Biology subjects

Harasymowicz, N.

Publications and source records attributed to Harasymowicz, N..

4 recordsLinked to original sources

bioRxiv2025

Maternal high-fat/high-sugar diet has short-term dental effects and long-term sex-specific skeletal effects on adult offspring mice

BackgroundMaternal nutrition is increasingly recognized as a modulator of offspring skeletal development. While genetics has long been considered the primary determinant of craniofacial morphology, emerging evidence suggests that prenatal and early postnatal dietary exposures also influence facial morphology. However, how maternal diet differentially affects male and female craniofacial structures remains unclear. This study aimed to examine the effects of a maternal high-fat, high-sugar (HFHS) diet on craniofacial and dental morphology in first-(F1) and second-(F2) generation adult mice. Materials and MethodsFemale mice were fed a HFHS diet for six weeks before mating and throughout pregnancy and lactation. F1 offspring were weaned to a standard chow diet, and a subset of female F1 offspring were bred to produce F2 offspring, also maintained on chow. Craniofacial skeletal and dental structures of adult F1 and F2 mice at 1-year of age were assessed using micro-computed tomography for linear and geometric morphometrics. ResultsHFHS diet exposure significantly reduced midfacial and mandibular length in F1 females, and these effects persisted in F2 females. Mandibular shape differences were also observed in both generations of females. In males, skull size remained unchanged, though subtle mandibular shape changes were noted in F1 only. Tooth size was reduced in both sexes of F1 offspring but not in F2. ConclusionMaternal HFHS diet induces sex- and jaw-specific alterations in craniofacial morphology, with skeletal changes persisting in females across generations, while dental effects did not persist beyond one generation. These findings highlight the potential for maternal dietary habits to exert lasting, intergenerational influences on offspring facial form.

developmental biology↗

bioRxiv2024

PIEZO1-Mediated Mechanotransduction Regulates Collagen Synthesis on Nanostructured 2D and 3D Models of Fibrosis

Progressive fibrosis causes tissue malfunction and organ failure due to the pathologic accumulation of a collagen-rich extracellular matrix. In vitro models provide useful tools for deconstructing the roles of specific biomechanical or biological mechanisms involved in these processes and identifying potential therapeutic targets. In particular, recent studies have implicated cellular mechanosensing of substrate micro- and nanoscale architecture as a regulator of fibrosis. In this study, we investigated how the mechanosensitive ion channel PIEZO1 and intracellular mechanotransduction pathways influence fibrotic gene and protein expression in adipose-derived stem cells (hASCs). Specifically, we examined the role of PIEZO1 and the mechano-sensitive transcription factors YAP/TAZ in sensing aligned or non-aligned substrate architecture to regulate collagen formation. We utilized both 2D microphotopatterned substrates and 3D electrospun polycaprolactone (PCL) substrates to study the role of culture dimensionality. We found that PIEZO1 regulates collagen production in hASCs in a manner that is sensitive to substrate architecture. Activation of PIEZO1 induced significant morphological changes in hASCs, particularly when they were cultured on aligned substrates. While YAP translocated to the cytoplasm following PIEZO1 activation, depleting YAP and TAZ did not change collagen expression significantly downstream of PIEZO1 activation, implying that YAP/TAZ translocation out of the nucleus and increased collagen production may be independent outputs of PIEZO1 activation. Our studies demonstrate a role for PIEZO1 in cellular mechanosensing of substrate architecture and provide targetable pathways for treating fibrosis as well as for enhancing tissue-engineered and regenerative approaches for fibrous tissue repair.

bioengineering↗

bioRxiv2019

Gene Therapy for Follistatin Mitigates Systemic Metabolic Inflammation and Post-Traumatic Osteoarthritis in High-Fat Diet-Induced Obese Mice

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Recent studies indicate that follistatin (FST), a protein which binds myostatin and activin, may have the potential to enhance muscle formation while neutralizing inflammation induced by these proteins. Here, we hypothesized that adeno-associated virus (AAV9) delivery of FST will enhance muscle formation and mitigate metabolic inflammation and knee OA caused by a high fat diet in mice. Obese mice receiving AAV-mediated FST delivery exhibited decreased inflammatory adipokines and cytokines systemically in the serum as well as locally in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. While obesity disrupted the mitochondrial oxidative phosphorylation (OXPHOS) system in adipocytes, gene therapy for FST restored the key proteins involved in mitochondrial biogenesis, such as PPAR{gamma} coactivator 1 and AKT protein kinase 1, leading to the browning of white adipose tissue. Taken together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.

physiology↗

bioRxiv2019

A Genome-engineered Bioartificial Implant for Autoregulated Anti-Cytokine Drug Delivery

Biologic drug therapies are effective treatments for autoimmune diseases such as rheumatoid arthritis (RA) but may cause significant adverse effects, as they are administered continuously at high doses that can suppress the immune system. Using CRISPR-Cas9 genome editing, we engineered stem cells containing a synthetic gene circuit expressing biologic drugs to antagonize interleukin-1 (IL-1) or tumor necrosis factor (TNF) in an autoregulated, feedback-controlled manner in response to activation of the endogenous chemokine (C-C) motif ligand 2 (Ccl2) promoter. To test this approach in vivo, cells were tissue-engineered into a stable cartilaginous construct and implanted subcutaneously in mice with inflammatory arthritis. Bioengineered anti-cytokine implants mitigated arthritis severity as measured by joint pain, structural damage, and systemic and local inflammation. The coupling of synthetic biology with tissue engineering promises a range of potential applications for treating chronic diseases using custom-designed cells that express therapeutic transgenes in response to dynamically changing biological signals.Competing Interest StatementThe authors have declared no competing interest.View Full Text

synthetic biology↗