F Rosa Rubicondior: Evolution News - An Atlas Of The Human Ovary Shows Common Ancestry of Mammals

Monday 8 April 2024

Evolution News - An Atlas Of The Human Ovary Shows Common Ancestry of Mammals

Human ovarian follicle
First atlas of the human ovary with cell-level resolution is a step toward artificial ovary | University of Michigan News

This piece of research caught my eye, not so much because it refutes creationism with its daft notion of the special creation of humans as separate from all the other animals but because it's reminiscent of the research I used to be involved with in my first profession - a research technician in Oxford University's Department of Human Anatomy.

The research our small group was doing involved the hormonal control of reproduction in guinea pigs, which involved preparing light microscope slides of sections of guinea pig ovaries, and later on, transmission electron micrographs of ovarian tissues.

Like humans, guinea pigs have oestrus cycles where they periodically shed eggs from their ovaries regardless of whether they have mated or not. This is unlike some other mammals which ovulate soon after mating, stimulated to do so by the act of mating. Unlike human females, guinea pigs are only receptive for two or three days before and just after they ovulate. Outside that receptive period, they have a closure membrane that makes penetration impossible.

The microscope slides we were looking at included sequences of maturing ovarian follicles over the 18-day oestrus cycle of the guinea pig up to the point of rupture to produce an egg, then formation of the corpus luteum which gradually atrophied as the next cycle progressed. We were interested in the hormonal control of this process which included measuring hormone levels through the oestrus cycle and relating them to changes in the ovarian follicles.
When did humans and guinea pigs last share a common ancestor and what was that common ancestor? Humans and guinea pigs last shared a common ancestor around 94 million years ago. The common ancestor of humans and guinea pigs would have been a small mammal species that lived during the Mesozoic Era, likely a member of the order Rodentia or a closely related group. Over millions of years, evolutionary divergence led to the emergence of distinct lineages, eventually giving rise to modern humans and guinea pigs, which belong to different orders (Primates and Rodentia, respectively).
Guinea pig ovarian follicles
The striking thing is how similar these micrographs of human ovaries are to those of guinea pig ovaries. It would be almost impossible to tell one from the other by appearance alone, yet humans (Primates) are only distantly related to guinea pigs (Rodentia).

What has happened during the 94 million years since they shared a common ancestor is that the process of egg formation and shedding has been highly conserved; the only physiological variation being in the length of the cycle (18 days for guinea pigs; 28 days for humans). The atlas of the human ovary was produced by researchers from the University of Michigan. Their work is the subject of an open access paper in Science Advances and a news item from the University of Michigan:
A new “atlas” of the human ovary provides insights that could lead to treatments restoring ovarian hormone production and the ability to have biologically related children, according to University of Michigan engineers.

This deeper understanding of the ovary means researchers could potentially create artificial ovaries in the lab using tissues that were stored and frozen before exposure to toxic medical treatments such as chemotherapy and radiation. Currently, surgeons can implant previously frozen ovarian tissue to temporarily restore hormone and egg production. However, this does not work for long because so few follicles—the structures that produce hormones and carry eggs—survive through reimplantation, the researchers say.

The new atlas reveals the factors that enable a follicle to mature, as most follicles wither away without releasing hormones or an egg. Using new tools that can identify what genes are being expressed at a single-cell level within a tissue, the team was able to home in on ovarian follicles that carry the immature precursors of eggs, known as oocytes.

Now that we know which genes are expressed in the oocytes, we can test whether affecting these genes could result in creating a functional follicle. This can be used to create an artificial ovary that could eventually be transplanted back into the body.

Associate Professor Ariella Shikanov, co-corresponding author
Department of Biomedical Engineering
University of Michigan, Ann Arbor, MI, USA.
The majority of the follicles, called primordial follicles, remain dormant and are located in the outer layer of the ovary, called the cortex. A small portion of these follicles activate periodically and migrate into the ovary, to a region known as the growing pool. Only a few of those growing follicles go on to produce mature eggs that get released into the fallopian tube.

