Altered Biology of Testicular VSELs and SSCs by Neonatal Endocrine Disruption Results in Defective Spermatogenesis, Reduced Fertility and Tumor Initiation in Adult Mice

Kaushik, Ankita; Anand, Sandhya; Bhartiya, Deepa

doi:10.1007/s12015-020-09996-3

Cited by 25 publications

(20 citation statements)

References 58 publications

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“…But organoids are formed by actively dividing cancer cells and may not truly mirror the CSCs that are relatively quiescent in nature and survive oncotherapy. Our group recently showed that testicular cancer was initiated in adult mice, by treating them during neonatal life with diethylstilbestrol, due to excessive self-renewal of VSELs (increased seven folds) as confirmed by flow cytometry (cells were always centrifuged at 1000g to enumerate VSELs) along with their blocked differentiation due to disruption of NP95 expression [25]. This study provides first evidence that cancer results as a result of aberrant behavior of VSELs.…”

Section: Main Textmentioning

confidence: 55%

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Adult tissue-resident stem cells—fact or fiction?

Bhartiya

2021

Stem Cell Res Ther

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Life-long tissue homeostasis of adult tissues is supposedly maintained by the resident stem cells. These stem cells are quiescent in nature and rarely divide to self-renew and give rise to tissue-specific “progenitors” (lineage-restricted and tissue-committed) which divide rapidly and differentiate into tissue-specific cell types. However, it has proved difficult to isolate these quiescent stem cells as a physical entity. Recent single-cell RNAseq studies on several adult tissues including ovary, prostate, and cardiac tissues have not been able to detect stem cells. Thus, it has been postulated that adult cells dedifferentiate to stem-like state to ensure regeneration and can be defined as cells capable to replace lost cells through mitosis. This idea challenges basic paradigm of development biology regarding plasticity that a cell enters point of no return once it initiates differentiation. The underlying reason for this dilemma is that we are putting stem cells and somatic cells together while processing for various studies. Stem cells and adult mature cell types are distinct entities; stem cells are quiescent, small in size, and with minimal organelles whereas the mature cells are metabolically active and have multiple organelles lying in abundant cytoplasm. As a result, they do not pellet down together when centrifuged at 100–350g. At this speed, mature cells get collected but stem cells remain buoyant and can be pelleted by centrifuging at 1000g. Thus, inability to detect stem cells in recently published single-cell RNAseq studies is because the stem cells were unknowingly discarded while processing and were never subjected to RNAseq. This needs to be kept in mind before proposing to redefine adult stem cells.

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Section: Main Textmentioning

confidence: 55%

“…VSELs also survive in atrophied mouse uterus after bilateral ovariectomy [23]. Unlike hES/iPS cells that differentiate into their fetal counterparts, VSELs have the potential to regenerate adult tissues [24] and possibly also have a role to initiate cancers [25].…”

Section: Main Textmentioning

confidence: 99%

Adult tissue-resident stem cells—fact or fiction?

Bhartiya

2021

Stem Cell Res Ther

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“…org/ licen ses/ by/3. 0/) alteration of epigenetic modifications in imprinted genes, they may initiate self-renewal and promote testicular cancer [36]. Furthermore reduced sperm count and infertility can occur as a result of increased VSEL proliferation and impaired differentiation [37].…”

