Unveiling uterine aging: Much more to learn

Wu, Yaling; Li, Milu; Zhang, Jinjin; Wang, Shixuan

doi:10.1016/j.arr.2023.101879

Cited by 22 publications

(17 citation statements)

References 126 publications

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“…In addition, the Stro-1:Stro-2 ratio (i.e., between the two types of MYH11 subtypes, for ECM secretion and angiogenesis, respectively) is increased, possibly contributing to uterine tissue fibrosis observed in the aging uterus. Finally, it has been shown that during uterine aging, the ability of endometrial stromal cells to decidualize decreases gradually (86) and here we find that the early dS cells (Stro-8) are significantly reduced, while later dS cells, Stro-10, are lost in the postmenopausal sample.…”

Section: Resultssupporting

confidence: 62%

Cellular heterogeneity and dynamics of the human uterus in healthy premenopausal women

Ulrich,

Vargo,

et al. 2024

Preprint

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The human uterus is a complex and dynamic organ whose lining grows, remodels, and regenerates in every menstrual cycle or upon tissue damage. Here we applied single-cell RNA sequencing to profile more the 50,000 uterine cells from both the endometrium and myometrium of 5 healthy premenopausal individuals, and jointly analyzed the data with a previously published dataset from 15 subjects. The resulting normal uterus cell atlas contains more than 167K cells representing the lymphatic endothelium, blood endothelium, stromal, ciliated epithelium, unciliated epithelium, and immune cell populations. Focused analyses within each major cell type and comparisons with subtype labels from prior studies allowed us to document supporting evidence, resolve naming conflicts, and to propose a consensus annotation system of 39 subtypes. We release their gene expression centroids, differentially expressed genes, and mRNA patterns of literature-based markers as a shared community resource. We find many subtypes show dynamic changes over different phases of the cycle and identify multiple potential progenitor cells: compartment-wide progenitors for each major cell type, transitional cells that are upstream of other subtypes, and potential cross-lineage multipotent stromal progenitors that may be capable of replenishing the epithelial, stromal, and endothelial compartments. When compared to the healthy premenopausal samples, a postpartum and a postmenopausal uterus sample revealed substantially altered tissue composition, involving the rise or fall of stromal, endothelial, and immune cells. The cell taxonomy and molecular markers we report here are expected to inform studies of both basic biology of uterine function and its disorders.

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Section: Resultssupporting

confidence: 62%

Cellular heterogeneity and dynamics of the human uterus in healthy premenopausal women

Ulrich,

Vargo,

et al. 2024

Preprint

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“…Histological analysis showed the uterus has a reduced stroma layer and a decrease in the number of endometrial glands (Figures 1B,C and S1B). Additionally, stroma from older mice (>22 weeks) has indications of hyalinization and fibrosis (Figure S1B), suggesting inflammation and tissue remodeling 27 . Examination of the uteri of 21‐day‐old prepubertal females showed normal gross and histological morphology with the exception that fewer endometrial glands were present (Figure 1B,C).…”

Section: Resultsmentioning

confidence: 99%

Chromatin architectural factor CTCF is essential for progesterone‐dependent uterine maturation

Hewitt,

Gruzdev,

Willson

et al. 2023

The FASEB Journal

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Receptors for estrogen and progesterone frequently interact, via Cohesin/CTCF loop extrusion, at enhancers distal from regulated genes. Loss‐of‐function CTCF mutation in >20% of human endometrial tumors indicates its importance in uterine homeostasis. To better understand how CTCF‐mediated enhancer‐gene interactions impact endometrial development and function, the Ctcf gene was selectively deleted in female reproductive tissues of mice. Prepubertal Ctcfd/d uterine tissue exhibited a marked reduction in the number of uterine glands compared to those without Ctcf deletion (Ctcff/f mice). Post‐pubertal Ctcfd/d uteri were hypoplastic with significant reduction in both the amount of the endometrial stroma and number of glands. Transcriptional profiling revealed increased expression of stem cell molecules Lif, EOMES, and Lgr5, and enhanced inflammation pathways following Ctcf deletion. Analysis of the response of the uterus to steroid hormone stimulation showed that CTCF deletion affects a subset of progesterone‐responsive genes. This finding indicates (1) Progesterone‐mediated signaling remains functional following Ctcf deletion and (2) certain progesterone‐regulated genes are sensitive to Ctcf deletion, suggesting they depend on gene‐enhancer interactions that require CTCF. The progesterone‐responsive genes altered by CTCF ablation included Ihh, Fst, and Errfi1. CTCF‐dependent progesterone‐responsive uterine genes enhance critical processes including anti‐tumorigenesis, which is relevant to the known effectiveness of progesterone in inhibiting progression of early‐stage endometrial tumors. Overall, our findings reveal that uterine Ctcf plays a key role in progesterone‐dependent expression of uterine genes underlying optimal post‐pubertal uterine development.

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“…The human female reproductive system displays early signs of ageing, marked by reduced fertility and hormonal dysfunctions [45]. While the mechanisms remain elusive, research indicates a correlation between extracellular matrix (ECM) protein composition and ageing [46, 47]. Fibronectin is a multi-functional protein that is important for embryogenesis, cell adhesion, and cell growth [48] that plays a major role in ECM assembly by binding to collagen, integrins, and other proteins [49].…”

Section: Resultsmentioning

confidence: 99%

Multi-scale tissue fluorescence mapping with fibre optic ultraviolet excitation and generative modelling

Yong

Tan

et al. 2022

Preprint

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Rapidly resolving microstructure and function from thick biological samples is a critical requirement from basic research to clinical diagnosis. The need for physical sectioning leads to limitations in the speed, cost, or ease of sample preparation and imaging. We introduce a fluorescence microscope with deep ultraviolet illumination via omnidirectional fibre optics, based on the concept of microscopy with ultraviolet surface excitation (MUSE). We further exploited precise control of directional illumination to produce 3D reconstructions of surface microtopography from 2D images. Our technology is applicable to diverse sample types, ranging from single cells and 3D cultures to large tissue samples while utilising conventional, widely available objective lenses in a compact and portable implementation. We demonstrated the use of our microscope with important fluorescent assays through quantitative viability studies in single cells to whole organs, organ-level studies comparable to standard H&E histology, and multiplexed immunohistochemistry staining. We also explored the potential for microtopography to provide additional insight into vascular and tissue texture and heterogeneity studies. This technology fills long-standing technological gaps in both the laboratory and clinic for a general-purpose microscope that is simple, portable, and cheap that can provide near real-time biological insights.

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Unveiling uterine aging: Much more to learn

Cited by 22 publications

References 126 publications

Cellular heterogeneity and dynamics of the human uterus in healthy premenopausal women

Cellular heterogeneity and dynamics of the human uterus in healthy premenopausal women

Chromatin architectural factor CTCF is essential for progesterone‐dependent uterine maturation

Multi-scale tissue fluorescence mapping with fibre optic ultraviolet excitation and generative modelling

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