With the ability to guide follicle development and tune ovarian environment, the team believes that engineered ovarian tissue could function for much longer than unmodified implanted tissue. This means that patients would have a longer fertility window as well as a longer period in which their bodies produce hormones that help regulate the menstrual cycle and support muscular, skeletal, sexual and cardiovascular health.

We’re not talking about utilizing a surrogate mother, or artificial insemination. The magic we’re working toward is being able to trigger an immature cell into maturity, but without knowing which molecules drive that process, we’re blind.

Associate Professor Jun Z. Li, co-corresponding author
Department of Computational Medicine and Bioinformatics
University of Michigan, Ann Arbor, MI, USA.
A fluorescent image of a human ovarian follicle U-M researchers collected during spatial analysis—clearly showing all the different compartments including the oocyte (the small oval), surrounding hormone-producing cells, blood vessels, immune cells and compartments. The scale bar is 0.2mm.

Image credit: University of Michigan.
U-M’s team utilized a relatively new technology, called spatial transcriptomics, to track all of the gene activity—and where it occurs—in tissue samples. They do this by reading strands of RNA, which are like notes taken from the DNA strand, revealing which genes are being read. Working with an organ procurement organization, U-M researchers performed RNA sequencing of ovaries from five human donors.

This was the first time where we could target ovarian follicles and oocytes and perform a transcription analysis, which enables us to see which genes are active. The majority of ovarian follicles, already present at birth, never enter the growing pool and eventually self-destruct. This new data allows us to start building our understanding of what makes a good egg—what determines which follicle is going to grow, ovulate, be fertilized and become a baby.

Associate Professor Ariella Shikanov.
University of Michigan BME graduate student Jordan Machlin shows to prof. Ariella Shikanov and fellows grad student Margaret Brunette the images of oocytes in ovarian tissue she collected using RNA-fluorescence in situ hybridization. Image credit: Marcin Szczepanski/Lead Multimedia Storyteller, Michigan Engineering U-M’s work is part of the Human Cell Atlas project, which seeks to create “maps of all the different cells, their molecular characteristics and where they are located, to understand how the human body works and what goes wrong in disease.” Shikanov, Li and U-M collaborators such as Sue Hammoud, U-M associate professor of human genetics and urology, are mapping other parts of the female reproductive system, including the uterus, fallopian tubes and ovaries. Other contributors include Andrea Suzanne Kuliahsa Jones, formerly of U-M and now at Duke University, and D. Ford Hannum, a U-M graduate student research assistant in bioinformatics.


The reproductive and endocrine functions of the ovary involve spatially defined interactions among specialized cell populations. Despite the ovary’s importance in fertility and endocrine health, functional attributes of ovarian cells are largely uncharacterized. Here, we profiled >18,000 genes in 257 regions from the ovaries of two premenopausal donors to examine the functional units in the ovary. We also generated single-cell RNA sequencing data for 21,198 cells from three additional donors and identified four major cell types and four immune cell subtypes. Custom selection of sampling areas revealed distinct gene activities for oocytes, theca, and granulosa cells. These data contributed panels of oocyte-, theca-, and granulosa-specific genes, thus expanding the knowledge of molecular programs driving follicle development. Serial samples around oocytes and across the cortex and medulla uncovered previously unappreciated variation of hormone and extracellular matrix remodeling activities. This combined spatial and single-cell atlas serves as a resource for future studies of rare cells and pathological states in the ovary.


