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.
Highlights
The high capacity of epithelial tissues for self-repair and renewal is effected through locally-regulated proliferation and differentiation of resident progenitor cells rather than recruitment of exogenous progenitor cells to the site
Urothelial cytodifferentiation and associated gene changes Expression of urothelium differentiation-restricted uroplakin 2 (UPK2) transcript was used as a marker to monitor the differentiation status of normal human urothelial (NHU) cell cultures
NHU cultures stably transduced with UPK2-enhanced GFP (eGFP) lentivirus contained few eGFP-expressing cells even at confluence (Fig. 1C)
Summary
The high capacity of epithelial tissues for self-repair and renewal is effected through locally-regulated proliferation and differentiation of resident progenitor cells rather than recruitment of exogenous progenitor cells to the site. As a model epithelium for regenerative studies, the uro-epithelial lining of the bladder and associated urinary tract provides an excellent system, being mitotically-quiescent with a low constitutive turnover rate, but with an exceptionally high capacity for regeneration [1]. In determining the mechanisms that orchestrate and mediate regeneration, a common perception is that the epithelium relies on the subjacent stroma. An elegant recent study in the mouse bladder has provided evidence of an inductive paracrine loop operating between urothelium and stroma [4]. There is considerable evidence for autonomous growth regulation, for example through autocrine activation of epidermal growth factor receptor (EGFR) signalling [5]
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