James Zwierzynski

All Publications

• 3D imaging of the pregnant uterus reveals an extensively invasive mouse placenta and early CXCL12-CXCR4 requirement. bioRxiv : the preprint server for biology Zwierzynski, J. B., Moufarrej, M. N., Red-Horse, K. 2026

  Abstract

  Successful pregnancy requires exquisite balance: the placenta must invade just enough to access maternal blood but not so deep it remains attached at birth. Disrupting this balance causes life-threatening pregnancy complications, for which treatments remain limited. Animal models are desperately needed to discover mechanisms underlying balanced uteroplacental development and how pregnancy complications arise, but this is hampered by the view that mouse placentation lacks human characteristics such as extensive trophoblast invasion and targeting of uterine spiral arteries. Here, we utilize 3D imaging, mouse genetics, and pharmacological perturbations to demonstrate that: (1) The mouse placenta invades more extensively than previously recognized with most spiral arteries heavily enveloped by fetal trophoblasts, (2) This process is disrupted without CXCL12-CXCR4 signaling specifically during early pregnancy, and (3) Disrupting early uteroplacental development ultimately results in excessively deep trophoblast invasion, closely mimicking the pregnancy complication placenta accreta. Mechanistically, uterine epithelium, stroma, and arteries activate CXCR4 signaling in early pregnancy, and inhibition causes decidualization failure, followed by dissolution of spiral artery development. Trophoblasts consequently migrate deep into uterine muscle and its arteries, reproducing hallmarks of human accreta. Thus, with 3D imaging, the mouse more effectively models human uteroplacental development and defines an early etiological window for intervention.

  View details for DOI 10.64898/2026.04.06.716785

  View details for PubMedID 41993342

  View details for PubMedCentralID PMC13081843

• Role of Maternal Obesity in Offspring Cardiovascular Development and Congenital Heart Defects. Journal of the American Heart Association McMullan, A., Zwierzynski, J. B., Jain, N., Haneline, L. S., Shou, W., Kua, K. L., Hota, S. K., Durbin, M. D. 2025: e039684

  Abstract

  BACKGROUND: Congenital heart disease is a leading cause of death in newborns, yet many of its molecular mechanisms remain unknown. Both maternal obesity and diabetes increase the risk of congenital heart disease in offspring, with recent studies suggesting these conditions may have distinct teratogenic mechanisms. The global prevalence of obesity is rising, and while maternal obesity is a known risk factor for fetal congenital heart disease, the specific mechanisms are largely unexplored.METHODS AND RESULTS: We used a murine model of diet-induced maternal obesity, without diabetes, to produce dams that were overweight but had normal blood glucose levels. Embryos were generated and their developing hearts analyzed. Transcriptome analysis was performed using single-nucleus and bulk RNA sequencing. Global and phospho-enriched proteome analysis was performed using tandem mass tag-mass spectroscopy. Immunobloting and histologic evaluation were also performed. Analysis revealed disrupted oxidative phosphorylation and reactive oxygen species formation, with reduced antioxidant capacity, evidenced by downregulation of genes Sod1 and Gp4x, and disrupted Hif1a signaling. Evidence of oxidative stress, cell death signaling, and alteration in Rho GTPase and actin cytoskeleton signaling was also observed. Genes involved in cardiac morphogenesis, including Hand2, were downregulated, and fewer mature cardiomyocytes were present. Histologic analysis confirmed increased cardiac defects in embryos exposed to maternal obesity.CONCLUSIONS: These findings demonstrate that maternal obesity alone can result in cardiac defects through mechanisms similar to those associated with maternal hyperglycemia. This study provides valuable insight into the role of maternal obesity, a growing and modifiable risk factor, in the development of the most common birth defect, congenital heart disease.

  View details for DOI 10.1161/JAHA.124.039684

  View details for PubMedID 40314345