Single-Cell Analysis of Human Ovarian Cortex Identifies Distinct Cell Populations But No Oogonial Stem Cells

Wagner, Magdalena; Yoshihara, Masahito; Douagi, Iyadh; Damdimopoulos, Anastasios; Panula, Sarita; Petropoulos, Sophie; Lu, Haojiang; Pettersson, Karin; Palm, Kerstin; Katayama, Shintaro; Hovatta, Outi; Kere, Juha; Lanner, Fredrik; Damdimopoulou, Pauliina

doi:10.1097/ogx.0000000000000805

Cited by 41 publications

(76 citation statements)

References 63 publications

(123 reference statements)

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“…These contrasting studies suggest other possible explanations for the observations made in Zou et al (2009) and White et al (2012) including culture‐induced de‐differentiation of the isolated cells into putative stem cells, but were unable to validate the presence of any mitotically active germline stem cells in postnatal ovaries. The presence of germline stem cells has also been explored in human ovaries, but without evidence for the existence of these cells (Wagner et al, 2020).…”

Section: Perspectivesmentioning

confidence: 99%

Pathways coordinating oocyte attrition and abundance during mammalian ovarian reserve establishment

Grive

2020

Molecular Reproduction Devel

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The mammalian ovarian reserve is comprised of a finite pool of primordial follicles, representing the lifetime reproductive capacity of females. In most mammals, the reserve is produced during embryonic and early postnatal development with oocyte numbers peaking during mid‐to‐late gestation, and then experiencing a dramatic decline continuing until shortly after birth. Oocytes remaining after the bulk of this attrition are subsequently surrounded by a layer of somatic pre‐granulosa cells with these units then referred to as “primordial follicles.” The complex and varied cell death mechanisms intrinsic to this process are not only characteristic of, but also essential for, the proper formation of this pool of follicles, and as a result must be immaculately balanced to ensure long‐term fertility and reproductive health. Too few follicles can lead to Primary Ovarian Insufficiency, resulting in fertility loss and other features of aging, such as an overall shorter lifespan. On the other hand, whereas an excess of follicles might extend reproductive lifespan, this might also be the underlying etiology of other ovarian pathologies. The last decade, in particular, has vastly expanded our understanding of oocyte attrition and determinants of ovarian reserve abundance. By continuing to decipher the intricacies underlying the cell death processes and development of the initial primordial follicle pool, we may be in a much better position to understand idiopathic cases of premature follicle depletion and improve ovarian health in reproductive‐age women.

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Section: Perspectivesmentioning

confidence: 99%

Pathways coordinating oocyte attrition and abundance during mammalian ovarian reserve establishment

Grive

2020

Molecular Reproduction Devel

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“…This higher speed does not affect the stem cells as they have minimal cytoplasm. This is the basic issue with study reported by Wagner et al 1 where they did all processing at 300 g as mentioned in their Material and Methods section. Like Wagner's group, even Tilly's group uses 300 g to study OSCs but suggest to increase speed to 600 g if number of DDX-4 positive cells is not enough [18].…”

mentioning

confidence: 87%

“…The controversy surrounding ovarian stem cells does not seem to end. Recently a group from Karolinska Institute, Sweden carried out single-cell RNA-seq and transcriptome analysis to study human ovarian cortical tissue and concluded that it does not harbor stem cells and rather comprises six distinct cell types including oocytes, granulosa cells, immune cells, endothelial cells, perivascular cells, and stromal cells [1]. On the contrary, ovary harbors two populations of stem cells including pluripotent, 2-6 μm, very small embryonic-like stem cells (VSELs) and 6-8 μm ovarian stem cells (OSCs) [2].…”

mentioning

confidence: 99%

“…DDX-4 is expressed on the OSCs/germ cells [6] and getting its expression on the perivascular cells by Wagner's group [1] is suggestive of non-specific binding and technical issues. A careful study of the methodology by Wagner's group [1] makes it very evident that the ovarian stem cells were unknowingly discarded while processing samples for single-cell RNA-seq and this could explain their negative results. We need to understand that stem cells differ from differentiated cells in size ( Fig.…”

mentioning

confidence: 99%

“…Use of 600 g may lead to pelleting down of OSCs but VSELs will remain elusive even when cells are spun at 600 g and require a higher speed of 1000 g to pellet down. Stem cells possibly never got collected and analyzed by RNA-seq and flow cytometry studies leading to an erroneous conclusion that ovary does not harbor stem cells [1].…”

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confidence: 99%

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Ovary does harbor stem cells - size of the cells matter!

