Deli Hays

Recent advancements in tissue engineering and stem cell science have positioned bone disease treatment as a promising frontier in regenerative medicine. This review explores the hormonal and signaling pathways critical to bone regeneration, with a focus on their clinical relevance. Key endocrine factors, including thyroid hormones (T3 and T4), insulin-like growth factor 1 (IGF-1), bone morphogenetic proteins (BMPs), parathyroid hormone (PTH), calcitonin, and fibroblast growth factor 23 (FGF23), play pivotal roles in bone remodeling by regulating osteoblast activity, bone resorption, and mineralization. These factors primarily act through the Wnt/β-catenin, BMP, and FGF signaling pathways, which govern bone repair and regeneration. While animal models, such as axolotls, zebrafish, and Xenopus laevis, provide valuable findings about these mechanisms, translating these findings into human applications presents challenges. This review underscores the therapeutic potential of modulating these hormonal networks to enhance bone regeneration while cautioning against possible adverse effects, such as uncontrolled tissue proliferation or metabolic imbalances. By integrating knowledge from regenerative models, this work provides a foundation for optimizing hormone-based therapies for clinical applications in bone repair and disease treatment.

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.

Amphioxus, a cephalochordate, is an ideal animal to address the questions about the evolution of regenerative ability and mechanisms behind the invertebrate to vertebrate transition in chordates. However, the cellular and molecular basis of tail regeneration in amphioxus remains largely ill-defined. We confirmed that the tail regeneration of amphioxus Branchiostoma japonicum is a vertebrate-like epimorphosis process. We performed transcriptome analysis of the tail regenerates, which provided many clues for exploring the mechanism of tail regeneration. Importantly, we showed that BMP2/4 and its related signaling are essential for the process of tail regeneration, revealing an evolutionarily conserved genetic regulatory system involved in regeneration in many metazoans. We serendipitously discovered that, bmp2/4 expression is immediately inducible by general wounds and that the expression of bmp2/4 can be regarded as a biomarker of wounds in amphioxus. Collectively, our results provide a framework for understanding the evolution and diversity of cellular and molecular events of tail regeneration in vertebrates.