The Mesenchymal Stroma Negatively Regulates B Cell Lymphopoiesis through the Expression of Activin A

Shoham, Tsipi; Parameswaran, Reshmi; Shav‐Tal, Yaron; Barda‐Saad, Mira; Zipori, Dov

doi:10.1111/j.1749-6632.2003.tb03253.x

Cited by 23 publications

(21 citation statements)

References 23 publications

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“…83 Moreover, in vivo polyclonal B-cell activation induced by LPS injection was accompanied by a notable reduction of bA expression in bone marrow and spleen (Figure 3a). 84 Several experiments have shown that the inhibitory signals provided by activin A occur at early stages of B-cell development. Analysis of B-cell lymphopoiesis in vitro showed that functional activin A is observed at early stage of cultures, whereas the appearance of B220 + B-cell colonies correlated with a lower titer of functional activin A and high levels of FS and inhibin a-chain expression (Figure 3a).…”

Section: Role Of Activins/inhibins On Adaptive Immune Cells B Cellsmentioning

confidence: 99%

“…85 Conversely, the use of a mouse endothelialadipocyte cell line, which lacks functional activin A, resulted in the early accumulation of CD43 lo B220 À and CD43 lo B220 + B-cell colonies. 84 Hence, activin A behaves as a ''brake'' signal on B-cell differentiation under steady conditions, but once inflammatory signals have emerged, such as those triggered by LPS, activin A expression in the bone marrow is turned off, allowing B-cell differentiation and the expansion of the B-cell repertoire (Figure 3a).…”

Section: Role Of Activins/inhibins On Adaptive Immune Cells B Cellsmentioning

confidence: 99%

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When versatility matters: activins/inhibins as key regulators of immunity

Alemán-Muench

Soldevila

2011

Immunol Cell Biol

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Activins and inhibins are members of the transforming growth factor-b superfamily that have been considered crucial regulators of cell processes, such as differentiation, proliferation and apoptosis, in different cell types. Initial studies about the function of activin A in the immune system focused on the regulation of hematopoiesis in the bone marrow under homeostatic and inflammatory conditions. Recent data provide a more comprehensive understanding about the role of activins/inhibins in the immune system. Novel findings included in this review point out the important requirement of activin/inhibin signaling to maintain the balance between homeostatic and inflammatory signals that are required for the optimal development and function of immune cells. The purpose of this review is to highlight the versatile nature of activins/inhibins as key regulators of both the innate and adaptive immune responses. Keywords: activin; inhibin; inflammation; immune cells; immunity; tolerance Activins and inhibins are members of the transforming growth factor-b (TGF-b) superfamily that were initially described as regulators of reproductive processes in mammals, and were first named after their positive and negative effect in the release of follicle-stimulating hormone from the pituitary gland, respectively. 1 These dimeric ligands have been shown to modulate a variety of cellular functions such as apoptosis, proliferation, differentiation, cellular migration, among others. 2,3 Activin A (bA/bA) is the best-characterized ligand of this subfamily, although there are other bioactive forms, activin B (bB/bB) and activin AB (bA/bB), which differ in their potency and cellular function. 4 Activin A is a molecule with pleiotropic functions, which shares with TGF-b the SMAD2/3 canonical signaling pathway (reviewed by Shi and Massague 5 ) but uses distinct type II (ActRIIs) and type I (ALK2, ALK4 and ALK7) receptors. [6][7][8][9] The biological function of activins can be blocked by follistatin (FS), a glycoprotein that binds activin A with high affinity, functioning as a ligand trap. 10 On the other hand, inhibins are heterodimers formed by uncommon a-and b-subunits and exist in two isoforms, inhibin A (a/bA) and B (a/bB). Inhibins have been shown to antagonize activinmediated functions by a mechanism that involves binding to b-glycan (TGFbRIII) and formation of a ternary complex with ActRIIs. As a consequence, activin type I receptors (ALK4 and ALK2) are excluded from the receptor complex, leading to the inhibition of SMADmediated signaling. 3,[11][12][13][14] Despite the fact that inhibins have been classically considered as activin antagonists, there is evidence showing that they do not always antagonize activin-mediated functions in several cell types, suggesting the existence of an independent inhibinmediated signaling pathway. 3 Compelling evidence has shown that activins also regulate various non-reproductive processes, such as mesoderm induction, liver proliferation, skin morphogenesis, erythropoiesis, bone formation, neu...

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Section: Role Of Activins/inhibins On Adaptive Immune Cells B Cellsmentioning

confidence: 99%

Section: Role Of Activins/inhibins On Adaptive Immune Cells B Cellsmentioning

confidence: 99%

When versatility matters: activins/inhibins as key regulators of immunity

Alemán-Muench

Soldevila

2011

Immunol Cell Biol

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“…The observed differentiation of intestinal tissue from pancreas by supplemented activin A closely resembles our observations including onset of Shh and iFABP expression. Activin A is constitutively expressed by the mesenchymal spleen stroma (Shoham et al 2003). bSM and wild-type splenic mesenchyme (wSM) isolated at e13.5 were positive for the Activin ␤A subunit by RT-PCR (Fig.…”

Section: Wild-type Spleen Mesenchyme Induces Cyst Formationmentioning

confidence: 99%

Spleen versus pancreas: strict control of organ interrelationship revealed by analyses of Bapx1^−/− mice

Asayesh¹,

Sharpe²,

Watson³

et al. 2006

Genes Dev.

