Derivation of Stromal (Skeletal and Mesenchymal) Stem-Like Cells from Human Embryonic Stem Cells

Mahmood, Amer; Harkness, Linda; Abdallah, Basem M.; Elsafadi, Mona; Al-Nbaheen, May; Aldahmash, Abdullah; Kassem, Moustapha

doi:10.1089/scd.2012.0035

Cited by 20 publications

(10 citation statements)

References 59 publications

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“…Obviously, the association of CD73 with ccRCC CSC remains ambiguous. CD73 is a biomarker for human mesenchymal stem cells (MSCs) [ 59 , 60 ], which can also be isolated from the kidney and renal cancer cells [ 61 , 62 ]. The cells originated in ccRCC are not definitively known whilst ccRCCs is commonly thought to arise from renal proximal epithelial cells [ 63 ], tubular epithelium is normally mitotically quiescent, but demonstrates a considerable regenerative capacity upon renal injury, the putative connection between renal stem cells and carcinomas is not clarified, since the understanding of the renal stem cell system is not complete yet [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Ecto-5′-nucleotidase (CD73) is a biomarker for clear cell renal carcinoma stem-like cells

Song

Cui

et al. 2017

Oncotarget

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Identification of a specific biomarker for cancer stem cells (CSCs) is of potential applications in the development of effective therapeutic strategies for renal cell carcinoma (RCC). In this study, both the RCC cell line 786-O and surgically removed clear cell RCC (ccRCC) tissues were implemented to grew as spheroids in serum-free medium supplemented with mitogens. This subpopulation possessed key characteristics defining CSCs. We also identified that surgically removed ccRCC tissues were heterogenic and there was a subpopulation of cells that was highly stained with rhodamine-123. Based on membrane-proteomic analyses, CD73 was identified as a candidate biomarker. We further found that CD73high cells were highly tumorigenic. As few as 100 CD73high cells were capable of forming xenograft tumors in non obese diabetic/severe combined immunodeficiency disease mice, whereas 1 × 105 CD73low cells did not initiate tumor formation. During successive culture, the CD73high population regenerated both CD73high and CD73low cells, whereas the CD73low population remained low expression level of CD73. Furthermore, the CD73high cells were more resistant to radiation and DNA-damaging agents than the CD73low cells, and expressed a panel of ‘stemness’ genes at a higher level than the CD73low cells. These findings suggest that a high level of CD73 expression is a bona fide biomarker of ccRCC stem-like cells. Future research will aim at the elucidation of the underlying mechanisms of CD73 in RCC development and the distinct aspects of ccRCC stem-like cells from other tumor types.

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Section: Discussionmentioning

confidence: 99%

Ecto-5′-nucleotidase (CD73) is a biomarker for clear cell renal carcinoma stem-like cells

Song

Cui

et al. 2017

Oncotarget

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“…CD73 is a glycosyl-phosphatidylinositol (GPI)-linked nucleotidase present in cell membrane lipid rafts (24). CD73 is also a well-known surface marker of mesenchymal stem cells (30,31), defined as a multipotent population of slow-growing, self-renewing cells (3). Bussolati et al reported that the population of CD73-overexpressed cells showed several stem cell properties: clonogenic ability, capacity of non-adhesive spheroid formation, bipotent differentiation potential into epithelial and endothelial cell types, and in vivo generation of serially transplantable carcinomas in renal cancer cells (32).…”

