Biology subjects

Hu, K. M.

Publications and source records attributed to Hu, K. M..

3 recordsLinked to original sources

bioRxiv2026

Sex-Specific Pathophysiological Signatures in Allometric Dosing-Controlled Bleomycin Acute Lung Injury Model

IntroductionIn acute lung injury (ALI), clinical data show that while mortality rates are similar between sexes, women require shorter ventilation times and intensive care unit stays than men, yet preclinical studies show conflicting sex-specific vulnerabilities. We reasoned that a hidden dosing bias may explain the inconsistency, as intratracheal bleomycin is scaled to body weight, even though lung mass grows more slowly than total body mass, so age-matched males, whose body mass outpaces lung growth, inevitably receive more drug per gram of lung than females. MethodsWe compared age-matched (12-week) and body-weight-matched ([~]300g) Sprague-Dawley rats receiving intratracheal bleomycin (2.5mg/kg) or saline. Both cohorts underwent functional assessments (plethysmography, lung mechanics, arterial gases, histology) at day 7; weight-matched animals exclusively underwent mechanistic profiling (BALF analysis, cytokine multiplex, paired mRNA/miRNA-sequencing, immunoblotting). ResultsMales developed worse hypoxemia (PaO2: age-matched p = 0.045; weight-matched p = 0.027) with higher respiratory rates (both cohorts p < 0.05). Weight-matched males showed greater compliance loss (p = 0.029), increased BALF protein (p = 0.008), and elevated IL-1{beta} (p =0.005) and TNF- (p = 0.017). RNA-sequencing identified 2,393 male versus 1,533 female differentially-expressed genes, with males activating complement-coagulation cascades while females enriched ECM-remodeling/BMP-signaling pathways. Males exhibited significant miR-672-3p suppression (p < 0.0001), inversely correlating with inflammatory targets. SERPINA3 and its upstream regulator STAT3 showed significantly higher induction in males (both p < 0.0001), whereas females exhibited higher BMPR2 protein levels (p = 0.009) and preserved IL-10 (p = 0.023). ConclusionsBody-weight matching corrects unrecognized allometric bias affecting preclinical ALI sex-difference studies. Both cohorts demonstrated male vulnerability with worse hypoxemia and increased respiratory rates. Weight-matched molecular analyses revealed distinct responses: males showed significant miR-672-3p suppression with concurrent inflammatory mediator upregulation, including higher SERPINA3, IL-1{beta}, and TNF-. In contrast, females maintained higher miR-672-3p levels alongside elevated BMPR2/IL-10, suggesting that divergent post-transcriptional regulation contributes to functional differences and may inform sex-specific therapeutic strategies.

physiology↗

bioRxiv2025

Reduced TBX5 dosage undermines developmental control of atrial cardiomyocyte identity in a model of human atrial disease

While atrial septal defects (ASDs) and atrial fibrillation (AF) present differently, there is evidence that they share some genetic basis. Here, we used directed differentiation of human induced pluripotent stem cells into atrial or ventricular cardiomyocytes (CMs) to delineate gene regulatory networks (GRNs) that define each identity. We uncovered accessible chromatin regions, transcription factor motifs and key regulatory nodes specific to, or shared by, both CM types, including the transcription factor TBX5, which is linked to genetic susceptibility of ASDs and AF in humans. Complete TBX5 loss resulted in a near absence of atrial CMs with a concomitant increase in the abundance of other cell types. Reduced dosage of TBX5 in human atrial CMs caused cellular, electrophysiologic and molecular phenotypes consistent with features of atrial CM dysfunction. This included dose-dependent aberrant accessibility of many chromatin regions and perturbation of gene regulatory networks of atrial CM identity. These results suggest that, in addition to stemming from ion channel or extracellular matrix dysfunction, atrial diseases such as ASDs or AF may result from disruptions of atrial CM identity.

developmental biology↗

bioRxiv2024

A TBX5-dependent compartment boundary patterns the cardiac interventricular septum

Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect (CHD), but mechanisms for patterning the IVS are largely unknown. Here, we show that a Tbx5+/Mef2cAHF+ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first- and second heart field interface. Ablation of Tbx5+/Mef2cAHF+ progenitors cause IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the CHD transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects (VSDs) and patterning defects, including misexpression of Slit2 and Ntn1, which encode guidance cues. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes VSDs and perturbed septal lineage distributions. Thus, we identify Tbx5 as a candidate selector gene, directing progenitors and regulating essential cues, to pattern a compartment boundary for proper cardiac septation, revealing mechanisms for cardiac birth defects.

developmental biology↗