Section: Residual Embryonic Cellsmentioning

confidence: 99%

Pluripotent Stem Cells: Cancer Study, Therapy, and Vaccination

Barati

Akhondi

et al. 2021

Stem Cell Rev and Rep

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Introduction Pluripotent stem cells (PSCs) are promising tools for modern regenerative medicine applications because of their stemness properties, which include unlimited self-renewal and the ability to differentiate into all cell types in the body. Evidence suggests that a rare population of cells within a tumor, termed cancer stem cells (CSCs), exhibit stemness and phenotypic plasticity properties that are primarily responsible for resistance to chemotherapy, radiotherapy, metastasis, cancer development, and tumor relapse. Different therapeutic approaches that target CSCs have been developed for tumor eradication. Results and DiscussionIn this review, we first provide an overview of different viewpoints about the origin of CSCs. Particular attention has been paid to views believe that CSCs are probably appeared through dysregulation of very small embryoniclike stem cells (VSELs) which reside in various tissues as the main candidate for tissue-specific stem cells. The expression of pluripotency markers in these two types of cells can strengthen the validity of this theory. In this regard, we discuss the common properties of CSCs and PSCs, and highlight the potential of PSCs in cancer studies, therapeutic applications, as well as educating the immune system against CSCs. Conclusion In conclusion, the resemblance of CSCs to PSCs can provide an appropriate source of CSC-specific antigens through cultivation of PSCs which brings to light promising ideas for prophylactic and therapeutic cancer vaccine development.

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“…In a recent study, mice pups were exposed to estradiol (20 μg/pup/day on days 5–7) or diethylstilbestrol (2 μg/pup/day on days 1–5) and later studies were undertaken on D100 of adult life. Treatment affected the testicular stem cells and resulted in pathologies including disrupted spermatogenesis, reduced sperm counts, infertility and tumor-like changes were observed in DES treated group [ 56 ]. Expression of Fshr1 and Fshr3 was studied on D100 by qRT-PCR (Fig.…”

Section: Main Textmentioning

confidence: 99%

Endogenous, tissue-resident stem/progenitor cells in gonads and bone marrow express FSHR and respond to FSH via FSHR-3

et al. 2021

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Follicle stimulating hormone (FSH) is secreted by the anterior pituitary and acts on the germ cells indirectly through Granulosa cells in ovaries and Sertoli cells in the testes. Extragonadal action of FSH has been reported but is still debated. Adult tissues harbor two populations of stem cells including a reserve population of primitive, small-sized, pluripotent very small embryonic-like stem cells (VSELs) and slightly bigger, tissue-specific progenitors which include ovarian stem cells (OSCs) in ovaries, spermatogonial stem cells (SSCs) in testes, endometrial stem cells (EnSCs) in uterus and hematopoietic stem cells (HSCs) in the bone marrow. Data has accumulated in animal models showing FSHR expression on both VSELs and progenitors in ovaries, testes, uterus and bone marrow and eventually gets lost as the cells differentiate further. FSH exerts a direct action on the stem/progenitor cells via alternatively spliced FSHR-3 rather than the canonical FSHR-1. FSH stimulates VSELs to undergo asymmetrical cell divisions to self-renew and give rise to the progenitors that in turn undergo symmetrical cell divisions and clonal expansions followed by differentiation into specific cell types. Excessive self-renewal of VSELs results in cancer and this explains ubiquitous expression of embryonic markers including nuclear OCT-4 along with FSHR in cancerous tissues. Focus of this review is to compile published data to support this concept. FSHR expression in stem/progenitor cells was confirmed by immuno-fluorescence, Western blotting, in situ hybridization and by quantitative RT-PCR. Two different commercially available antibodies (Abcam, Santacruz) were used to confirm specificity of FSHR expression along with omission of primary antibody and pre-incubation of antibody with immunizing peptide as negative controls. Western blotting allowed detection of alternatively spliced FSHR isoforms. Oligoprobes and primers specific for Fshr-1 and Fshr-3 were used to study these alternately-sliced isoforms by in situ hybridization and their differential expression upon FSH treatment by qRT-PCR. To conclude, stem/progenitor cells in adult tissues express FSHR and directly respond to FSH via FSHR-3. These findings change the field of FSH-FSHR biology, call for paradigm shift, explain FSHR expression on cancer cells in multiple organs and provide straightforward explanations for various existing conundrums including extragonadal expression of FSHR.

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Altered Biology of Testicular VSELs and SSCs by Neonatal Endocrine Disruption Results in Defective Spermatogenesis, Reduced Fertility and Tumor Initiation in Adult Mice

Cited by 25 publications

References 58 publications

Adult tissue-resident stem cells—fact or fiction?

Adult tissue-resident stem cells—fact or fiction?

Pluripotent Stem Cells: Cancer Study, Therapy, and Vaccination

Endogenous, tissue-resident stem/progenitor cells in gonads and bone marrow express FSHR and respond to FSH via FSHR-3

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