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Am J Physiol Cell Physiol 284: C209-C219, 2003. First published September 11, 2002; doi:10.1152/ajpcell.00557.2001
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Vol. 284, Issue 1, C209-C219, January 2003

Three-dimensional tissue structure affects sensitivity of fibroblasts to TGF-beta 1

Leoni A. Kunz-Schughart, Sabine Wenninger, Thomas Neumeier, Paula Seidl, and Ruth Knuechel

Institute of Pathology, University of Regensburg, D-93042 Regensburg, Germany

Transforming growth factor-beta (TGF-beta ) is known to induce alpha -smooth muscle actin (alpha -SMA) in fibroblasts and is supposed to play a role in myofibroblast differentiation and tumor desmoplasia. Our objective was to elucidate the impact of TGF-beta 1 on alpha -SMA expression in fibroblasts in a three-dimensional (3-D) vs. two-dimensional (2-D) environment. In monolayer culture, all fibroblast cultures responded in a similar fashion to TGF-beta 1 with regard to alpha -SMA expression. In fibroblast spheroids, alpha -SMA expression was reduced and induction by TGF-beta 1 was highly variable. This difference correlated with a differential regulation in the TGF-beta receptor (TGFbeta R) expression, in particular with a reduction in TGF-beta RII in part of the fibroblast types. Our data indicate that 1) sensitivity to TGF-beta 1-induced alpha -SMA expression in a 3-D environment is fibroblast-type specific, 2) fibroblast type-independent regulatory mechanisms, such as a general reduction/loss in TGF-beta RIII, contribute to an altered TGFbeta R expression profile in spheroid compared with monolayer culture, and 3) fibroblast type-specific alterations in TGFbeta R types I and II determine the sensitivity to TGF-beta 1-induced alpha -SMA expression in the 3-D setting. We suggest that fibroblasts that can be induced by TGF-beta 1 to produce alpha -SMA in spheroid culture reflect a "premyofibroblastic" phenotype.

normal fibroblasts; tumor-derived fibroblasts; multicellular spheroid; transforming growth factor-beta 1; transforming growth factor-beta receptor; alpha -smooth muscle actin, ED-A fibronectin


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