Hedgehog signaling regulates the generation of ameloblast progenitors in the continuously growing mouse incisor

Abstract

SUMMARYIn many organ systems such as the skin, gastrointestinal tract and hematopoietic system, homeostasis is dependent on the continuous generation of differentiated progeny from stem cells. The rodent incisor, unlike human teeth, grows throughout the life of the animal and provides a prime example of an organ that rapidly deteriorates if newly differentiated cells cease to form from adult stem cells. Hedgehog (Hh) signaling has been proposed to regulate self-renewal, survival, proliferation and/or differentiation of stem cells in several systems, but to date there is little evidence supporting a role for Hh signaling in adult stem cells. We used in vivo genetic lineage tracing to identify Hh-responsive stem cells in the mouse incisor and we show that sonic hedgehog (SHH), which is produced by the differentiating progeny of the stem cells, signals to several regions of the incisor. Using a hedgehog pathway inhibitor (HPI), we demonstrate that Hh signaling is not required for stem cell survival but is essential for the generation of ameloblasts, one of the major differentiated cell types in the tooth, from the stem cells. These results therefore reveal the existence of a positive-feedback loop in which differentiating progeny produce the signal that in turn allows them to be generated from stem cells.

Roles for Hedgehog signaling in adult organ homeostasis and repair

“…During development, SHH signaling plays a key role in early tooth germ initiation, as well as in tooth growth and morphogenesis (Dassule et al, 2000). More recently, it was shown that during the growth of the adult rodent incisor, SHH is secreted by the differentiating pre-amelioblasts and signals back to their parental Gli1-expressing amelioblast stem cells at the proximal end of the incisor (Seidel et al, 2010). Blocking SHH signaling resulted in decreased amelioblast production and tooth growth, but did not deplete the GLI1+ stem cell pool (Seidel et al, 2010).…”

“…More recently, it was shown that during the growth of the adult rodent incisor, SHH is secreted by the differentiating pre-amelioblasts and signals back to their parental Gli1-expressing amelioblast stem cells at the proximal end of the incisor (Seidel et al, 2010). Blocking SHH signaling resulted in decreased amelioblast production and tooth growth, but did not deplete the GLI1+ stem cell pool (Seidel et al, 2010). Thus, SHH signaling in the incisor epithelium appears not to be required for stem cell survival but instead for maintaining the ability of stem cells to expand the amelioblast lineage, perhaps similar to the function of SHH in the adult forebrain SVZ in producing TACs.…”

Signaling Networks Regulating Tooth Organogenesis and Regeneration, and the Specification of Dental Mesenchymal and Epithelial Cell Lineages

“…4A). The asymmetry arises from differences between the lingual and labial cervical loops as only the larger labial cervical loop contains label-retaining stem cells and transient amplifying (TA) cells (Harada et al 1999;Seidel et al 2010). The stem cells reside within the stellate reticulum cells in the core of cervical loop, which is surrounded by dental mesenchyme.…”

“…Fgf and Shh signaling play a role in the postnatal homeostasis of the TA cell production in the mouse incisors but not in stem cell survival (Parsa et al 2010;Seidel et al 2010). On the other hand, Wnt signaling activity is not detected in the stem cells in the cervical loops (Suomalainen and Thesleff 2010).…”

Les cellules souches épithéliales dentaires exprimantSox2participent au renouvellement de l’incisive de souris

“…Malgré la description déjà ancienne des capacités de renouvellement des incisives de rongeurs [2], la localisation des niches de cellules souches est relativement récente [3]. Depuis, de nombreuses études se sont attachées à identifier les réseaux moléculaires permettant le maintien et la différen-ciation des cellules souches épithéliales de l'incisive, sans pour autant parvenir à localiser précisément ces cellules [4,5]. De nombreuses questions restent ainsi en suspens.…”