Pregnancy-induced remodeling of the murine reproductive tract: a longitudinal in vivo magnetic resonance imaging study.

Mammalian pregnancy requires gradual yet extreme remodeling of the reproductive organs to support the growth of the embryos and their birth. After delivery, the reproductive organs return to their non-pregnant state. As pregnancy has traditionally been understudied, there are many unknowns pertaining to the mechanisms behind this remarkable remodeling and repair process which, when not successful, can lead to pregnancy-related complications such as maternal trauma, pre-term birth, and pelvic floor disorders. This study presents the first longitudinal imaging data that focuses on revealing anatomical alterations of the vagina, cervix, and uterine horns during pregnancy and postpartum using the mouse model. By utilizing advanced magnetic resonance imaging (MRI) technology, T1-weighted and T2-weighted images of the reproductive organs of three mice in their in vivo environment were collected at five time points: non-pregnant, mid-pregnant (gestation day: 9-10), late pregnant (gestation day: 16-17), postpartum (24-72 h after delivery) and three weeks postpartum. Measurements of the vagina, cervix, and uterine horns were taken by analyzing MRI segmentations of these organs. The cross-sectional diameter, length, and volume of the vagina increased in late pregnancy and then returned to non-pregnant values three weeks after delivery. The cross-sectional diameter of the cervix decreased at mid-pregnancy before increasing in late pregnancy. The volume of the cervix peaked at late pregnancy before shortening by 24-72 h postpartum. As expected, the uterus increased in cross-sectional diameter, length, and volume during pregnancy. The uterine horns decreased in size postpartum, ultimately returning to their average non-pregnant size three weeks postpartum. The newly developed methods for acquiring longitudinal in vivo MRI scans of the murine reproductive system can be extended to future studies that evaluate functional and morphological alterations of this system due to pathologies, interventions, and treatments.

Modeling lymphangiogenesis: Pairing in vitro and in vivo metrics.

Lymphangiogenesis is the mechanism by which the lymphatic system develops and expands new vessels facilitating fluid drainage and immune cell trafficking. Models to study lymphangiogenesis are necessary for a better understanding of the underlying mechanisms and to identify or test new therapeutic agents that target lymphangiogenesis. Across the lymphatic literature, multiple models have been developed to study lymphangiogenesis in vitro and in vivo. In vitro, lymphangiogenesis can be modeled with varying complexity, from monolayers to hydrogels to explants, with common metrics for characterizing proliferation, migration, and sprouting of lymphatic endothelial cells (LECs) and vessels. In comparison, in vivo models of lymphangiogenesis often use genetically modified zebrafish and mice, with in situ mouse models in the ear, cornea, hind leg, and tail. In vivo metrics, such as activation of LECs, number of new lymphatic vessels, and sprouting, mirror those most used in vitro, with the addition of lymphatic vessel hyperplasia and drainage. The impacts of lymphangiogenesis vary by context of tissue and pathology. Therapeutic targeting of lymphangiogenesis can have paradoxical effects depending on the pathology including lymphedema, cancer, organ transplant, and inflammation. In this review, we describe and compare lymphangiogenic outcomes and metrics between in vitro and in vivo studies, specifically reviewing only those publications in which both testing formats are used. We find that in vitro studies correlate well with in vivo in wound healing and development, but not in the reproductive tract or the complex tumor microenvironment. Considerations for improving in vitro models are to increase complexity with perfusable microfluidic devices, co-cultures with tissue-specific support cells, the inclusion of fluid flow, and pairing in vitro models of differing complexities. We believe that these changes would strengthen the correlation between in vitro and in vivo outcomes, giving more insight into lymphangiogenesis in healthy and pathological states.