Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway

Abstract

Controlling basic fibroblast growth factor (bFGF) signaling is important for both tissueengineering purposes, controlling proliferation and differentiation potential, and for cancer biology, influencing tumor progression and metastasis. Here, we observed that human mesenchymal stromal cells (hMSCs) no longer responded to soluble or covalently bound bFGF when cultured on microfibrillar substrates, while fibroblasts did. This correlated with a downregulation of FGF receptor 1 (FGFR1) expression of hMSCs on microfibrillar substrates, compared to hMSCs on conventional tissue culture plastic (TCP). hMSCs also expressed less SRF on ESP scaffolds, compared to TCP, while fibroblasts maintained high FGFR1 and SRF expression. Inhibition of actin-myosin tension or the MRTF/SRF pathway decreased FGFR1 expression in hMSCs, fibroblasts and MG63 osteosarcoma cells. This downregulation was functional, as hMSCs became irresponsive to bFGF in the presence of MRTF/SRF inhibitor. Together, our data show that hMSCs, but not fibroblasts, are irresponsive to bFGF when cultured on microfibrillar susbtrates by downregulation of FGFR1 through the MRTF/SRF pathway. This is the first time FGFR1 expression has been shown to be mechanosensitive and adds to the sparse literature on FGFR1 regulation. These results could open up new targets for cancer treatments and could aid designing tissue engineering constructs that better control cell proliferation.

Introducing height to mechanobiology

“…On top of 2D gels, many large focal adhesions formed, but when a gel was pipetted on top of MSCs attached to 2D gels, or when cells were embedded in 3D hydrogels, only few and small focal adhesions were observed. We have recently shown a similar decrease of focal adhesions in stiff 3D electrospun and additive manufactured scaffolds, compared to 2D films of the same stiff material [118,119] . Rather than forming large protein complexes that tightly anchor the cell to the 2D substrate, the focal adhesion proteins are distributed more diffusely through the cell and regulate protrusion activity and matrix deformation [115,120] .…”

“…However, the MRTF/SRF pathway has not yet been investigated 3D MSC differentiation in tissue-engineering constructs. We have recently shown that the MRTF/SRF pathway influences proliferation of MSCs in 3D ESP scaffolds through the regulation of FGFR1 [119] . Given the profound effects of MRTF/SRF on 2D MSC differentiation, investigating their role in a 3D setting would be highly interesting.…”