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During early stages of pancreatic development, the mesenchyme that contributes to the spleen overlies the dorsal pancreatic endoderm. Here, we show that interactions between splenic mesenchyme and pancreas proceed via a highly orchestrated morphogenetic program. Disruption of morphogenesis, as occurs in the Bapx1(Nkx3.2) −/− embryo, results in transformation of these tissues into well-organized, ectopic gut-like structures. Bapx1 plays a crucial organizing role effecting position and separation of the spleen and pancreas to prevent this metaplastic transformation. Similar transformations occur in organ cultures employing wild-type pancreatic endoderm and spleen mesenchyme, revealing the developmental plasticity of the pancreas and that precise spatial and temporal control of tissue interactions are required for development of both organs. Epithelial-mesenchymal interactions are central to the development of the primitive gut tube endoderm and are necessary to form fully functional parts of the gastrointestinal tract. Such interactions come into play in a stepwise manner during development of the dorsal pancreas and begin with patterning signals from the mesectoderm. Later signals from the notochord repress endodermal SHH and thereby permit expression of pancreatic genes in the dorsal pancreatic anlage. Formation of the dorsal aorta will separate the notochord from the pancreatic endoderm and will in turn provide signals that induce insulin expression (Lammert et al. 2001 and references therein). Finally, splanchnic mesenchyme will accumulate around the dorsal pancreatic bud and will promote growth and differentiation of the developing pancreatic epithelium (Kim and Hebrok 2001). Studies indicate that this accumulated mesenchyme provides permissive, rather than instructive, cues (Edlund 2002). Hence, the primary role of the mesenchymal signals at this stage is to stimulate proliferation of the different pancreatic components and not to determine developmental fate. Apart from being important for interaction with underlying epithelium, the mesenchyme surrounding the dorsal pancreas also contributes to development of the spleen during early stages of development ( Fig. 1A; Kanzler and Dear 2001;Hecksher-Sorensen et al. 2004).The mammalian homeobox gene Bapx1 (Nkx3.2) encodes a putative transcription factor that belongs to the Nkx gene family, most similar to the Drosophila homolog bap (Kim and Nirenberg 1989). Bapx1-null mutants show visceral mesoderm defects manifesting as asplenia and impaired pyloric sphincter formation (Lettice et al. 1999;Tribioli and Lufkin 1999;Akazawa et al. 2000). To better understand the dynamic developmental relationships between the spleen and pancreas, we have analyzed the Bapx1-null mutant, a model in which direct interaction between spleen and pancreas can be addressed. Here we show that heterotopic tissue outgrowths with the differentiated characteristics of gut form in the mutant. These are derived from the transformation of pancreatic endoderm and adjacent mesenchyme. Metaplasia w...

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“…8,9 Contrary to their well-known effect on T cells and antigen-presenting cells, the effect of MSC on B cells remains unclear. MSC have been implicated in B-cell development, in bone marrow, spleen and lymphoid follicles, 10 exerting a negative control on B-cell lymphopoiesis through the expression of activin A, a pleiotropic molecule which is a member of the transforming growth factor-β superfamily. In addition, Corcione et al reported that B-cell proliferation is inhibited by MSC, 11 but this has not been confirmed by other authors.…”

Section: Introductionmentioning

confidence: 99%

The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes

Tabera¹,

Pérez-Simón²,

et al. 2008

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BackgroundMesenchymal stem cells are multilineage non-hematopoietic progenitor cells that play a key role in supporting the lymphohematopoietic system. Their distribution in bone marrow and secondary lymphoid organs allows an intimate interaction with T-and B-lymphocytes. While their effect on T-lymphocytes has been extensively analyzed, data on the effect of mesenchymal stem cells on B cells are more limited. We analyzed the effects of mesenchymal stem cells on B-lymphocytes and the pathways involved in these effects.

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The Mesenchymal Stroma Negatively Regulates B Cell Lymphopoiesis through the Expression of Activin A

Cited by 23 publications

References 23 publications

When versatility matters: activins/inhibins as key regulators of immunity

When versatility matters: activins/inhibins as key regulators of immunity

Spleen versus pancreas: strict control of organ interrelationship revealed by analyses of Bapx1^−/− mice

The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes

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The Mesenchymal Stroma Negatively Regulates B Cell Lymphopoiesis through the Expression of Activin A

Cited by 23 publications

References 23 publications

When versatility matters: activins/inhibins as key regulators of immunity

When versatility matters: activins/inhibins as key regulators of immunity

Spleen versus pancreas: strict control of organ interrelationship revealed by analyses of Bapx1−/− mice

The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes

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Product

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Spleen versus pancreas: strict control of organ interrelationship revealed by analyses of Bapx1^−/− mice