High Sox2 expression predicts taste lineage competency of lingual progenitors in vitro

Abstract

Taste buds on the tongue contain taste receptor cells (TRCs) that detect sweet, sour, salty, umami and bitter stimuli. Like non-taste lingual epithelium, TRCs are renewed from basal keratinocytes, many of which express the transcription factor SOX2. Genetic lineage tracing has shown that SOX2+ lingual progenitors give rise to both taste and non-taste lingual epithelium in the posterior circumvallate taste papilla (CVP) of mice. However, SOX2 is variably expressed among CVP epithelial cells, suggesting that their progenitor potential may vary. Using transcriptome analysis and organoid technology, we show that cells expressing SOX2 at higher levels are taste-competent progenitors that give rise to organoids comprising both TRCs and lingual epithelium. Conversely, organoids derived from progenitors that express SOX2 at lower levels are composed entirely of non-taste cells. Hedgehog and WNT/β-catenin are required for taste homeostasis in adult mice. However, manipulation of hedgehog signaling in organoids has no impact on TRC differentiation or progenitor proliferation. By contrast, WNT/β-catenin promotes TRC differentiation in vitro in organoids derived from higher but not low SOX2+ expressing progenitors.

SOX2-Sensing: Insights into the Role of SOX2 in the Generation of Sensory Cell Types in Vertebrates

“…Innovative culture systems such as organoids could be instrumental to identifying all the key factors required to form a specific sensory organ/sensory cell type, and this system was recently used to investigate the roles of SOX2, SHH and WNT signaling in taste bud formation [36]. Hearing deficits have been described in patients carrying mutations in the Sox2 gene [12], confirming a key role of SOX2 also in human hair cells and supporting the idea of using SOX2 to regenerate hair cells in vitro or in vivo.…”

“…Sox2 expression levels vary in the lingual epithelium, and depending on the quantity of SOX2 protein present in lingual progenitors, it is possible to predict if the progenitors will give rise, in vitro, to organoids comprising TRCs or non-taste cells. As mentioned above, cells with high expression of Sox2 have been shown to be taste-competent progenitors [36]. Among genes enriched in cells with high levels of SOX2 are the transcription factors FOXA1 and FOXA2, which are downstream effectors of the Shh pathway (Table 1).…”

“…Cells expressing SOX2 at high levels in adult mouse CvPs are taste-competent progenitors that have the capacity of giving rise to organoids composed of all TRC types. In addition, the ability of Sox2expressing progenitors to give rise to TRCs expressing lingual organoids was increased by the activation of the Wnt pathway, but not the Shh pathway, indicating that SOX2 cooperates with other signaling pathways to induce TRCs [36] (Table 1).…”

Environmental and molecular control of tissue-specific ionocyte differentiation in zebrafish

“…Basal stem cells are heterogeneous populations and different subtypes or states have different potencies. In tastebuds, only a subpopulation of SOX2 high basal cells can differentiate into taste-receptor cells 47 and in the pulmonary epithelium, subtypes of basal stem cell populations give rise to different lineages 48 . In the frog epidermis, basal cells differentiate into multiciliated cells, small secretory cells and ionocytes 49,50 , while in zebrafish basal cells give rise not only to skin and Nm ionocytes, but also to other cell types such as keratinocytes, mucous cells and Merkel cells [51][52][53] .…”

Gustatory-neuron-supplied R-spondin-2 is required for taste bud replenishment

“…Unlike in other epithelial tissues, in taste buds maintenance and regeneration are strictly dependent on innervation, which was noted almost 150 years ago (11,12). Yet, single isolated Lgr5 + or Lgr6 + taste stem/progenitor cells can grow into everexpanding 3-D structures (termed as "taste organoids") and generate taste cells in the absence of neurons or other types of cells ex vivo, suggesting that a soluble factor in the organoid culture medium may substitute for neuronal input to activate taste stem/progenitor cells to produce taste cells (13)(14)(15)(16). As in other organoid culture systems, R-spondin, EGF, and Noggin are key components of the medium used for culturing taste organoids (17,18).…”