TGF-beta and BMP dueling in a stem cell niche

Regeneration of adult tissue relies on the activation of quiescent stem cells regulated through multiple signals in specialized microenvironments, called stem cell niches. Transforming growth factor beta (TGF-beta) signaling in the hair follicle niche induces specific gene expressions in the stem cells to counteract quiescent signals and drives them into a tissue regenerative state.

HFSP Long-Term Fellow Naoki Oshimori and colleagues
authored on Fri, 09 March 2012

Tissue homeostasis and regeneration are regulated through balancing quiescence and activation of stem cells. Hair follicles in mouse skin offer a unique opportunity to explore this process. Throughout adult life, they undergo dynamic, synchronized cycles of degeneration, resting, and regeneration phases and produce one hair in each cycle. In the hair follicle, epithelial and melanocyte stem cells reside in a niche, composed of an inner layer of differentiated hair follicle cells, and an underlying cluster of mesenchymal cells, called dermal papilla. Smooth muscle fibers, sensory neurons, adipocytes, blood vessels and a sheath of dermal fibroblasts add to the complexity of the niche. During the resting phase, bone morphogenetic protein (BMP) signaling maintains stem cell quiescence. Once communication between quiescent stem cells and dermal papilla generates sufficient activating cues to overcome BMP repressive signals in the niche, stem cells start to proliferate and regenerate a new hair follicle. It is likely that the combination of growth factors and crosstalk among the intracellular signaling pathways defines stem cell behaviors. However, exactly how the transition from quiescent to active state comes about remains unclear, as do the downstream events that drive stem cells into a tissue regenerative state.

Figure: Immunofluorescent image of mouse adult hair follicle at the transition from resting to regeneration phases. Blue: Keratinocytes of epidermis and hair follicle, Red: TGF-beta2 protein localization, Green: Nuclear, phosphorylated Smad2 protein, Cyan: Dermal papilla. Note: Green signal of hair shafts is auto fluorescence.

TGF-beta signaling induces Smad2/3-mediated gene expression and functions in tissue morphogenesis, homeostasis and cancer formation by regulating diverse biological processes including proliferation, differentiation, migration and extracellular matrix production. Interestingly, although TGF-beta is a growth inhibitor for most epithelial cells, it has multiple and often opposing effects depending on the tissue and the type of cells. In this work, we uncovered a hitherto unrecognized TGF-beta signaling that is transmitted from dermal papilla activates Smad2/3 signaling in hair follicle stem cells at the transition from quiescent to regeneration stages. This signaling is critical: hair follicle stem cells that cannot sense TGF-beta exhibit significant delays in hair follicle regeneration, whereas exogenous TGF-beta stimulates stem cells both in vivo and in vitro. 

We engineered TGF-beta- and BMP-reporter mice and showed that TGF-beta signaling antagonizes repressive BMP signaling in hair follicle stem cells. TGF-beta and BMP pathways utilize a common transcription coactivator Smad4, however, BMP repression by TGF-beta was not through competition for limiting amount of Smad4. Rather, our microarray, molecular and genetic studies unveiled Tmeff1 as a direct TGF-beta/Smad2/3 target gene, expressed in activated hair follicle stem cells and physiologically relevant in restricting and lowering BMP threshold in the niche. Furthermore, by carrying out an epidermis-specific lentiviral in vivo knockdown, we showed that Tmeff1 is a mediator of stem cell activation for the initiation of hair follicle regeneration. Our study also demonstrated that stem cells in the hair follicle and epidermis differ in their responses to TGF-beta, a feature which may at least in part be related to their distinct microenvironments. As an underlying mechanism, while TGF-beta was known to inhibit proliferation of epidermal keratinocytes, TGF-beta’s stimulatory effect on hair follicle stem cells was dependent upon its ability to antagonize BMP signaling. Connecting BMP activity to a stem cell’s response to TGF-beta may explain why these signaling factors wield such diverse cellular effects.

Reference

Paracrine TGF-beta Signaling Counterbalances BMP-Mediated Repression in Hair Follicle Stem Cell Activation. Oshimori N., Fuchs E., Cell Stem Cell 2012 Jan 6; 10(1):63-75.

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