In the womb, mammals possess all of the preliminary sexual structures necessary to become either male or female. This includes the Mullerian duct, which develops into the Fallopian tubes, uterus, cervix, and vagina in female fetuses. In male fetuses, the testis secretes a hormone called Mullerian inhibiting substance (MIS). This triggers the activity of a small group of cells, known as Misr2+ cells, that cause the Mullerian duct to degenerate, preventing males from developing female sexual organs. It was not clear what happens to Misr2+ cells in female fetuses or if they affect how the uterus develops. Saatcioglu et al. now show that in newborn female mice and rats, a type of Misr2+ cell that sits within a thin inner layer of the developing uterus still responds to MIS. At this time, the uterus is in a critical early period of development. Treating the mice and rats with MIS protein during their first six days of life eventually caused the Misr2+ cells to die. The treatment also prevented a layer of connective tissue, known as the endometrial stroma, from forming in the uterus. As a result, the mice and rats were infertile and had severely underdeveloped uteri. While the Misr2+ cells are present in newborn rats and mice, Saatcioglu et al. found that they disappeared before birth in humans. However, the overall results suggest that Misr2+ cells act as progenitor cells that develop into the cells of the endometrial stroma. Future work could investigate the roles these cells play in causing uterine developmental disorders and infertility disorders. Furthermore, the finding that MIS inhibits the Misr2+ cells could help researchers to develop treatments for uterine cancer and other conditions where the cells of the uterus grow and divide too much.
Summary The regenerative capacity of the human endometrium requires a population of local stem cells. However, the phenotypes, locations, and origin of these cells are still unknown. In a mouse menstruation model, uterine stromal SM22α+-derived CD34+KLF4+ stem cells are activated and integrate into the regeneration area, where they differentiate and incorporate into the endometrial epithelium; this process is correlated with enhanced protein SUMOylation in CD34+KLF4+ cells. Mice with a stromal S...
Summary Tumor-infiltrating myeloid cells (TIMs) comprise monocytes, macrophages, dendritic cells, and neutrophils, and have emerged as key regulators of cancer growth. These cells can diversify into a spectrum of states, which might promote or limit tumor outgrowth but remain poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to map TIMs in non-small-cell lung cancer patients. We uncovered 25 TIM states, most of which were reproducibly found across patients. To facilitate tr...
#1M. L. Mucenski(Cincinnati Children's Hospital Medical Center)H-Index: 17
#1Michael L. Mucenski(Cincinnati Children's Hospital Medical Center)H-Index: 7
Last. S. Steven Potter(Cincinnati Children's Hospital Medical Center)H-Index: 68
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The uterus is a remarkable organ that must guard against infections while maintaining the ability to support growth of a fetus without rejection. The Hoxa10 and Hoxa11 genes have previously been shown to play essential roles in uterus development and function. In this report we show that the Hoxa9,10,11, Hoxc9,10,11, Hoxd9,10,11 genes play a redundant role in the formation of uterine glands. In addition, we use single cell RNA-seq to create a high resolution gene expression atlas of the developi...
During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblast–decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua...
Context: There is increasing evidence for Mullerian-inhibiting substance (MIS)/anti-Mullerian hormone (AMH) physiologic activity in the human uterus, so it is relevant to study how MIS/AMH levels impact pregnancy. Objective: To investigate the association of MIS/AMH levels with the risk of adverse obstetric outcomes. Design: Retrospective cohort study. Setting: Academic fertility center. Patients: Women who became pregnant through in vitro fertilization between January 2012 and October 2016. Exc...
#1Rachel D. Mullen(University of Texas MD Anderson Cancer Center)H-Index: 10
#2Ying Wang(University of Texas MD Anderson Cancer Center)H-Index: 21
Last. Richard R. Behringer(University of Texas MD Anderson Cancer Center)H-Index: 8
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In mammals, the developing reproductive tract primordium of male and female fetuses consists of the Wolffian duct and the Mullerian duct (MD), two epithelial tube pairs surrounded by mesenchyme. During male development, mesenchyme–epithelia interactions mediate MD regression to prevent its development into a uterus, oviduct, and upper vagina. It is well established that transforming growth factor-β family member anti-Mullerian hormone (AMH) secreted from the fetal testis and its type 1 and 2 rec...
Summary The mammalian nervous system executes complex behaviors controlled by specialized, precisely positioned, and interacting cell types. Here, we used RNA sequencing of half a million single cells to create a detailed census of cell types in the mouse nervous system. We mapped cell types spatially and derived a hierarchical, data-driven taxonomy. Neurons were the most diverse and were grouped by developmental anatomical units and by the expression of neurotransmitters and neuropeptides. Neur...
#1Bruce A. Hay(California Institute of Technology)H-Index: 54
#2Juan Li(California Institute of Technology)H-Index: 7
Last. Ming Guo(UCLA: University of California, Los Angeles)H-Index: 31
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There is a need for permanent, non-surgical methods of contraception for many animal species. Here we discuss the hypothesis that transgene-mediated expression of fertility inhibiting molecules such as monoclonal antibodies, ligands for cell surface receptors, receptor decoys, or small RNAs can provide such a method, which we term vectored contraception. We outline the technologies involved, progress made, and discuss challenges to implementation.
