Molecular Signaling and Epigenetic Mechanisms for Osteoblast Progenitor Maintenance during Bone Regeneration and Development
Loading...
Date
2020-02-27
Authors
Yette, Gabriel
Journal Title
Journal ISSN
Volume Title
Publisher
University of Oregon
Abstract
Severe bone ailments and fractures often surpass the innate repair capabilities of humans, frequently necessitating painful, costly and imperfect surgical interventions. Understanding mechanisms that promote bone repair and remodeling would enable innovative therapeutic approaches. Zebrafish have the innate ability to robustly and repeatedly regenerate bones by re-activating developmental pathways in mature cells. Understanding how zebrafish achieve this feat could provide clues how to unlock similar restorative properties in humans. Key questions remain including how the fin always regains its pre-injured shape and how mature cells reprogram gene expression profiles to return to and then maintain progenitor states to enable regeneration.
Wnt ligands keep developmental pathways active including by maintaining bone cell progenitor states until regeneration ends. Inhibiting the Wnt pathway rapidly and irreversibly halts regeneration, hinting that Wnt cessation could naturally signal the end of regeneration. We identified a Wnt source of specialized cells we term the regenerative niche at the distal end of the regenerating fin. The niche gradually depletes during regeneration, likely explaining how regeneration slows and then stops. With this information, we generated a mathematical model predicting regenerating fin length dependent on initial niche size and perdurance.
Chromatin landscapes including histone modifications influence gene expression during development. It is becoming increasingly evident they also play crucial roles during regeneration. An initial publication ten years ago implicated dynamic tri-methylation of lysine 27 of histone H3 (H3K27me3), a modification associated with gene repression, during regeneration. H3K27me3 is deposited by the Polycomb Repressive Complex 2 (PRC2) and removed by Kdm6 demethylases. More recent studies found PRC2 is required for reprograming cardiomyocytes during heart regeneration. However, PRC2 function during bone regeneration has not been investigated. We made CRISPR mutants of ezh2 and ezh1, the methyltransferase components of PRC2, and used a newly identified ezh2 hypomorph allele to investigate PRC2 during bone development and regeneration. We found PRC2 promotes osteoblast progenitor maintenance, skeletal patterning and cell fate decisions. Pilot studies described herein suggest PRC2 may fulfill similar roles during regeneration.
Our findings provide valuable insights how cell organizing centers, cell allocation and cell state establishment and maintenance contribute to organ composition, size, and shape.
Description
Keywords
Bone, Development, Epigenetics, H3K27me3, Regeneration, Zebrafish