OCT4 and downstream factors are expressed in human somatic urogenital epithelia and in culture of epididymal spheres

Kristensen, David M.; Nielsen, John; Kalisz, Mark; Dalgaard, Marlene Danner; Audouze, Karine; Larsen, Malene Erup; Jacobsen, Grete Krag; Horn, Thomas; Brunak, Søren; Skakkebæk, Niels E.; Leffers, Henrik

doi:10.1093/molehr/gaq008

Cited by 32 publications

(34 citation statements)

References 36 publications

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“…In turn, Oct4 repressed miR-145 transcription implying a reciprocal regulation in stem cell pluripotency (6,47). In adult cells, the possible role of Oct4 expression is still uncertain and it might be related to self renewal (19). We here found that CD133 ϩ progenitors express low-Oct4 levels and not other pluripotency genes such as Sox-2.…”

Section: Discussionmentioning

confidence: 58%

Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133⁺progenitors through Oct4/miR-145 balance

Bussolati

Moggio²,

Collino³

et al. 2012

American Journal of Physiology-Renal Physiology

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Low-oxygen tension is an important component of the stem cell microenvironment. In rodents, renal resident stem cells have been described in the papilla, a relatively hypoxic region of the kidney. In the present study, we found that CD133+ cells, previously described as renal progenitors in the human cortex, were enriched in the renal inner medulla and localized within the Henle's loop and thin limb segments. Once isolated, the CD133+ cell population expressed renal embryonic and stem-related transcription factors and was able to differentiate into mature renal epithelial cells. When injected subcutaneously in immunodeficient mice within Matrigel, CD133+ cells generated canalized structures positive for renal specific markers of different nephron segments. Oct4A levels and differentiation potential of papillary CD133+ cells were higher than those of CD133+ cells from cortical tubuli. Hypoxia was able to promote the undifferentiated phenotype of CD133+ progenitors from papilla. Hypoxia stimulated clonogenicity, proliferation, vascular endothelial growth factor synthesis, and expression of CD133 that were in turn reduced by epithelial differentiation with parallel HIF-1α downregulation. In addition, hypoxia downregulated microRNA-145 and promoted the synthesis of Oct4A. Epithelial differentiation increased microRNA-145 and reduced Oct4 level, suggesting a balance between Oct4 and microRNA-145. MicroRNA-145 overexpression in CD133+ cells induced downrelation of Oct4A at the protein level, inhibited cell proliferation, and stimulated terminal differentiation. This study underlines the role of the hypoxic microenvironment in controlling the proliferation and maintaining a progenitor phenotype and stem/progenitor properties of CD133+ cells of the nephron. This mechanism may be at the basis of the maintenance of a CD133+ population in the papillary region and may be involved in renal regeneration after injury.

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Section: Discussionmentioning

confidence: 58%

Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133⁺progenitors through Oct4/miR-145 balance

Bussolati

Moggio²,

Collino³

et al. 2012

American Journal of Physiology-Renal Physiology

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“…Cantz et al , 2008; Kristensen et al , 2010). All studies showed, like our present one, that the antibodies against OCT4 must be carefully characterized.…”

Section: Discussionmentioning

confidence: 99%

False-positive antibody signals for the pluripotency factor OCT4A (POU5F1) in testis-derived cells may lead to erroneous data and misinterpretations

