Biology subjects

Mahendroo, M.

Publications and source records attributed to Mahendroo, M..

7 recordsLinked to original sources

bioRxiv2026

Olfactomedin 4 marks luminal progenitor cells that give rise to a secretory cell lineage in the mouse cervix

Development of the female reproductive tract in mice occurs in early postnatal life. The current model identifies Trp63 as the master regulator that initiates differentiation of simple columnar Keratin 8+ epithelium in the cervix and vagina into a stratified squamous epithelium. Thereafter Trp63+ basal progenitors maintain cervicovaginal epithelial cell homeostasis and in the adult serve as the progenitor for hormone-regulated shifts in stratified squamous and secretory luminal cells. This model differs from the human in which two progenitors, one columnar and the other basal gives rise to secretory cells in the endocervix and stratified squamous epithelia in the ectocervix and vagina respectively. In the current study, we identify a population of Krt8+, Tp63- epithelial cells that are retained in the cervicovaginal epithelium during the postnatal developmental period and into adulthood. Single cell datasets from the cervices of adult mice, identify Olfactomedin 4 (Olfm4), as a unique marker of the Krt8+Trp63- population. Adult lineage tracing and reassessment of gene markers during postnatal development support a revised model in which two progenitors are delineated in the mouse cervix and vagina by PND15. Olfactomedin 4+ progenitors give rise to specialized secretory goblet cells, while Trp63+ basal progenitors give rise to stratified squamous luminal cells in the cervix and vagina of nonpregnant and pregnant mice. Consistent with the expansion of goblet cells in pregnancy, the Olfm4+ progenitor is highly proliferative in early pregnancy and progesterone regulates increased goblet cell differentiation. These findings reveal a previously unrecognized species similarity between mice and humans in which goblet cell and squamous keratinized cell subtypes are derived from two progenitor populations respectively. HIGHLIGHTSO_LITwo epithelial progenitors (Trp63 and Olfm4) populations are delineated in the cervix and vagina within the first two weeks of postnatal life. C_LIO_LIThe Trp63+ progenitor gives rise to keratinized epithelial cells, whereas the Olfm4+ progenitor cells give rise to secretory goblet cells. C_LIO_LIlfm4 is not required for maintenance of the luminal progenitor or differentiation of goblet cells in the cervix and vagina during adulthood and pregnancy. C_LIO_LIIn adults, progesterone promotes differentiation of Olfm4+ progenitors into goblet cells. C_LI

developmental biology↗

bioRxiv2026

ECHOS enables spatial epigenome profiling at subcellular resolution

Biological structures and the epigenome are intertwined. For example, complex tissues are often the combined products of various groups of spatially patterned cell types with distinct epigenetic states. Furthermore, chromatin at various subnuclear locations within a cell often differ in their epigenetic properties. Thus, a systematic understanding of the relationship between the epigenome and its spatial distribution across biological scales would inform tissue and cellular functions as well as gene regulatory mechanisms. Yet, spatially resolved epigenome profiling--particularly at subcellular resolution--remains technically challenging. Here, we present Epigenetic CUT&Tag via High-resolution Optical Selection (ECHOS), a platform that combines high-resolution imaging and high-throughput sequencing to enable precise, spatially targeted epigenetic profiling across biological scales. At the cellular scale, ECHOS generates high-quality DNA-binding protein and histone modification datasets that show strong concordances with datasets from ChIP-seq and CUT&Tag experiments. Further optimization of ECHOS (ECHOS+) enables the characterization of the histone modification landscape of chromatin at the sub-micron resolution. Using ECHOS+, we revealed distinct gene regulatory logics at different layers of human ectocervical epithelium. We also showed that micronuclei--small nucleus-like structures formed by mitotic errors--exhibited a different epigenetic state from the same chromosome regions on the intact nuclei. Finally, we found that human aging altered the epigenetic state of the inactive X chromosome located in a subcellular nuclear structure called the Barr body, which may contribute to genes escaping X chromosome inactivation during female aging. Together, ECHOS and ECHOS+ represent a scalable and generalizable framework for spatial epigenomic analyses, with broad potential applications in various domains of biology.

genetics↗

bioRxiv2025

Regulation of Female Reproductive Aging by the Spag17 Gene

Reproductive aging in females is characterized by a decline in oocyte quantity and quality, as well as uterine and cervical dysfunction that contributes to infertility and pregnancy complications. To investigate mechanisms underlying reproductive aging, we explored the contribution of Spag17, a cilia-related gene associated with tissue homeostasis and fibrosis. Spag17 was expressed throughout the female reproductive tract; however, its expression declined with age in ovarian tissue, while high expression levels were observed in the cervix of young females during cervical tissue remodeling in the pre- and post-parturition periods. Loss of Spag17 in mice resulted in impaired fertility, obstructed labor, and maternal death. This phenotype was associated with accelerated ovarian aging, increased fibrosis, and cervical stiffness, further complicating parturition. At the molecular level, Spag17 loss activated key aging-associated pathways, including proinflammatory, profibrotic, and senescence signaling, suggesting that SPAG17 may be a critical player in female reproductive aging. TEASERSpag17 is a key modulator of female reproductive aging.

cell biology↗

bioRxiv2024

Lysyl Oxidases are Necessary for Myometrial Contractility and On-Time Parturition in Mice

