhance epithelial cell restitution through TGF-β-dependent pathways. In contrast, members of the trefoil factor family (TFF peptides) appear to stimulate epithelial restitution in conjunction with mucin glycoproteins through a TGF-β-independent mechanism from...

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“…It also is possible that GnRH meets the above criteria but there are no serum concentration data available during human senescence to make this determination. While activins have been shown to promote cell proliferation in some tissues, it is unlikely they would represent the mitogenic factor, since they more frequently inhibit cell proliferation and promote differentiation [Dalkin et al, 1996;Dignass et al, 2002;Engelse et al, 1999]. Therefore, the likely candidates for the mitogenic factor(s) are GnRH, LH, and/or FSH ( fig.…”

Section: Mitogenic Factor(s)mentioning

confidence: 99%

Living and Dying for Sex

2004

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A mechanistic understanding of aging has yet to be described; this paper puts forth a new theory that has the potential to explain aging in all sexually reproductive life forms. The theory also puts forth a new definition of aging – any change in an organism over time. This definition includes not only the changes associated with the loss of function (i.e. senescence, the commonly accepted definition of aging), but also the changes associated with the gain of function (growth and development). Using this definition, the rate of aging would be synonymous with the rate of change. The rate of change/aging is most rapid during the fetal period when organisms develop from a single cell at conception to a multicellular organism at birth. Therefore, ‘fetal aging’ would be determined by factors regulating the rate of mitogenesis, differentiation, and cell death. We suggest that these factors also are responsible for regulating aging throughout life. Thus, whatever controls mitogenesis, differentiation and cell death must also control aging. Since life-extending modalities consistently affect reproduction, and reproductive hormones are known to regulate mitogenesis and differentiation, we propose that aging is primarily regulated by the hormones that control reproduction (hence, the Reproductive-Cell Cycle Theory of Aging). In mammals, reproduction is controlled by the hypothalamic-pituitary-gonadal (HPG) axis hormones. Longevity inducing interventions, including caloric restriction, decrease fertility by suppressing HPG axis hormones and HPG hormones are known to affect signaling through the well-documented longevity regulating GH/IGF-1/PI3K/Akt/Forkhead pathway. This is exemplified by genetic alterations in Caenorhabditis elegans where homologues of the HPG axis pathways, as well as the daf-2 and daf-9 pathways, all converge on daf-16, the homologue of human Forkhead that functions in the regulation of cell cycle events. In summary, we propose that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence.

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Functional Relevance of Activin A in the Intestinal Epithelium

Abstract: Activin A may play an important role in the modulation of intestinal epithelial cell function, thus providing a new approach to modulate intestinal wound repair.

Cited by 27 publications

References 24 publications

Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model

Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model

Epithelial restitution and wound healing in inflammatory bowel disease

Living and Dying for Sex

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