Thy-1/β3 Integrin Interaction-Induced Apoptosis of Dermal Fibroblasts Is Mediated by Up-Regulation of FasL Expression

Schmidt, Manuela; Gutknecht, Danny; Anastassiadis, Konstantinos; Eckes, Beate; Anderegg, Ulf; Saalbach, Anja

doi:10.1016/j.jid.2015.10.063

Cited by 12 publications

(14 citation statements)

References 10 publications

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“…Accordingly, only Thy-1-positive human myometrial and orbital fibroblasts were able to differentiate into myofibroblasts after TGF-b stimulation (45). Consistently, Thy-1-deficient mice displayed diminished granulation tissue formation, increased fibroblast proliferation, decreased apoptosis, and down-regulation of FasL (37,46,47). Generally, Thy-1 plays significant roles in tissue repair and fibrosis.…”

Section: Fibroblastsmentioning

confidence: 88%

Thy‐1: more than a marker for mesenchymal stromal cells

Saalbach

Anderegg

2019

FASEB j.

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Balanced differentiation of mesenchymal stromal cells (MSCs) into osteoblasts and adipocytes is essential for healthy bone and fat homeostasis. A disturbed balance of MSC differentiation results in bone loss and increased adipogenesis as observed in several human conditions, such as osteoporosis, obesity, and aging. This reflects the importance of MSC fate decision. Therefore, it is important to identify factors that regulate the balance between osteogenic and adipogenic differentiation of MSCs so as to identify new targets to improve bone formation in osteoporosis and control adipose tissue development. There is accumulating evidence that thymus cell antigen 1 (Thy‐1), also known as CD90, expressed on MSCs, plays a critical role in the fate decision of MSCs. Recently, Thy‐1 has been shown to promote osteogenic differentiation of MSCs and thus bone formation while inhibiting adipogenic differentiation and restricting adipose tissue accumulation. The clinical importance of these findings was validated by the detection of reduced serum soluble Thy‐1 in patients with disturbed bone remodeling. In this review, we aim to summarize data on the impact of Thy‐1 on the control of MSC differentiation and its consequences for bone and fat formation.—Saalbach, A., Anderegg, U. Thy‐1: more than a marker for mesenchymal stromal cells. FASEB J. 33, 6689–6696 (2019). http://www.fasebj.org

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Section: Fibroblastsmentioning

confidence: 88%

Thy‐1: more than a marker for mesenchymal stromal cells

Saalbach

Anderegg

2019

FASEB j.

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“…The tightly controlled lineage commitment of MSCs plays a critical role in the maintenance of bone homeostasis and lean body composition. Recent studies indicate a crucial role of Thy-1 in the control of differentiation of mesenchyme-derived fibroblasts (15,22). Therefore, we investigated whether Thy-1 acts as a molecular regulator balancing adipogenic and osteogenic differentiation of MSCs.…”

Section: Thy-1 Promotes Differentiation Of Mscs Into Osteoblasts Whilmentioning

confidence: 99%

“…1, F and G). To distinguish whether Thy-1 or integrin 3 signaling is responsible for the control of MSC differentiation, Thy-1-deficient MSCs were seeded on immobilized recombinant Thy-1 (rThy-1) fused to an Fc domain (15,22). Thy-1 deficiency did not alter the adhesion of MSCs to rThy-1 or Fc ( fig.…”

Section: Thy-1 Promotes Differentiation Of Mscs Into Osteoblasts Whilmentioning

confidence: 99%

“…Integrins such as 2, 3, 5, CD97, and syndecan-4 were described as ligands/counter-receptors for Thy-1 (17)(18)(19)(20)(21). In mesenchymal fibroblasts, Thy-1 controls the balance between proliferation and apoptosis as well as the differentiation of fibroblasts to myofibroblasts (15,22). In healthy human lung, most of the fibroblasts express Thy-1, whereas in fibroblastic foci of idiopathic pulmonary fibrosis, Thy-1 expression is lost (23).…”

