Hsp90 Is Required in Epimorphic Regeneration

Hsp90, a critical molecular chaperone, is instrumental in modulating an array of signaling path-ways, transcription factors, and cytokines, with its overexpression intricately tied to the onset of tumorigenesis. While the modulation of Hsp90 holds potential for facilitating tissue regeneration, its functional implications in epimorphic regeneration remain largely uncharted. This study ex-plored the role of Hsp90 in tail regeneration in axolotls and compared it to its roles in other epi-morphic regeneration processes, such as tail fin regeneration in zebrafish and tail regeneration in amphioxus. Our findings indicated that Hsp90α, the inducible subtype of Hsp90, exhibited dis-tinctive and dynamic expression patterns throughout these regeneration processes. The knock-down of Hsp90α via morpholinos or the pharmacological inhibition of Hsp90 using geldanamycin following tail amputation in axolotls hindered regeneration. Similar phenotypes of failed regen-eration due to Hsp90 inhibition were also observed in zebrafish and amphioxus. Furthermore, cellular evidence suggested that the suppression of Hsp90 results in diminished cell proliferation and elevated apoptosis, partially accounting for the observed impairment in regeneration. RNA-seq analysis of Hsp90-inhibited and control axolotls and zebrafish provided deeper insights into the regulatory mechanism of Hsp90 in regeneration. Numerous differentially expressed genes identified are transcription factor genes or key signaling genes involved in cell proliferation, apoptosis, cancer development, and the immune response. These findings imply that Hsp90 is essential in epimorphic regeneration processes and its functional roles appear to be conserved among chordates as a pivotal regulator in the regeneration process.