Differentiation-Associated Reprogramming of the Transforming Growth Factor β Receptor Pathway Establishes the Circuitry for Epithelial Autocrine/Paracrine Repair

Jonathan M. Fleming, Saqib Shabir, Claire L. Varley, Lisa A. Kirkwood, Angela White, Julie Holder, Ludwik K. Trejdosiewicz, Jennifer Southgate, Yao Liang Tang

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Transforming growth factor (TGF) β has diverse and sometimes paradoxical effects on cell proliferation and differentiation, presumably reflecting a fundamental but incompletely-understood role in regulating tissue homeostasis. It is generally considered that downstream activity is modulated at the ligand:receptor axis, but microarray analysis of proliferative versus differentiating normal human bladder epithelial cell cultures identified unexpected transcriptional changes in key components of the canonical TGFβ R/activin signalling pathway associated with cytodifferentiation. Changes included upregulation of the transcriptional modulator SMAD3 and downregulation of inhibitory modulators SMURF2 and SMAD7. Functional analysis of the signalling pathway revealed that non-differentiated normal human urothelial cells responded in paracrine mode to TGFβ by growth inhibition, and that exogenous TGFβ inhibited rather than promoted differentiation. By contrast, in differentiated cell cultures, SMAD3 was activated upon scratch-wounding and was involved in promoting tissue repair. Exogenous TGFβ enhanced the repair and resulted in hyperplastic scarring, indicating a feedback loop implicit in an autocrine pathway. Thus, the machinery for autocrine activation of the SMAD3-mediated TGFβR pathway is established during urothelial differentiation, but signalling occurs only in response to a trigger, such as wounding. Our study demonstrates that the circuitry of the TGFβR pathway is defined transcriptionally within a tissue-specific differentiation programme. The findings provide evidence for re-evaluating the role of TGFβR signalling in epithelial homeostasis as an autocrine-regulated pathway that suppresses differentiation and promotes tissue repair. This provides a new paradigm to help unravel the apparently diverse and paradoxical effect of TGFβ signalling on cell proliferation and differentiation.

Original languageEnglish (US)
Article numbere51404
JournalPloS one
Volume7
Issue number12
DOIs
StatePublished - Dec 19 2012
Externally publishedYes

Fingerprint

transforming growth factors
Growth Factor Receptors
Transforming Growth Factors
Repair
receptors
Cell proliferation
Tissue
tissue repair
Cell culture
cell differentiation
Modulators
Tissue homeostasis
Cell Differentiation
cell proliferation
homeostasis
cell culture
Homeostasis
Cell Culture Techniques
Cell Proliferation
activins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Differentiation-Associated Reprogramming of the Transforming Growth Factor β Receptor Pathway Establishes the Circuitry for Epithelial Autocrine/Paracrine Repair. / Fleming, Jonathan M.; Shabir, Saqib; Varley, Claire L.; Kirkwood, Lisa A.; White, Angela; Holder, Julie; Trejdosiewicz, Ludwik K.; Southgate, Jennifer; Tang, Yao Liang.

In: PloS one, Vol. 7, No. 12, e51404, 19.12.2012.

Research output: Contribution to journalArticle

Fleming, Jonathan M. ; Shabir, Saqib ; Varley, Claire L. ; Kirkwood, Lisa A. ; White, Angela ; Holder, Julie ; Trejdosiewicz, Ludwik K. ; Southgate, Jennifer ; Tang, Yao Liang. / Differentiation-Associated Reprogramming of the Transforming Growth Factor β Receptor Pathway Establishes the Circuitry for Epithelial Autocrine/Paracrine Repair. In: PloS one. 2012 ; Vol. 7, No. 12.
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