Section: Introductionmentioning

confidence: 99%

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Thy-1 (CD90) promotes bone formation and protects against obesity

et al. 2018

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Osteoporosis and obesity result from disturbed osteogenic and adipogenic differentiation and present emerging challenges for our aging society. Because of the regulatory role of Thy-1 in mesenchyme-derived fibroblasts, we investigated the impact of Thy-1 expression on mesenchymal stem cell (MSC) fate between osteogenic and adipogenic differentiation and consequences for bone formation and adipose tissue development in vivo. MSCs from Thy-1-deficient mice have decreased osteoblast differentiation and increased adipogenic differentiation compared to MSCs from wild-type mice. Consistently, Thy-1-deficient mice exhibited decreased bone volume and bone formation rate with elevated cortical porosity, resulting in lower bone strength. In parallel, body weight, subcutaneous/epigonadal fat mass, and bone fat volume were increased. Thy-1 deficiency was accompanied by reduced expression of specific Wnt ligands with simultaneous increase of the Wnt inhibitors sclerostin and dickkopf-1 and an altered responsiveness to Wnt. We demonstrated that disturbed bone remodeling in osteoporosis and dysregulated adipose tissue accumulation in patients with obesity were mirrored by reduced serum Thy-1 concentrations. Our findings provide new insights into the mutual regulation of bone formation and obesity and open new perspectives to monitor and to interfere with the dysregulated balance of adipogenesis and osteogenesis in obesity and osteoporosis.

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“…However, reduced Thy-1 expression was reported to be associated with aberrant proliferation and activation of lung fibroblasts in LPS or bleomycin-induced pulmonary fibrosis [12,13]. Thy-1 also binds to integrin β3 (Itgb3) and inhibits skin dermal cell proliferation, and its depletion could induce the proliferation of skin dermal cells [14].…”

Section: Introductionmentioning

confidence: 99%

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

Wan

Xie

et al. 2019

Laboratory Investigation

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ARTICLEThy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis Abstract Lipopolysaccharide (LPS)-induced autophagy inhibition in lung fibroblasts is closely associated with the activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K-Akt-mTOR) pathway. However, the underlying mechanism remains unknown. In this study, we demonstrated that LPS activated the PI3K-Akt-mTOR pathway and inhibited lung fibroblast autophagy by depleting thymocyte differentiation antigen-1 (Thy-1) and upregulating integrin β3 (Itgb3). Challenge of the human lung fibroblast MRC-5 cell line with LPS resulted in significant upregulation of integrin β3, activation of the PI3K-Akt-mTOR pathway and inhibition of autophagy, which could be abolished by integrin β3 silencing by specific shRNA or treatment with the integrin β3 inhibitor cilengitide. Meanwhile, LPS could inhibit Thy-1 expression accompanied with PI3K-Akt-mTOR pathway activation and lung fibroblast autophagy inhibition; these effects could be prevented by Thy-1 overexpression. Meanwhile, Thy-1 downregulation with Thy-1 shRNA could mimic the effects of LPS, inducing the activation of PI3K-Akt-mTOR pathway and inhibiting lung fibroblast autophagy. Furthermore, protein immunoprecipitation analysis demonstrated that LPS reduced the binding of Thy-1 to integrin β3. Thy-1 downregulation, integrin β3 upregulation and autophagy inhibition were also detected in a mouse model of LPS-induced pulmonary fibrosis, which could be prohibited by intratracheal injection of Thy-1 overexpressing adeno-associated virus (AAV) or intraperitoneal injection of the integrin β3 inhibitor cilengitide. In conclusion, this study demonstrated that Thy-1 depletion and integrin β3 upregulation are involved in LPS-induced pulmonary fibrosis, and may serve as potential therapeutic targets for pulmonary fibrosis.

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Thy-1/β3 Integrin Interaction-Induced Apoptosis of Dermal Fibroblasts Is Mediated by Up-Regulation of FasL Expression

Cited by 12 publications

References 10 publications

Thy‐1: more than a marker for mesenchymal stromal cells

Thy‐1: more than a marker for mesenchymal stromal cells

Thy-1 (CD90) promotes bone formation and protects against obesity

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

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