Congratulations to Dr. Nicholas Gigliotti on successfully defending his thesis, entitled “Investigation of multiscale collagen remodeling mechanisms in the cervical extracellular matrix during pregnancy”. Check out the abstract, below. Congratulations, Nick! We can’t wait to see what you do next!
Abstract:
Premature birth (PTB) occurs in 1 in 10 pregnancies, affecting millions of mothers and children every year. Lack of effective diagnostic measures and therapeutic interventions have led to little or no improvement in the incidence and prognosis of PTB, highlighting the need for a greater understanding of the mechanisms involved. The cervix, which acts as a selective barrier from the uterus to the birth canal, plays a pivotal role in dictating the timing of labor. While the causes of preterm birth are varied and often unknown, all instances result in the premature softening of the cervix, making it a key target for research in this area. The mechanisms governing the softening of the cervix remain poorly understood and are the focal point of this work.
To understand the underlying biological mechanisms responsible for the softening of the cervix, we first look at the structural evolution of collagen within the cervix. To achieve this, a machine learning workflow was developed for automated image analysis of collagen fibril architecture, improving the accuracy and resolution with which we can detect subtle changes in the fibrillar structure from TEM images. Using this workflow, we identified trends in the evolution of collagen structure at various length scales. We developed an analytical model linking these structural descriptors to bulk tissue mechanics, demonstrating that mechanical changes in the cervix can be attributed to the observed changes in collagen structure.
Subsequent studies were aimed at isolating collagen from other confounding biological factors to study the mechanisms behind these specific structural trends. Lysyl oxidase (LOX) is an enzyme known to induce crosslinking in collagen and likely plays a pivotal role in the remodeling of the cervix. We employed collagen hydrogels to directly assess the impact of LOX and one of its isoforms, LOXL2, on collagen structure and matrix mechanics, allowing us to better understand the catalytic roles of these molecules in the remodeling process and how their activity alters molecular packing density and fibrillar size.
To further assess the impact of these enzymes on remodeling, we also developed a cell-laden hydrogel system to assess how LOX and LOXL2 impact cell-mediated remodeling events. Our findings suggest that LOX and LOXL2 play distinct roles in cell signaling pathways, significantly altering gene expression, ECM deposition, matrix structure, and mechanics. Together, these findings advance our understanding of the physical and biological impacts of lysyl oxidase enzymes on collagen ultrastructure and mechanics and highlight the potential of LOX-based therapeutics for PTB and other tissue remodeling applications
