Cochlear Fibrocyte and Osteoblast Lineages Expressing Type 2 Deiodinase Identified with a Dio2CreERt2 Allele

Abstract

Abstract Type 2 deiodinase (Dio2) amplifies levels of 3,5,3′-L-triiodothyronine (T3), the active form of thyroid hormone, and is essential for cochlear maturation and auditory development. However, cellular routes for endocrine signaling in the compartmentalized, anatomically complex cochlea are little understood. Dio2 generates T3 from thyroxine (T4), a more abundant thyroid hormone precursor in the circulation, and is dramatically induced in the cochlea before the onset of hearing. The evidence implies that specific Dio2-expressing cell types critically mediate T3 signaling but these cell types are poorly defined because Dio2 is expressed transiently at low levels. Here, using a Dio2CreERt2 knockin that activates a fluorescent reporter, we define Dio2-expressing cochlear cell types at high resolution in male or female mice. Dio2-positive cells were detected in vascularized supporting tissues but not in avascular internal epithelia, indicating segregation of T3-generating and T3-responding tissues. In the spiral ligament and spiral limbus, Dio2-positive fibrocytes clustered around vascular networks that convey T4 into cochlear tissues. In the otic capsule, Dio2-positive osteoblasts localized at cartilage surfaces as the bony labyrinth matures. We corroborated the identities of Dio2-positive lineages by RNA-sequencing of individual cells. The results suggest a previously unrecognized role for fibrocytes in mediating hormonal signaling. We discuss a model whereby fibrocytes mediate paracrine-like control of T3 signaling to the organ of Corti and epithelial target tissues.