Last. Rahul Satija(NYU: New York University)H-Index: 51
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A new computational approach enables integrative analysis of disparate single-cell RNA–sequencing data sets by identifying shared patterns of variation between cell subpopulations.
Background Disorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. In order to identify the underlying genetic etiology, we had performed exome sequencing in a subset of DSD cases with 46,XY karyotype and were able to identify the causative genetic variant in 35% of cases. While the genetic etiology was not ascertained in more...
Mullerian inhibiting substance (MIS/AMH), produced by granulosa cells of growing follicles, is an important regulator of folliculogenesis and follicle development. Treatment with exogenous MIS in mice suppresses follicle development and prevents ovulation. To investigate the mechanisms by which MIS inhibits follicle development, we performed single-cell RNA sequencing of whole neonatal ovaries treated with MIS at birth and analyzed at postnatal day 6, coinciding with the first wave of follicle g...
Last. John A. Kessler(NU: Northwestern University)H-Index: 94
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Summary Various human diseases and pregnancy-related disorders reflect endometrial dysfunction. However, rodent models do not share fundamental biological processes with the human endometrium, such as spontaneous decidualization, and no existing human cell cultures recapitulate the cyclic interactions between endometrial stromal and epithelial compartments necessary for decidualization and implantation. Here we report a protocol differentiating human pluripotent stem cells into endometrial strom...
Last. Qinglei Li(A&M: Texas A&M University)H-Index: 28
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Transforming growth factor β (TGFβ) signaling plays critical roles in reproductive development and function. TGFβ ligands signal through the TGFβ receptor type 2 (TGFBR2)/TGFBR1 complex. As TGFBR2 and TGFBR1 form a signaling complex upon ligand stimulation, they are expected to be equally important for propagating TGFβ signaling that elicits cellular responses. However, several genetic studies challenge this concept and indicate that disruption of TGFBR2 or TGFBR1 may lead to contrasting phenoty...
#2Terhi Piltonen(OUH: Oulu University Hospital)H-Index: 26
Last. Linda C. Giudice(UCSF: University of California, San Francisco)H-Index: 113
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Background Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. An endometrial component has been suggested to contribute to subfertility and poor reproductive outcomes in affected women. Objective and rationale The aim of this review was to determine whether there is sufficient evidence to support that endometrial function is altered in women with PCOS, whether clinical features of PCOS affect the endometrium, and whether there are evidence-based interventions t...
Anti-Mullerian hormone (AMH), also called Mullerian inhibiting substance, was shown to be synthesized by the ovary in the eighties. This article reviews the main findings of the past 20 years on the regulation of the expression of AMH and its specific receptor AMHR2 by granulosa cells, the mechanism of action of AMH, the different roles it plays in the reproductive organs, its clinical utility and its involvement in the principal pathological conditions affecting women. The findings in respect o...
The endometrium is a dynamic tissue that exhibits remarkable resilience to repeated episodes of differentiation, breakdown, regeneration, and remodeling. Endometrial physiology relies on a complex interplay between the stromal and epithelial compartments with the former containing a mixture of fibroblasts, vascular, and immune cells. There is evidence for rare populations of putative mesenchymal progenitor cells located in the perivascular niche of human endometrium, but the existence of an equi...
#1Zhiyong Liu(SDUTCM: Shandong University of Traditional Chinese Medicine)H-Index: 3
#2Zhonghua Sun(SDUTCM: Shandong University of Traditional Chinese Medicine)H-Index: 1
Last. Wei Shi(SDUTCM: Shandong University of Traditional Chinese Medicine)H-Index: 1
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BACKGROUND Adenomyosis (AM) is a common benign chronic gynaecological disorder; however, the precise pathogenesis of adenomyosis is still poorly understood. Single-cell RNA sequencing (scRNA-seq) can uncover rare subpopulations, explore genetic and functional heterogeneity, and reveal the uniqueness of each cell. It provides us a new approach to reveal biological issues from a more detailed and microscopic perspective. Here, we utilize this revolutionary technology to identify the changes of gen...
The conduits of life; the animal oviducts and human fallopian tubes are of paramount importance for reproduction in amniotes. They connect the ovary with the uterus and are essential for fertility as they provide the appropriate environment for gamete maintenance, fertilisation and preimplantation embryonic development. However, some of the most serious pathologies, such as ectopic pregnancy, malignancy and severe infections, occur in the oviducts. They can have drastic effects on fertility, and...
#1Sonia Iyer(MIT: Massachusetts Institute of Technology)H-Index: 9
#2Shuang Zhang(NYU: New York University)H-Index: 5
Last. Robert A. Weinberg(MIT: Massachusetts Institute of Technology)H-Index: 198
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Despite advances in immuno-oncology, the relationship between tumor genotypes and response to immunotherapy remains poorly understood, particularly in high-grade serous tubo-ovarian carcinomas (HGSC). We developed a series of mouse models that carry genotypes of human HGSCs and grow in syngeneic immunocompetent hosts to address this gap. We transformed murine-fallopian tube epithelial cells to phenocopy homologous recombination–deficient tumors through a combined loss of Trp53, Brca1, Pten, and ...