Biology subjects

Jaeger, P. K.

Publications and source records attributed to Jaeger, P. K..

3 recordsLinked to original sources

bioRxiv2025

Matrix maturation and cytoskeletal tension define strain thresholds for stretch-induced calcium signaling in human tendon cells

The extracellular matrix (ECM) and mechanical loading shape cellular behavior, yet their interaction remains obscure. We developed a dynamic proto-tissue model using human tendon cells and live-cell calcium imaging to study how ECM and cell mechanics regulate mechanotransduction. Stretch-induced calcium signaling served as a functional readout. We discovered that ascorbic acid-dependent ECM deposition is essential for proto-tissue maturation and stretch-induced calcium signaling at physiological strains. Proto-tissue maturation enhanced stretch sensitivity, reducing the strain needed to trigger a calcium response from [~]40% in isolated cells to [~]5% in matured proto-tissues. A strong correlation between tissue rupture and calcium signaling suggests a mechanistic link to ECM damage. Disrupting ECM integrity, cell alignment, or cytoskeletal tension reduced mechanosensitivity, showcasing the influence of ECM and cytoskeletal mechanics on stretch-induced calcium signaling. Fundamentally, our work replicates calcium signaling observed in rodent tendon explants in vitro and bridges the gap between cell-scale and tissue-scale mechanotransduction. TeaserMatrix matters: tendon cells tune their response to stretch as their mechanical environment develops.

bioengineering↗

bioRxiv2025

HIF1α gates tendon response to overload and drives tendinopathy independently of vascular recruitment

Tendons are mostly avascular dense connective tissues that link muscles to bones, withstanding some of the highest mechanical stresses in the body. Mechanical overload and tissue hypervascularity are implicated in tendinopathy, a common musculoskeletal disorder, but mechanistic understanding of their roles is largely lacking. Here, we identify HIF1 not only as a marker but as a driver of tendinopathy. Initial histological and multi-omics evaluation of human tendinopathic samples revealed extensive extracellular matrix remodeling, including pathological collagen crosslinking coinciding with active hypoxic signaling. Hypothesizing a causal contribution of hypoxia signaling, we generated mice with tenocyte-targeted deletions of the Von Hippel-Lindau (VHL) gene, which controls hypoxia signaling by regulating HIF degradation. We demonstrated that VHL inactivation suffices to induce pathological hallmarks of tendinopathy, such as collagen matrix disorganization, crosslinking, altered mechanics and neuro-vascular ingrowth. This phenotype was HIF1-dependent, since co-deleting HIF1 rescued tendon morphology and mechanics. Moreover, deleting vascular endothelial growth factor A (VEGFA) alongside VHL effectively decoupled the effects of vascular ingrowth from persistently aberrant extracellular matrix remodeling and mechanical dysfunction, emphasizing a direct role of HIF1 in driving tendon disease that is independent of angiogenesis. Mechanistically, we linked tendon mechanical overload to the onset of HIF1 signaling in primary cultured human tendon cells. Furthermore, genetically removing HIF1 from tenocytes prevented aberrant tendon remodeling in response to chronic overload. These findings position HIF1 signaling as a central driver of tendinopathy that acts through a maladaptive tissue response to chronic overload, providing mechanistic insights that could be leveraged for improved therapeutic approaches. One Sentence SummaryHIF1 activation promotes tendinopathy and its inhibition prevents overload-induced maladaptation, suggesting therapeutic potential.

cell biology↗

bioRxiv2023

IL-6 SIGNALING EXACERBATES HALLMARKS OF CHRONIC TENDON DISEASE BY STIMULATING PROGENITOR PROLIFERATION & MIGRATION TO DAMAGE.

Tendinopathies are debilitating diseases currently increasing in prevalence and associated costs. There is a need to deepen our understanding of the underlying cell signaling pathways to unlock effective treatments. In this work, we screen cell signaling pathways in human tendinopathies and find positively enriched IL-6/JAK/STAT signaling alongside signatures of cell populations typically activated by IL-6 in other tissues. In human tendinopathic tendons, we also confirm the strong presence and co-localization of IL-6, IL6R, and CD90, an established marker of reparative fibroblasts. To dissect the underlying causalities, we combine IL-6 knock-out mice with an explant-based assembloid model of tendon damage to successfully connect IL-6 signaling to reparative fibroblast activation and recruitment. Vice versa, we show that these reparative fibroblasts promote the development of tendinopathy hallmarks in the damaged explant upon IL-6 activation. We conclude that IL-6 activates tendon fibroblast populations which then initiate and deteriorate tendinopathy hallmarks.

bioengineering↗