The development, differentiation, and spatial organization of the many cell populations in the human ovary are essential for its reproductive and endocrine functions. The outer ~1.5-mm layer of the organ, the ovarian cortex, contains quiescent primordial follicles, which constitute the follicular reserve, and transitioning and primary follicles and is identified by its dense tissue structure and lesser vasculature (1, 2). The inner part of the organ, the medulla, contains the growing secondary and antral follicles, as well as corpora lutea, presents with a looser extracellular matrix (ECM) structure, and contains more abundant vasculature (2, 3). Both regions are maintained by constant interactions among the stromal, immune, and endothelial cells and other rarer cell types (4). The functional unit of the ovary, the ovarian follicle, contains an oocyte in the center, surrounded by specialized somatic cells that secrete hormones and support the many steps of oocyte maturation (5). In women of reproductive age, a small portion of quiescent primordial follicles are periodically activated to join the pool of growing follicles (6). The growing follicles expand across both the cortex and medulla, each taking on a multilayered three-dimensional architecture containing the oocyte surrounded by cumulus granulosa, and outer layers of mural granulosa, and theca cells, which are separated from the cumulus-oocyte complex by a fluid-filled antrum (7). Paracrine cross-talk among the follicular cells and endocrine signals from the hypothalamic-pituitary-ovarian axis work together to trigger ovulation, which produces mature eggs for fertilization (5). The cellular diversity of the ovary and the complex spatially defined structures in growing follicles have been difficult to study, largely due to the scarcity of tissue from healthy women of reproductive age, the lack of unbiased functional profiling, and the technical limitations of spatial transcriptomics (ST). Past studies using animal models have identified major classes of ovarian structures and their putative functions using transcriptomics (4, 8). However, human follicle development and the role of nonfollicular cells in this process remain poorly understood, supporting an ST-based characterization of the human ovary to understand follicle development, hormone production, and ovarian aging.

The ovarian cortex is of particular research interest as the home of the follicular reserve and the microenvironment in which follicle activation occurs. In recent years, a few single-cell sequencing studies have reported that the cortex and the medulla contain the same general cell types (9), but the two regions are histologically distinct, e.g., having different ECMs tailored to their functions and different gradients of growth factors (10). The mechanisms driving follicle activation, either within the follicular structure or from the microenvironment outside the follicles, are poorly understood. Studies of the oocyte compartment of primordial and primary follicles have aimed to identify markers of quiescence and activation, but isolation of oocytes for sequencing may alter their transcriptome or lead to spontaneous activation (11, 12), underscoring the need to collect data from intact tissues to understand what defines these early stages of follicle development. With the recently emerged ST technology, primordial and primary follicles and the surrounding cortical stroma can be sampled with minimal perturbation to uncover cortex-specific gene activities related to early folliculogenesis. Likewise, ST presents a previously unattainable opportunity to profile the gene activities in diverse types of follicles recognized by their morphology and spatial context. Previous studies have reported on the transcriptional profiles of granulosa and theca cells (9, 13), but hypotheses surrounding oocyte-cumulus granulosa cell bidirectional cross-talk and factors influencing the follicular cell phenotypes have not been validated using a spatial approach.

In this study, we compiled a functionally targeted ST dataset of the human ovary, composed of 257 regional samples collected using NanoString’s GeoMx platform from the ovaries of two reproductive-age, premenopausal donors. We also collected single-cell RNA sequencing (scRNA-seq) data of 21,198 dissociated cells from three additional donors. Using these data, we uncovered transcriptional profiles of primordial and primary oocytes sampled from their native microenvironment, gene signatures of theca and granulosa cells, spatially defined patterns of gene expression across the medulla and cortex, and major stromal and immune cell types of the human ovary. Comparisons between our ST and scRNA-seq datasets confirmed the robustness of the GeoMx platform for sampling specific local regions of small size and distinct function. This integrated analysis led to a comprehensive cell atlas of the healthy reproductive-age human ovary, revealing spatially defined transcriptional patterns and adding to our knowledge on the cellular diversity of this organ.
These physiological similarities and differences which, like genetic and anatomical similarities, can be fitted into consistent nested hierarchies like the fossil record, are another strand of evidence for common origins, showing how the Theory of Evolution by descent with modification is much more than an explanation for the fossil record that seems to obsess creationists; it is the fundamental unifying theory of biology.

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