Biology subjects

Cutler, A. A.

Publications and source records attributed to Cutler, A. A..

4 recordsLinked to original sources

bioRxiv2026

Redundant YAP and TAZ functions are essential for skeletal muscle regeneration

Muscle stem cells orchestrate skeletal muscle regeneration through complex fate decisions. The transcriptional co-activators Yes-associated protein 1 (YAP) and WW domain-containing transcription regulator 1 (TAZ) contribute to multiple stages of myogenesis, yet their individual contributions to regeneration remain unclear due to substantial functional overlap. We genetically titrated YAP and TAZ expression in MuSCs with double knockout and single allele mutants by crossing Pax7CreERT mice with TAZflox/flox;YAPflox/flox mice. Conditional deletion of both YAP and TAZ in muscle stem cells severely disrupted muscle regeneration with dramatically increased fibrosis and impaired myofiber formation following injury. In contrast, a single allele of either YAP or TAZ was sufficient to rescue injured muscle weight and myofiber cross-sectional area. Similarly, the reduced proliferation of double knockout muscle stem cells on isolated myofibers was restored by a single allele of either YAP or TAZ. In addition, disrupted actin cytoskeleton organization and reduced focal adhesion formation drove double knockout muscle stem cell migration defects, negatively impacting muscle stem cell congregation prior to fusion. Thus, YAP and TAZ function redundantly as critical transcriptional co-activators to regulate progenitor proliferation and migration during muscle regeneration. By challenging myogenesis with double knockout of both YAP and TAZ, we unmasked regenerative requirements previously undetected in single-gene loss models, highlighting genetic redundancy as a key principle buffering regenerative robustness.

cell biology↗

bioRxiv2026

Bioprinted Human Primary Arteries Recapitulate Inflammatory Activation and Pharmacologic Rescue

Chronic inflammation drives persistent systemic cytokine signaling that contributes to vascular dysfunction and secondary vasculitis, yet mechanistic studies are limited by models that fail to capture the multicellular architecture and dynamics of human arteries. In contrast, perfusing intact vessels ex vivo has limited tractability because of material availability and difficulty of genetic or biochemical manipulation. We developed a modular, perfused artery-on-a-chip platform by tri-axially bioprinting primary human vascular cells to recapitulate the concentric organization of the intimal, medial, and adventitial layers. The engineered vessels are viable longer than 21 days, with functional endothelial barriers, contractile smooth muscle behavior, and actively remodeled extracellular matrices bearing hallmarks of native vascular tissue. Addition of tumor necrosis factor alpha (TNF) induces altered transcript levels of proinflammatory mediators and secretion of cytokines and matrix-remodeling enzymes without compromising vessel viability. Importantly, this secretory response is effectively attenuated by both a small-molecule JAK1 inhibitor (ABT-317) and anti-TNF antibody (Infliximab), demonstrating the models utility for therapeutic evaluation.

bioengineering↗

bioRxiv2026

Activating FGFR1 restores Integrin-β1--mediated fibronectin sensing in satellite cells of aged mice

Muscle satellite cells (SCs), essential for skeletal muscle regeneration, decline in number and function with age, contributing to sarcopenia. A fully defined viscoelastic hydrogel that preserves SC-myofiber interactions and supports tunable densities of fibronectin-derived RGD ligands was used to investigate age-related defects in extracellular matrix sensing by SCs. Elevating RGD density increased the number of activating and proliferating SCs on myofibers from young mice, whereas SCs from aged mice were unresponsive. Loss of FGF receptor 1 signaling in SCs from aged mice abrogated the coordinated Syndecan-4 and Integrin-{beta}1 matrix response observed in SCs from young mice. Activating Integrin-{beta}1 promoted asymmetric division and self-renewal in SCs from young mice whereas combined FGFR1 and Integrin-{beta}1 signaling drove symmetric expansion. In SCs from aged mice, FGFR1 dysfunction disrupted this balance, impairing asymmetric division, but constitutive FGFR1 activation restored receptor co-localization, self-renewal, and fibronectin responsiveness. Therefore, FGFR1 integrates matrix and growth factor signals, suggesting that targeting the FGFR1-Integrin-{beta}1 axis may enhance SC regenerative potential in aging organisms.

cell biology↗

bioRxiv2021

Myonuclear maturation dynamics in aged and adult regenerating mouse skeletal muscle

Skeletal muscle cells are multinucleated syncytial cells arising from cell fusion, yet despite sharing a common cytoplasm individual myonuclei express distinct transcriptional programs. Whether individual myonuclei acquire heterogenous transcriptional states via differences in their progenitors, during differentiation, or once their anatomical position is acquired, is not known. We performed transcriptome and pseudotime analysis of single myogenic nuclei from uninjured and post-injury murine skeletal muscle to assess when myonuclear heterogeneity is acquired. Two distinct progenitors contribute to myonuclei, one a non-myogenic fibroblast subtype, and skeletal muscle stem cells the other. Both progenitors enter a single pseudotime trajectory that bifurcates as myonuclei mature into two branches segregated by myosin isoform expression and metabolic profiles, suggesting transcriptional heterogeneity is acquired as myonuclei mature. In aged skeletal muscle myogenic progenitor expansion is perturbed and nuclei from aged muscle display distinct pseudotemporal kinetics compared to nuclei from young mice. In aged mice, the inferred myogenic differentiation trajectory is delayed, altering the distribution of myogenic nuclei in pseudotime, suggesting that altered transcriptional dynamics in nuclei in aged mice may drive age-associated muscle deficits and bias myonuclei towards acquiring oxidative metabolic profiles.

molecular biology↗