Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

Yamashita, Shinichi; Maeshima, Akito; Kojima, Itaru; Nojima, Yoshihisa

doi:10.1097/01.asn.0000103225.68136.e6

Cited by 131 publications

(120 citation statements)

References 52 publications

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“…This is consistent with the effects of other members of the TGF-b family such as activin and TGF-b1 in various tissues (Wada et al 2004, Yamashita et al 2004, Verrechia et al 2006. Using the multipotent mesenchymal embryonic C3H10T1/2 cell line, it was possible in our J N ARTAZA and others .…”

Section: Discussionsupporting

confidence: 74%

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

Artaza¹,

Singh²,

Ferrini³

et al. 2007

Journal of Endocrinology

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Tissue fibrosis, the excessive deposition of collagen/extracellular matrix combined with the reduction of the cell compartment, defines fibroproliferative diseases, a major cause of death and a public health burden. Key cellular processes in fibrosis include the generation of myofibroblasts from progenitor cells, and the activation or switch of already differentiated cells to a fibrotic synthetic phenotype. Myostatin, a negative regulator of skeletal muscle mass, is postulated to be involved in muscle fibrosis. We have examined whether myostatin affects the differentiation of a multipotent mesenchymal mouse cell line into myofibroblasts, and/or modulates the fibrotic phenotype and Smad expression of the cell population. In addition, we investigated the role of follistatin in this process. Incubation of cells with recombinant myostatin protein did not affect the proportion of myofibroblasts in the culture, but significantly upregulated the expression of fibrotic markers such as collagen and the key profibrotic factors transforming growth factor-b1 (TGF-b1) and plasminogen activator inhibitor (PAI-1), as well as Smad3 and 4, and the pSmad2/3. An antifibrotic process evidenced by the upregulation of follistatin, Smad7, and matrix metalloproteinase 8 accompanied these changes. Follistatin inhibited TGF-b1 induction by myostatin. Transfection with a cDNA expressing myostatin upregulated PAI-1, whereas an shRNA against myostatin blocked this effect. In conclusion, myostatin induced a fibrotic phenotype without significantly affecting differentiation into myofibroblasts. The concurrent endogenous antifibrotic reaction confirms the view that phenotypic switches in multipotent and differentiated cells may affect the progress or reversion of fibrosis, and that myostatin pharmacological inactivation may be a novel therapeutic target against fibrosis.

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Section: Discussionsupporting

confidence: 74%

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

Artaza¹,

Singh²,

Ferrini³

et al. 2007

Journal of Endocrinology

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“…However, previous studies have shown that activin A is capable of causing an increase in the proliferation of human lung fibroblasts (Heeren et al 2015) as well as promoting proliferation of cultured rat renal interstitial fibroblasts and increasing the expression of type I collagen (Yamashita et al 2004). We have observed that activin A did not affect the expression of FBN1 or FBN2 or the other TGFβ-associated genes examined in our human samples.…”

Section: Discussionmentioning

confidence: 47%

Regulation of fibrillins and modulators of TGFβ in fetal bovine and human ovaries

et al. 2016

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Fibrillins 1-3 are stromal extracellular matrix proteins that play important roles in regulating TGFβ activity, which stimulates fibroblasts to proliferate and synthesize collagen. In the developing ovary, the action of stroma is initially necessary for the formation of ovigerous cords and subsequently for the formation of follicles and the surface epithelium of the ovary. FBN3 is highly expressed only in early ovarian development and then it declines. In contrast, FBN1 and 2 are upregulated in later ovarian development. We examined the expression of FBN1-3 in bovine and human fetal ovaries. We used cell dispersion and monolayer culture, cell passaging and tissue culture. Cells were treated with growth factors, hormones or inhibitors to assess the regulation of expression of FBN1-3. When bovine fetal ovarian tissue was cultured, FBN3 expression declined significantly. Treatment with TGFβ-1 increased FBN1 and FBN2 expression in bovine fibroblasts, but did not affect FBN3 expression. Additionally, in cultures of human fetal ovarian fibroblasts (9-17 weeks gestational age), the expression of FBN1 and FBN2 increased with passage, whereas FBN3 dramatically decreased. Treatment with activin A and a TGFβ family signaling inhibitor, SB431542, differentially regulated the expression of a range of modulators of TGFβ signaling and of other growth factors in cultured human fetal ovarian fibroblasts suggesting that TGFβ signaling is differentially involved in the regulation of ovarian fibroblasts. Additionally, since the changes in FBN1-3 expression that occur in vitro are those that occur with increasing gestational age in vivo, we suggest that the fetal ovarian fibroblasts mature in vitro.

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“…HUVEC were cultured in HuMedia-EB2 supplemented with HuMedia-EG for 48 h, and HUVEC-derived conditioned media (HUVEC-CM) were collected. Protein extraction was performed as described previously (36). Human Matrix Metalloproteinase Antibody Array I (Raybiotech, Norcross, GA) was used according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Enhancement of in vitro human tubulogenesis by endothelial cell-derived factors: implications for in vivo tubular regeneration after injury

Miya¹,

Maeshima²,

Mishima³

et al. 2011

American Journal of Physiology-Renal Physiology

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Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

Cited by 131 publications

References 52 publications

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

Regulation of fibrillins and modulators of TGFβ in fetal bovine and human ovaries

Enhancement of in vitro human tubulogenesis by endothelial cell-derived factors: implications for in vivo tubular regeneration after injury

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