Dysfunctional Ovarian Stem Cells Due to Neonatal Endocrine Disruption Result in PCOS and Ovarian Insufficiency in Adult Mice

Sharma, Diksha; Bhartiya, Deepa

doi:10.1007/s12015-022-10414-z

Cited by 9 publications

(5 citation statements)

References 69 publications

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“…Under normal physiological conditions, VSELs and OSCs undergo neo-oogenesis and primordial follicle assembly in a regular manner across the estrous cycle ( Sharma and Bhartiya, 2021b ). In contrast, one study found that neonatal exposure to endocrine disruption in mouse pups (by treating them with estradiol and diethylstilbestrol) resulted in polycystic ovarian syndrome and primary ovarian insufficiency in adult life ( Sharma and Bhartiya, 2022a ). Epithelial cell smears from aged ovaries have shown VSELs, OSCs, and increased numbers of germ cell nests.…”

Section: Introductionmentioning

confidence: 97%

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Very small embryonic-like stem cells have the potential to win the three-front war on tissue damage, cancer, and aging

Bhartiya¹,

Jha²,

Tripathi³

et al. 2023

Front. Cell Dev. Biol.

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The concept of dedifferentiation and reprogramming of mature somatic cells holds much promise for the three-front “war” against tissue damage, cancer, and aging. It was hoped that reprogramming human somatic cells into the induced pluripotent state, along with the use of embryonic stem cells, would transform regenerative medicine. However, despite global efforts, clinical applications remain a distant dream, due to associated factors such as genomic instability, tumorigenicity, immunogenicity, and heterogeneity. Meanwhile, the expression of embryonic (pluripotent) markers in multiple cancers has baffled the scientific community, and it has been suggested that somatic cells dedifferentiate and “reprogram” into the pluripotent state in vivo to initiate cancer. It has also been suggested that aging can be reversed by partial reprogramming in vivo. However, better methods are needed; using vectors or Yamanaka factors in vivo, for example, is dangerous, and many potential anti-aging therapies carry the same risks as those using induced pluripotent cells, as described above. The present perspective examines the potential of endogenous, pluripotent very small embryonic-like stem cells (VSELs). These cells are naturally present in multiple tissues; they routinely replace diseased tissue and ensure regeneration to maintain life-long homeostasis, and they have the ability to differentiate into adult counterparts. Recent evidence suggests that cancers initiate due to the selective expansion of epigenetically altered VSELs and their blocked differentiation. Furthermore, VSEL numbers have been directly linked to lifespan in studies of long- and short-lived transgenic mice, and VSEL dysfunction has been found in the ovaries of aged mice. To conclude, a greater interest in VSELs, with their potential to address all three fronts of this war, could be the “light at the end of the tunnel.”

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Section: Introductionmentioning

confidence: 97%

“…Moreover, meiosis and further differentiation into oocytes were blocked. Thus, ovarian aging occurs due to VSEL dysfunction and a compromised niche ( Sharma and Bhartiya, 2022b ). The conversion of a pluripotent VSEL with open chromatin into OSCs involves extensive epigenetic changes, and this process is affected by aging.…”

Section: Introductionmentioning

confidence: 99%

Very small embryonic-like stem cells have the potential to win the three-front war on tissue damage, cancer, and aging

Bhartiya¹,

Jha²,

Tripathi³

et al. 2023

Front. Cell Dev. Biol.

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“…Mareckova et al [24] have reviewed the impact of single-cell genomics on human reproduction towards building cellular atlases which could help to better understand reproductive pathologies but role of stem cells is not highlighted. Our studies on mouse ovarian stem cells (VSELs and OSCs) isolated in the OSE by enzymatic digestion successfully delineated how stem cells function in a subtle manner to undergo neo-oogenesis in adult ovaries [16] and it is stem cells dysfunction that results in senescence of aged ovaries [19] and pathologies like PCOS and POI [25] challenge the data being generated by both temporal and spatial scRNAseq.…”

Section: Main Textmentioning

confidence: 99%

“…VSELs and OSCs express ERα, ERβ and FSHR [16] and thus are directly vulnerable to endocrine disruption. Rather than genetic changes/mutations, stem cells dysfunctions due to endocrine disrupting chemicals result in defective oogenesis observed in PCOS and POI ovaries in a recently published study on mice [25] and these endocrine disrupting chemicals also affect aging [29]. VSELs are also implicated in ovarian cancers [20,21].…”

Section: Main Textmentioning

confidence: 99%

VSELs and OSCs together sustain oogenesis in adult ovaries and their dysfunction results in age-related senescence, PCOS, POI and cancer

