Hypoxia Inducible Factor 1a (Hif1a) and Hypoxia in Tendon Development and Disease
Year: 2026
Type: dissertation
Abstract: Tendons and ligaments are collagen-rich tissues required for the transmission of force from muscle to bone or bone to bone, respectively. During postnatal development, cells within the tendon/ligament and withing the tendon-bone interface (e.g., the enthesis or osteochondral interface) synthesize and organize the collagen-rich extracellular matrix (ECM) required for tissue maturation. Prior studies have shown that postnatal tendon development is dependent on mechanical cues; however, the extent to which local oxygen availability, and oxygen-sensing pathways such as Hif1a modulates tendon and enthesis cell behavior and the ECM deposition needed to establish mechanical functions remain poorly defined. Our studies aimed to investigate tendon development and disease by 1) interrogating how the loss of the transcription factor Hypoxia Inducible Factor 1a (Hif1a) in tendon progenitors drives changes in Achilles tendon and enthesis structure and function; 2) determining how Hif1a and hypoxia (e.g., low oxygen) regulate tendon fibroblast physiology and matrix deposition in vitro; and 3) evaluating how the reduction or increase in Hif1a expression affects tendon healing post-injury. Tendinopathies and enthesopathies are among the most prevalent musculoskeletal diseases. These disorders are generally characterized by reduced mechanical function, largely due to the reduction in quality native ECM (e.g., organized Collagen-I). Often, tendinopathy or enthesopathy may be caused by an acute injury such as an Achilles tendon rupture, or they can be caused by repeat use over time where gradual injury is accumulated causing partial tears. Tendons and the interfacial tissue connecting tendons to bone have limited regenerative capabilities post-injury largely due to the reduced cellularity and thus the reduced capacity to generate native-type ECM. In our studies, we characterize the effect oxygen tension and Hif1a has on generating ECM post-injury using bulk-RNA sequencing, histology, and radiography. Further, we interrogate how hypoxia and a hypoxia-inducible gene regulate tendon and enthesis development, cell physiology, and tendon and enthesis healing post-injury. To do this, we utilize 2D and 3D in vitro approaches using genetically modified mice and/or pharmacological and environmental perturbation of Hif1a. Additionally, in our animals lacking Hif1a or exhibiting an overexpression of Hif1a in tendon and enthesis progenitor cells, we track tendon and enthesis development and healing over time. We use multiple imaging methods to look at tendon, enthesis, and bone health, in addition to biomechanical testing of the tendon and enthesis, and transcriptomic analyses paired with cellular data to better understand how cells regulate tendon- and enthesis-ECM deposition. In our studies, we have found that the developing enthesis is hypoxic and Hif1a is required for tendon and enthesis postnatal development. Additionally, we have found that the overexpression of Hif1a post-injury improves tendon and enthesis healing by increasing collagen alignment in the tendon scar tissue. Further, RNA-sequencing in tandem with cell-based assays revealed Hif1a is required for cell survival and tissue delineation processes in tendon progenitor cells. This research has identified targetable pathways for tendon and enthesis regenerative approaches that may be used to treat tendon disease and injury.
DOI: 10.7302/dspace/29733
Author: Steltzer, Stephanie
Language: English
Subfield: Orthopedics and Sports Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7162428660