Section: Discussionmentioning

confidence: 99%

CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells

Katsuta

Tanaka

Mogushi

et al. 2015

International Journal of Oncology

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Identification and purification of cancer stem cells (CSCs) lead to the discovery of novel therapeutic targets; however, there has been no study on isolation of the CSC population among pancreatic neuroendocrine tumors (pNETs). This study aimed to identify pNET CSCs and to characterize a therapeutic candidate for pNET CSCs. We identified CSCs by aldehyde dehydrogenase (ALDH) activity in pNET clinical specimens and cell lines. We verified whether or not these cells have the stemness property in vivo and in vitro. ALDHhigh cells, but not control bulk cells, formed spheres, proliferated under hypoxic condition as well as normoxic condition and promoted cell motility, which are features of CSCs. Injection of as few as 10 ALDHhigh cells led to subcutaneous tumor formation, and 105 ALDHhigh cells, but not control bulk cells, established metastases in mice. Comprehensive gene expression analysis revealed that genes associated with mesenchymal stem cells, including CD73, were overexpressed in ALDHhigh cells. Additionally, the in vitro and in vivo effects of an inhibitor of CD73 were investigated. The CD73 inhibitor APCP significantly attenuated in vitro sphere formation and cell motility, as well as in vivo tumor growth observed for ALDHhigh cells. Finally, its expression was evaluated using clinical pNET tissue samples. Immunohistochemical analysis of clinical tissue samples demonstrated CD73 expression was significantly correlated with the invasion into adjacent organs. Since recent studies revealed CD73 as a potential biomarker of anti-PD-1 immune checkpoint therapy, CD73 might be a promising therapeutic target for pNET CSCs.

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“…Implants were removed after 8 weeks, transferred to 4% neutral buffered formalin for 24 h followed by incubation in formic acid for 3 days. The processed implants were paraffin-embedded, sectioned, and stained as described [ 30 ] with human-specific vimentin (Thermo Fisher Scientific, clone SP20) antibody or by hematoxylin-eosin [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

Fibroblasts direct differentiation of human breast epithelial progenitors

et al. 2020

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Background Breast cancer arises within specific regions in the human breast referred to as the terminal duct lobular units (TDLUs). These are relatively dynamic structures characterized by sex hormone driven cyclic epithelial turnover. TDLUs consist of unique parenchymal entities embedded within a fibroblast-rich lobular stroma. Here, we established and characterized a new human breast lobular fibroblast cell line against its interlobular counterpart with a view to assessing the role of region-specific stromal cues in the control of TDLU dynamics. Methods Primary lobular and interlobular fibroblasts were transduced to express human telomerase reverse transcriptase (hTERT). Differentiation of the established cell lines along lobular and interlobular pathways was determined by immunocytochemical staining and genome-wide RNA sequencing. Their functional properties were further characterized by analysis of mesenchymal stem cell (MSC) differentiation repertoire in culture and in vivo. The cells’ physiological relevance for parenchymal differentiation was examined in heterotypic co-culture with fluorescence-activated cell sorting (FACS)-purified normal breast primary luminal or myoepithelial progenitors. The co-cultures were immunostained for quantitative assessment of epithelial branching morphogenesis, polarization, growth, and luminal epithelial maturation. In extension, myoepithelial progenitors were tested for luminal differentiation capacity in culture and in mouse xenografts. To unravel the significance of transforming growth factor-beta (TGF-β)-mediated crosstalk in TDLU-like morphogenesis and differentiation, fibroblasts were incubated with the TGF-β signaling inhibitor, SB431542, prior to heterotypic co-culture with luminal cells. Results hTERT immortalized fibroblast cell lines retained critical phenotypic traits in culture and linked to primary fibroblasts. Cell culture assays and transplantation to mice showed that the origin of fibroblasts determines TDLU-like and ductal-like differentiation of epithelial progenitors. Whereas lobular fibroblasts supported a high level of branching morphogenesis by luminal cells, interlobular fibroblasts supported ductal-like myoepithelial characteristics. TDLU-like morphogenesis, at least in part, relied on intact TGF-β signaling. Conclusions The significance of the most prominent cell type in normal breast stroma, the fibroblast, in directing epithelial differentiation is largely unknown. Through establishment of lobular and interlobular fibroblast cell lines, we here demonstrate that epithelial progenitors are submitted to stromal cues for site-specific differentiation. Our findings lend credence to considering stromal subtleties of crucial importance in the development of normal breast and, in turn, breast cancer.

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Derivation of Stromal (Skeletal and Mesenchymal) Stem-Like Cells from Human Embryonic Stem Cells

Cited by 20 publications

References 59 publications

Ecto-5′-nucleotidase (CD73) is a biomarker for clear cell renal carcinoma stem-like cells

Ecto-5′-nucleotidase (CD73) is a biomarker for clear cell renal carcinoma stem-like cells

CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells

Fibroblasts direct differentiation of human breast epithelial progenitors

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