Bhartiya

Sharma

2023

J Ovarian Res

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Multiple studies using single-cell RNA sequencing (scRNAseq) have failed to detect stem cells in adult ovaries. We have maintained that two populations of ovarian stem cells including pluripotent, very small embryonic-like stem cells (VSELs) and tissue-committed ‘progenitors’ termed ovarian stem cells (OSCs) can easily be detected in Hematoxylin and Eosin-stained ovary surface epithelial (OSE) cells smears prepared from both mice and human ovaries. Most likely the stem cells never get subjected to scRNAseq since they pellet down only by centrifuging cells suspension at 1000 g while cells for scRNAseq were invariably prepared by centrifuging at 200-400 g. A recent article provided further explanation for the failure of scRNAseq to detect ovarian stem cells. Extensive reanalysis of data (generated by scRNAseq) using an advanced software successfully detected OSCs and meiotic markers supporting neo-oogenesis in adult human ovaries. But this article remained critical on the biological relevance of VSELs and their relationship with OSCs. By carefully studying the OSE cells smears (which hold VSELs, OSCs and germ cell nests GCNs), prepared by partial trypsin digestion of intact mice ovaries during different stages of estrus cycle, we have successfully delineated novel functions of VSELs/OSCs in vivo under physiological conditions. VSELs undergo asymmetrical divisions to self-renew and give rise to slightly bigger OSCs which in turn undergo symmetrical divisions and clonal expansion to form GCNs, regular neo-oogenesis and follicle assembly. GCNs have been earlier described in fetal ovaries and during OSE cells culture (from adult ovaries) in response to FSH treatment. Dysfunction of VSELs/OSCs (which express ERα, ERβ, FSHR) due to neonatal exposure to endocrine disruption results in ovarian insufficiency and polycystic ovaries. VSELs have also been implicated in ovarian cancer. Age-related ovarian senescence/menopause is also due to dysfunction and blocked differentiation of VSELs/OSCs. These novel findings in vivo along with abundant in vitro and lineage tracing studies data in published literature provides huge scope for further research, offers novel avenues to manage ovarian pathologies and calls for re-writing of textbooks.

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“…Neonatal exposure to endocrine disruption (estradiol E2 or hexestrol DES) was found to affect ovarian stem cells and their differentiation (neo-oogenesis) and primordial follicle assembly in adult ovaries. Neonatal exposure to E2 leads to features typical of polycystic ovary syndrome, whereas DES-treated ovaries show POI-like manifestations [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Aberrant HPO Axis Alterations and Autoimmune Abnormalities in PCOS Patients with DOR: A Retrospective Analysis

Geng

Bao

et al. 2023

JCM

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Background: There is a group of polycystic ovary syndrome (PCOS) patients in clinic who have diminished ovarian reserve (DOR) in combination. This study was designed to evaluate the differences in glucolipid metabolism, hypothalamic–pituitary–ovarian (HPO) axis-related parameters, and autoimmune antibodies in PCOS patients with and without DOR. Methods: A total of 2307 PCOS patients, including 1757 patients with PCOS alone and 550 patients who have both PCOS and DOR, were enrolled in this retrospective study. Parameters of glucolipid metabolism, HPO axis-related parameters, and autoimmune antibodies were measured and analyzed. Results: The prevalence of DOR among all patients with PCOS was 23.84%. Many HPO axis-related parameters, such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and prolactin (PRL) were significantly different in PCOS with DOR compared with PCOS without DOR. The FSH levels were positively correlated with LH, testosterone (T), and androstenedione (AD) levels, but had no association with glucolipid metabolism after adjusting for body mass index (BMI). Moreover, anti-ovarian antibody (AOAb) and anti-21-OH antibody (21-OHAb) levels were significantly elevated in PCOS patients with DOR. Conclusions: PCOS patients with DOR showed more chaotic HPO axis hormone levels and elevated autoimmune antibodies, suggesting that autoimmune factors may be the cause of DOR in women with PCOS.

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Dysfunctional Ovarian Stem Cells Due to Neonatal Endocrine Disruption Result in PCOS and Ovarian Insufficiency in Adult Mice

Cited by 9 publications

References 69 publications

Very small embryonic-like stem cells have the potential to win the three-front war on tissue damage, cancer, and aging

Very small embryonic-like stem cells have the potential to win the three-front war on tissue damage, cancer, and aging

VSELs and OSCs together sustain oogenesis in adult ovaries and their dysfunction results in age-related senescence, PCOS, POI and cancer

Aberrant HPO Axis Alterations and Autoimmune Abnormalities in PCOS Patients with DOR: A Retrospective Analysis

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