The extracellular matrix (ECM) plays a pivotal role in the maintenance of tissue mechanical homeostasis. Collagens and elastic fibers are the most predominant fibrous ECM proteins providing tissue mechanical function through covalent cross-linking which is mediated by the lysyl oxidase family of enzymes. In this study, the function of lysyl oxidases in maintaining the integrity of the extracellular matrix in the myometrium and its impact on parturition-timing was investigated. Gene and protein expression analyses demonstrate that a sub-set of the lysyl oxidase family of enzymes are highly induced in pregnant myometrium. Inhibition of the activity of the lysyl oxidase family of enzymes through {beta}-aminopropionitrile (BAPN) delays parturition in mice, in part, due to myometrial dysfunction. In BAPN treated mice, the expression of genes encoding contraction associated proteins such as connexin 43, oxytocin receptor and prostaglandin synthase 2 is significantly reduced in the myometrium compared to the untreated control mice. Proteomic analysis revealed that the composition of the ECM is altered in response to BAPN treatment which demonstrates that the inhibition of the activity of lysyl oxidases disrupted the integrity of the myometrial ECM. Our findings demonstrate that the lysyl oxidases-mediated ECM function is necessary for the myometrium to transition from a quiescent to a contractile phenotype at term for on-time parturition.

physiology↗

bioRxiv2024

Relaxin Modulates the Genomic Actions and Biological Effects of Estrogen in the Myometrium by Reducing Estrogen Receptor Alpha Phosphorylation

Estradiol (E2) and relaxin (Rln) are steroid and polypeptide hormones, respectively, with important roles in the female reproductive tract, including myometrium. Some actions of Rln, which are mediated by its membrane receptor RXFP1, require or are augmented by E2 signaling through its cognate nuclear steroid receptor, estrogen receptor alpha (ER). In contrast, other actions of Rln act in opposition to the effects of E2. Here we explored the molecular and genomic mechanisms that underlie the functional interplay between E2 and Rln in the myometrium. We used both ovariectomized female mice and immortalized human myometrial cells expressing wild-type or mutant ER (hTERT-HM-ER cells). Our results indicate that Rln modulates the genomic actions and biological effects of estrogen in the myometrium and myometrial cells by reducing phosphorylation of ER on serine 118 (S118), as well as by reducing the E2-dependent binding of ER across the genome. These effects were associated with changes in the hormone-regulated transcriptome, including a decrease in the E2-dependent expression of some genes and enhanced expression of others. The inhibitory effects of Rln cotreatment on the E2-dependent phosphorylation of ER required the nuclear dual-specificity phosphatases DUSP1 and DUSP5. Moreover, the inhibitory effects of Rln were reflected in a concomitant inhibition of the E2-dependent contraction of myometrial cells. Collectively, our results identify a pathway that integrates Rln/RXFP1 and E2/ER signaling, resulting in a convergence of membrane and nuclear signaling pathways to control genomic and biological outcomes.

molecular biology↗

bioRxiv2024

Cervical collagen network porosity assessed by SHG endomicroscopy distinguishes preterm and normal pregnancy - a pilot study

Structured AbstractO_ST_ABSBackgroundC_ST_ABSPreterm birth (PTB) is a global public health issue affecting millions of newborns every year. Orchestrated remodeling of the cervix is essential for normal pregnancy and birth, while PTB is closely related with premature cervical ripening and loss of cervical mechanical strength. The structure and organization of fibrillar collagen in the extracellular matrix are of vital importance to the biomechanical properties of the cervix. Second harmonic generation (SHG) microscopy has proved capable of revealing the progressive changes in cervical collagen morphology over the course of pregnancy. To translate this promising imaging technology to clinical practice, a flexible SHG endomicroscope has long been envisaged for label-free, non-invasive visualization of cervical collagen architecture and for assessment of PTB risk. ObjectiveTo evaluate the potential of our newly-developed SHG endomicroscope for imaging-based differentiation of cervical collagen architecture between normal pregnant mice and RU486/mifepristone-induced PTB mouse models. Study DesignWe undertook endomicroscopy SHG imaging of cervical collagen on two types of ex vivo samples: 1) frozen cervical tissue sections ([~]50 {micro}m thick) and 2) resected intact cervices, and performed SHG-image-based quantitative collagen morphology analysis to distinguish RU486 mouse models from normal pregnant mice. ResultsEndomicroscopic SHG images of cervical tissue sections from mifepristone-treated mouse models exhibit statistically larger collagen fiber diameter, increased pore size, and reduced pore numbers than those of normal pregnant mice. Similar changes are also observed on SHG images of subepithelial collagen fibers acquired from intact cervices by the endomicroscope. ConclusionThe experiment results demonstrated that SHG endomicroscopy along with quantitative image analysis holds promising potential for clinical assessment of cervical collagen remodeling and preterm birth risk.

bioengineering↗

bioRxiv2022

Dynamic states of cervical epithelia during pregnancy and epithelial barrier disruption

The cervical epithelium undergoes continuous changes in proliferation, differentiation, and function that are critical before pregnancy to ensure fertility and during pregnancy to provide a physical and immunoprotective barrier for pregnancy maintenance. Barrier disruption can lead to the ascension of pathogens that elicit inflammatory responses and preterm birth. Here, we identify cervical epithelial subtypes in nonpregnant, pregnant, and in-labor mice using single-cell transcriptome and spatial analysis. We identify heterogeneous subpopulations of epithelia displaying spatial and temporal specificity. Notably, two goblet cell subtypes with distinct transcriptional programs and mucosal networks were dominant in pregnancy. Untimely basal cell proliferation and goblet cells with diminished mucosal integrity characterize barrier dysfunction in mice lacking hyaluronan. These data demonstrate how the cervical epithelium undergoes continuous remodeling to maintain dynamic states of homeostasis in pregnancy and labor, and provide a framework to understand perturbations in epithelial health and host-microbe interactions that increase the risk of premature birth.

cell biology↗