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• W2155321490 abstract "ObjectiveThe successful derivation of rare PGC from human hESC represents a potential novel treatment option for patients with infertility. Using the information learned from the mouse system, this study investigates mechanisms regulating human PGC development.DesignIn vitro differentiation of hPGC from H9 hESCMaterials and MethodsPGC were differentiated from hESC, isolated by flow cytometry, and screened for the presence of unique miRNAs. We modulated let-7 expression in hPGC by transfection with miRNA mimic and miRNA inhibitor. Lin28 overexpression and Blimp1 shRNA knock down was established using lentiviral based vectors.ResultsCompare to hESC, let-7 was undetectable in PGC. Upon transfection into hESC during differentiation, let-7 mimic exhibited a time and concentration dependent inhibition of PGC formation. Additionally, let-7 significantly suppressed Blimp1, a transcription factor required for PGC specification in mouse and known target of let-7, at all time points. When Blimp1 was stably knocked down, hESC failed to differentiate into PGC. In contrast, when endogenous let-7 was sequestered during differentiation, Blimp1 expression increased significantly and the rate of PGC formation increased >2.5 folds. As let-7 expression is negatively regulated by Lin28, we establish an hESC line that stably expresses Lin28; let-7 expression was significantly reduced, and the rate of PGC formation increased >2 folds when Lin28 was overexpressed. With the absence of let-7 expression in lin28-hESC derived PGC, Blimp1 levels were significantly increased. As expected, introduction of let-7 mimic into lin28-hESC also inhibited PGC formation.ConclusionThese studies demonstrate that consistent with work in mice, the Lin28-let7-Blimp1 regulatory loop is preserved in human PGC. Blimp1 is directly regulated by let-7 and its disruption causes a block in PGC specification. Lin28 regulates PGC specification by enhancing Blimp1 expression through its suppression of let-7. ObjectiveThe successful derivation of rare PGC from human hESC represents a potential novel treatment option for patients with infertility. Using the information learned from the mouse system, this study investigates mechanisms regulating human PGC development. The successful derivation of rare PGC from human hESC represents a potential novel treatment option for patients with infertility. Using the information learned from the mouse system, this study investigates mechanisms regulating human PGC development. DesignIn vitro differentiation of hPGC from H9 hESC In vitro differentiation of hPGC from H9 hESC Materials and MethodsPGC were differentiated from hESC, isolated by flow cytometry, and screened for the presence of unique miRNAs. We modulated let-7 expression in hPGC by transfection with miRNA mimic and miRNA inhibitor. Lin28 overexpression and Blimp1 shRNA knock down was established using lentiviral based vectors. PGC were differentiated from hESC, isolated by flow cytometry, and screened for the presence of unique miRNAs. We modulated let-7 expression in hPGC by transfection with miRNA mimic and miRNA inhibitor. Lin28 overexpression and Blimp1 shRNA knock down was established using lentiviral based vectors. ResultsCompare to hESC, let-7 was undetectable in PGC. Upon transfection into hESC during differentiation, let-7 mimic exhibited a time and concentration dependent inhibition of PGC formation. Additionally, let-7 significantly suppressed Blimp1, a transcription factor required for PGC specification in mouse and known target of let-7, at all time points. When Blimp1 was stably knocked down, hESC failed to differentiate into PGC. In contrast, when endogenous let-7 was sequestered during differentiation, Blimp1 expression increased significantly and the rate of PGC formation increased >2.5 folds. As let-7 expression is negatively regulated by Lin28, we establish an hESC line that stably expresses Lin28; let-7 expression was significantly reduced, and the rate of PGC formation increased >2 folds when Lin28 was overexpressed. With the absence of let-7 expression in lin28-hESC derived PGC, Blimp1 levels were significantly increased. As expected, introduction of let-7 mimic into lin28-hESC also inhibited PGC formation. Compare to hESC, let-7 was undetectable in PGC. Upon transfection into hESC during differentiation, let-7 mimic exhibited a time and concentration dependent inhibition of PGC formation. Additionally, let-7 significantly suppressed Blimp1, a transcription factor required for PGC specification in mouse and known target of let-7, at all time points. When Blimp1 was stably knocked down, hESC failed to differentiate into PGC. In contrast, when endogenous let-7 was sequestered during differentiation, Blimp1 expression increased significantly and the rate of PGC formation increased >2.5 folds. As let-7 expression is negatively regulated by Lin28, we establish an hESC line that stably expresses Lin28; let-7 expression was significantly reduced, and the rate of PGC formation increased >2 folds when Lin28 was overexpressed. With the absence of let-7 expression in lin28-hESC derived PGC, Blimp1 levels were significantly increased. As expected, introduction of let-7 mimic into lin28-hESC also inhibited PGC formation. ConclusionThese studies demonstrate that consistent with work in mice, the Lin28-let7-Blimp1 regulatory loop is preserved in human PGC. Blimp1 is directly regulated by let-7 and its disruption causes a block in PGC specification. Lin28 regulates PGC specification by enhancing Blimp1 expression through its suppression of let-7. These studies demonstrate that consistent with work in mice, the Lin28-let7-Blimp1 regulatory loop is preserved in human PGC. Blimp1 is directly regulated by let-7 and its disruption causes a block in PGC specification. Lin28 regulates PGC specification by enhancing Blimp1 expression through its suppression of let-7." @default.
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• W2155321490 date "2011-09-01" @default.
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• W2155321490 title "Lin28-let7-Blimp1 Circuitry regulates human primordial germ cells (hPGC) development from human embryonic stem cells (hESC)" @default.
• W2155321490 doi "https://doi.org/10.1016/j.fertnstert.2011.07.409" @default.
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