Warthemann

Eildermann

Debowski

et al. 2012

Molecular Human Reproduction

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Octamer-binding protein 4 (OCT4) is a key player in pluripotent embryonic stem (ES) cells and is essential for the generation of induced pluripotent stem cells. Recently, several reports indicated the spontaneous recovery of pluripotency in cultured adult human testis-derived cells. This was evidenced also by the detection of OCT4 using antibodies. However, the soundness of some data was recently put into question. During our attempts to derive pluripotent cells from the common marmoset monkey (Callithrix jacchus) testis, we obtained inconsistent data which prompted us to analyze deeper the characteristics of three independent OCT4 antibodies that were used in numerous published studies that received greatest attention. All antibodies detected OCT4 by immunofluorescence (IF) in a marmoset monkey ES cell line. Two of the three OCT4 antibodies also gave robust nuclear signals in testis-derived cells. However, the latter cells expressed no OCT4 mRNA as revealed by quantitative RT–PCR and turned out to be mesenchymal cells. When tested in western blot analyses, all antibodies detected heterologously expressed marmoset monkey OCT4 protein. But, importantly, those antibodies that resulted in non-specific signals in IF also showed additional non-specific bands in western blots. In summary, some commercially available OCT4 antibodies result in false-positive signals which may provoke erroneous conclusions when used in studies aiming at the generation of pluripotent cells in vitro. We conclude that (i) antibodies must be carefully characterized before use to prevent misleading observations and (ii) OCT4 expression must be monitored by a second antibody-independent method.

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“…However, the formation in human epididymal cell culture of epithelial spheres, 8 a characteristic of 'cancer stem cells' or 'tumour initiating cells', 14 suggests that these cells do exist.…”

Section: Cells-of-origin Of Epididymal Tumours Epididymal Stem Cellsmentioning

confidence: 99%

Why are epididymal tumours so rare?

Yeung¹,

Wang²,

Cooper³

2012

Asian J Androl

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Epididymal tumour incidence is at most 0.03% of all male cancers. It is an enigma why the human epididymis does not often succumb to cancer, when it expresses markers of stem and cancer cells, and constitutively expresses oncogenes, pro-proliferative and pro-angiogenic factors that allow tumour cells to escape immunosurveillance in cancer-prone tissues. The privileged position of the human epididymis in evading tumourigenicity is reflected in transgenic mouse models in which induction of tumours in other organs is not accompanied by epididymal neoplasia. The epididymis appears to: (i) prevent tumour initiation (it probably lacks stem cells and has strong anti-oxidative mechanisms, active tumour suppressors and inactive oncogene products); (ii) foster tumour monitoring and destruction (by strong immuno-surveillance and -eradication, and cellular senescence); (iii) avert proliferation and angiogenesis (with persistent tight junctions, the presence of anti-angiogenic factors and misplaced pro-angiogenic factors), which together (iv) promote dormancy and restrict dividing cells to hyperplasia. Epididymal cells may be rendered non-responsive to oncogenic stimuli by the constitutive expression of factors generally inducible in tumours, and resistant to the normal epididymal environment, which mimics that of a tumour niche promoting tumour growth. The threshold for tumour initiation may thus be higher in the epididymis than in other organs. Several anti-tumour mechanisms are those that maintain spermatozoa quiescent and immunologically silent, so the low incidence of cancer in the epididymis may be a consequence of its role in sperm maturation and storage. Understanding these mechanisms may throw light on cancer prevention and therapy in general.

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OCT4 and downstream factors are expressed in human somatic urogenital epithelia and in culture of epididymal spheres

Cited by 32 publications

References 36 publications

Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133⁺progenitors through Oct4/miR-145 balance

Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133⁺progenitors through Oct4/miR-145 balance

False-positive antibody signals for the pluripotency factor OCT4A (POU5F1) in testis-derived cells may lead to erroneous data and misinterpretations

Why are epididymal tumours so rare?

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OCT4 and downstream factors are expressed in human somatic urogenital epithelia and in culture of epididymal spheres

Cited by 32 publications

References 36 publications

Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133+progenitors through Oct4/miR-145 balance

Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133+progenitors through Oct4/miR-145 balance

False-positive antibody signals for the pluripotency factor OCT4A (POU5F1) in testis-derived cells may lead to erroneous data and misinterpretations

Why are epididymal tumours so rare?

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Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133⁺progenitors through Oct4/miR-145 balance

Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133⁺progenitors through Oct4/miR-145 balance