Tongue and Taste Organ Biology and Function: Homeostasis Maintained by Hedgehog Signaling

Abstract

The tongue is an elaborate complex of heterogeneous tissues with taste organs of diverse embryonic origins. The lingual taste organs are papillae, composed of an epithelium that includes specialized taste buds, the basal lamina, and a lamina propria core with matrix molecules, fibroblasts, nerves, and vessels. Because taste organs are dynamic in cell biology and sensory function, homeostasis requires tight regulation in specific compartments or niches. Recently, the Hedgehog (Hh) pathway has emerged as an essential regulator that maintains lingual taste papillae, taste bud and progenitor cell proliferation and differentiation, and neurophysiological function. Activating or suppressing Hh signaling, with genetic models or pharmacological agents used in cancer treatments, disrupts taste papilla and taste bud integrity and can eliminate responses from taste nerves to chemical stimuli but not to touch or temperature. Understanding Hh regulation of taste organ homeostasis contributes knowledge about the basic biology underlying taste disruptions in patients treated with Hh pathway inhibitors.

Recovery of taste organs and sensory function after severe loss from Hedgehog/Smoothened inhibition with cancer drug sonidegib

“…The acquisition of a conical apex in the FP that accompanies the loss of TB cells is characteristic of reduced HH pathway activity, as previously reported (7,8) and as observed here after sonidegib administration or Smo deletion. This reproducible phenotype with HH signaling suppression or inhibition is reminiscent of an acquired filiform papilla-like form observed in FP after prolonged periods of denervation (42).…”

“…In addition, after pathway inhibition we observed the loss of HH-responding cells in FP walls, known regions of TB progenitors (13,32); thus, another proposed progenitor/stem cell population is eliminated. We believe that there is more than one source of TB stem/progenitor cells and that these are regulated by HH signaling (8,11).…”

“…Because we have observed SHH protein expression in neurons of the GG and TG that include the soma for nerves innervating FP and have observed Shh + expression in fibers within the FP, we propose interactions between SHH + nerve fibers and Gli1 lacZ -positive stromal cells in maintaining the FP structure. Furthermore, Shh + fibers contact basal lamina components of the FP and remaining epithelial cells; these could participate in signaling interactions within a taste-organ niche (8).…”

“…In the tongue, HH pathway components are in distinct compartments of adult taste papillae and TB ( Fig. 1B), including actively proliferating TB progenitor cells (8,13). The secreted SHH ligand in epithelium is produced principally within TB cells (13,22), whereas the HH targets, Ptch1 and Gli1, are expressed within perigemmal cells around the TB, in basal cells of the stratified epithelium that lines the papilla core, and in stromal or connective tissue cells of the papilla core ( Fig.…”

“…Lingual taste organs are composed of (i) the TB, about 80-100 modified epithelial/neuroepithelial cells of several types; (ii) the sensory innervation to the TB and surrounding epithelium; and (iii) the papilla residence, a stratified epithelium over a core of stromal cells and connective tissue elements (8). Precise controls within each compartment are essential to integrate the cell processes that support taste organs and sensation.…”