β-Catenin Is a Mediator of the Response of Fibroblasts to Irradiation

Abstract

Radiation causes soft tissue complications that include fibrosis and deficient wound healing. ␤-Catenin , a key component in the canonical Wnt-signaling pathway , is activated in fibrotic processes and wound repair and , as such , could play a role in mediating cellular responses to irradiation. ␤-Catenin can form a transcriptionally active complex with members of the Tcf family. A reporter mouse model , in addition to human cell cultures , was used to demonstrate that ionizing radiation activates ␤-catenin-mediated , Tcf-dependent transcription both in vitro and in vivo. Furthermore , radiation activates ␤-catenin via a Wnt-mediated mechanism , as in the presence of dickkopf-1 , an inhibitor of Wnt receptor activation , ␤-catenin levels did not increase after irradiation. Fibroblast cell cultures were derived from mice expressing either null or stabilized ␤-catenin alleles. Cells expressing stabilized ␤-catenin alleles had a higher proliferation rate and formed more colony-forming units than wild-type or null cells after irradiation. Wound healing was studied in these same mice after irradiation. There was a positive correlation between the tensile strength of the wound , the expression levels of type 1 collagen in the skin , and ␤-catenin levels. Mice treated with lithium showed increased ␤-catenin levels and increased wound strength. ␤-Catenin mediates the effects of ionizing radiation in fibroblasts , and its modulation has the potential to decrease the severity of radiation-induced soft tissue complications.

Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells for Inhibiting Myofibroblastic Differentiation of Irradiated Human Lung Fibroblasts

“…The associations between the Wnt pathway and MSCs (Salazar et al 2009) were further examined in the present study. We found that irradiation of nHLFs enhanced Wnt signaling, consistent with earlier reports (Gurung et al 2009). Importantly, coculture of nHLFs with HUMSCs attenuated the effects of irradiation.…”

“…Salazar et al (2009) observed that the CM of MSCs contained Wnt proteins that were capable of stimulating lung fibroblast proliferation through activation of the canonical Wnt/β-catenin signaling pathway. Another group have reported that canonical Wnt signaling is activated in nHLFs following irradiation, and that β-catenin mediates the effects of ionizing radiation on fibroblasts, acting to decrease the severity of radiation-induced soft tissue complications (Gurung et al 2009). …”

“…Importantly, aberrant Wnt/β-catenin signaling contributes to RILI (Gurung et al 2009). The associations between the Wnt pathway and MSCs (Salazar et al 2009) were further examined in the present study.…”

“…In addition, Gurung et al (2009) have shown that irradiation of human lung fibroblasts (HLFs) results in activation of Wnt/β-catenin signaling. Taken together, these findings suggest that selective inhibition of Wnt/β-catenin signaling may have therapeutic potential for the treatment of pulmonary fibrosis.…”

Fibronectin and β-Catenin Act in a Regulatory Loop in Dermal Fibroblasts to Modulate Cutaneous Healing

“…A stress strain curve was generated, and loads were normalized to the cross-sectional area of the wound. The ultimate tensile strength and the work to failure were calculated (34,35).…”