Biology subjects

Chang, T.-L.

Publications and source records attributed to Chang, T.-L..

5 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

Branch-resolved IFN/STING-linked lesion-state architecture in psoriasis: multi-cohort derivation, held-out bulk replication and single-cell context analysis

Objective and designWe tested whether a frozen branch-resolved IFN/STING-linked lesion-state architecture derived from paired psoriasis transcriptomes would transport to an untouched bulk RNA-sequencing cohort and remain detectable within broad cell compartments. Material or subjectsSeven paired bulk cohorts formed the derivation backbone. GSE121212 provided held-out replication using 27 matched lesional/nonlesional pairs; treatment-facing cohorts and GSE228421 provided pharmacodynamic and cellular-context analyses. TreatmentNo intervention was administered by the authors; public datasets included ustekinumab-, etanercept-, secukinumab- and risankizumab-exposed samples. MethodsFrozen modules and branches were scored after cohort-wide gene standardization. GSE121212 counts underwent trimmed mean of M-values normalization and log2 counts-per-million transformation. Paired effects, upper-quartile STING-high contrasts, lesional Spearman coupling and prespecified rank concordance were evaluated. ResultsGSE121212 lesional-minus-nonlesional effects were 1.288 for STING-core, 1.478 for IFN-responsive activity and 1.188 for proximal-only STING; all lower 95% confidence limits exceeded zero. Coupling-vector concordance was strong (rho = 0.893, P = 0.0068), whereas STING-high effect concordance was moderate (rho = 0.536), yielding partial replication. ConclusionsHeld-out replication was partial: the IFN/STING lesion anchor and proximal/IFN-dominant coupling transported, while broader ordering did not fully transport. Transcriptomic findings do not establish biochemical STING activation, causality or clinical thresholds.

immunology↗

bioRxiv2026

Fibroblasts impair muscle stem cell self-renewal via excessive fibronectin deposition in viscoelastic hydrogel co-cultures

Muscle satellite cells (SCs) regenerate skeletal muscle, but their regenerative capacity declines with age, in part due to extracellular matrix (ECM) remodeling and aberrant fibroblast activation within the SC niche. In regenerating young mouse muscle, fibronectin remodeling is transient, whereas in aged mouse muscle, fibronectin remodeling is prolonged and disorganized. Fibroblasts in aged mice are activated, increasing fibronectin deposition and expressing elevated -smooth muscle actin (SMA), which negatively influence SC fate. We develop a viscoelastic hydrogel co-encapsulation system, enabling three-dimensional co-culture of intact myofibers with primary fibroblasts. Using this 3D co-culture system, we show that fibroblasts from young mice support SC quiescence and self-renewal, whereas fibroblasts from aged mice aberrantly activate SCs and promote their differentiation on myofibers isolated from either young or aged mice. Knocking down fibronectin (Fn1) in fibroblasts from aged mice partially restores SC function, promoting quiescence and limiting differentiation. Using a novel 3D hydrogel co-culture system, we demonstrate that fibroblast-deposited fibronectin is a key age-associated regulator negatively affecting SC fate within the SC niche of aged mice.

bioengineering↗

bioRxiv2026

The Muscle Tissue Environment Limits Muscle Stem Cells in Aged Mice

Frailty arising from loss of muscle function and mass is a significant health concern impacting quality of life and dramatically increasing health care costs as our population ages. Ameliorating frailty derived from reduced muscle function is thus a critical research priority to improve health span. Cell intrinsic defects in muscle stem cells (MuSC), or satellite cells, occur as skeletal muscle ages, reducing the capacity of MuSCs to maintain and repair skeletal muscle and are accompanied by cell nonautonomous changes. Although rejuvenating stem cells in aged tissues or organs has potential to improve muscle aging phenotypes, we found that the extracellular environment in aged mice abrogates rejuvenated muscle stem cell potential. MuSCs from young mice were unable to grow on extracellular matrix derived from aged mice that contains elevated collagen protein levels, establishing a critical role for the environment in contributing to muscle phenotypes in aging. Combining an inducible FGF receptor 1 (FGFR1) to rescue MuSC intrinsic aging defects with a drug to reduce fibrosis partially rescued muscle mass loss in aged mice. We conclude that aging affects tissues, and particularly skeletal muscle tissue, via complex multifactorial processes requiring multifaceted interventions to improve aging phenotypes.

cell biology↗

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↗