Bhartiya

Sharma

2020

J Ovarian Res

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A recent study published in the journal Nature Communications from Karolinska Institute, Sweden was unable to detect stem cells in adult human ovarian cortex by single-cell RNAseq and by studying cell surface antigen profiles by flow cytometry studies. Their findings are startling since stem cells have been well characterized in the adult mammalian ovary of several species including mouse, rabbit, monkey, sheep, pig and humans. Ovarian stem cells include pluripotent, very small embryonic-like stem cells (VSELs) and slightly bigger ovarian stem cells (OSCs) which are easily visualized in smears obtained by gently scraping the ovary surface. The potential of ovarian stem cells to differentiate into oocyte-like structures in vitro and also resulting in the birth of mouse pups has been reported. A possible role of ovarian VSELs in initiation of ovarian cancers has also been delineated. The ovarian stem cells can also be collected by enzymatic digestion of ovarian tissue for various studies, taking care to always pellet the cells suspension at 1000 g since this high speed is required to collect the small-sized stem cell populations (VSELs & OSCs) with high nucleo-cytoplasmic ratio. These stem cells invariably get discarded when cells suspension is spun at lower speed. The cells were spun at 300 g for various experiments in the Karolinska study and this is the underlying reason for their negative results. Stem cells were inadvertently and unknowingly discarded and never got analyzed by single-cell RNAseq and flow cytometry experiments. To conclude, stem cells surely exist in adult mammalian ovary and their role during neo-oogenesis and primordial follicle assembly under physiological conditions is currently being investigated.

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Single‐cell RNA‐sequencing of retrieved human oocytes and eggs in clinical practice and for human ovarian cell atlasing

Machlin

Shikanov

2022

Molecular Reproduction Devel

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With the advancement of single‐cell separation techniques and high‐throughput sequencing platforms, single‐cell RNA‐sequencing (scRNA‐seq) has emerged as a vital technology for understanding tissue and organ systems at cellular resolution. Through transcriptional analysis, it is possible to characterize unique or rare cell types, interpret their interactions, and reveal novel functional states or shifts in developmental stages. As such, this technology is uniquely suited for studying the cells within the human ovary. The ovary is a cellularly heterogeneous organ that houses follicles, the reproductive and endocrine unit that consists of an oocyte surrounded by hormone‐producing support cells, as well as many other cell populations constituting stroma, vasculature, lymphatic, and immune components. Here we review studies that have utilized scRNA‐seq technology to analyze cells from healthy human ovaries and discuss the single‐cell isolation techniques used. We identified two overarching applications for scRNA‐seq in the human ovary. The first applies this technology to investigate transcriptional differences in oocytes/eggs from patients undergoing in vitro fertilization treatments to ultimately improve clinical outcomes. The second utilizes scRNA‐seq for the pursuit of creating a comprehensive single‐cell atlas of the human ovary. The knowledge gained from these studies underscores the importance of scRNA‐seq technologies in unlocking a new biological understanding of the human ovary.

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Single-Cell Analysis of Human Ovarian Cortex Identifies Distinct Cell Populations But No Oogonial Stem Cells

Cited by 41 publications

References 63 publications

Pathways coordinating oocyte attrition and abundance during mammalian ovarian reserve establishment

Pathways coordinating oocyte attrition and abundance during mammalian ovarian reserve establishment

Ovary does harbor stem cells - size of the cells matter!

Single‐cell RNA‐sequencing of retrieved human oocytes and eggs in clinical practice and for human ovarian cell atlasing

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