Human pluripotent stem cell (hPSC) cultures are prone to genetic drift, because cells that have acquired specific abnormalities experience a selective advantage in vitro. These highly recurrent hPSC lines worldwide, but their functional consequences differentiating scarcely described. In this work, we show the loss of chromosome 18q impairs neuroectoderm commitment and downregulation SALL3, gene located common region, is responsible for failed neuroectodermal differentiation. Knockdown SALL3...

Gain of 20q11.21 is one the most common recurrent genomic aberrations in human pluripotent stem cells. Although it known that overexpression antiapoptotic gene Bcl-xL confers a survival advantage to abnormal cells, their differentiation capacity has not been fully investigated. RNA sequencing mutant and control hESC lines, line transgenically overexpressing Bcl-xL, shows sufficient cause transcriptional changes induced by gain 20q11.21. Moreover, differentially expressed genes lines are...

Abstract Children conceived through assisted reproductive technologies (ART) have an elevated risk of lower birthweight, yet the underlying cause remains unclear. Our study explores mitochondrial DNA (mtDNA) variants as contributors to birthweight differences by impacting function during prenatal development. We deep-sequenced mtDNA 451 ART and spontaneously (SC) individuals, 157 mother-child pairs 113 individual oocytes from either natural menstrual cycles or after ovarian stimulation (OS)...

(Abstracted from Nat Commun 2024;15:1232 Assisted reproductive technology (ART) has enabled many couples before considered untreatably infertile to have children, though there been concerns that children born using these technologies are at risk for adverse outcomes. These outcomes vary, and of them stem unknown causes.

ABSTRACT Chromosomal abnormalities acquired during cell culture can compromise the differentiation potential of human pluripotent stem cells (hPSCs). In this work, we identified a diminished capacity to retinal progenitor in embryonic (hESCs) with complex karyotypes that had common loss part chromosome 18q. Time‐course gene‐expression analysis spontaneous and single‐cell RNA sequencing found these variant lines poorly specified into anterior neuroectoderm, and, when progressing through...

Abstract Low differentiation propensity towards a targeted lineage can significantly hamper the utility of individual human pluripotent stem cell (hPSC) lines in biomedical applications. Here, we use monolayer and micropatterned cultures, as well transcriptomic profiling, to investigate how variability signalling pathway activity between embryonic affects their efficiency definitive endoderm (DE). We show that endogenous suppression WNT hPSCs at onset prevents switch from self-renewal DE...

ABSTRACT Skeletal muscle tissue is severely affected in myotonic dystrophy type 1 (DM1) patients, characterised by weakness, myotonia and immaturity the most severe congenital form of disease. Previously, it was not known at what stage during myogenesis DM1 phenotype appears. In this study we differentiated healthy human embryonic stem cells to myoblasts myotubes compared their differentiation potential using a comprehensive multi-omics approach. We found be abnormal with altered myotube...

SUMMARY Gains of 1q are a highly recurrent chromosomal abnormality in human pluripotent stem cells. In this work, we show that gains impact the differentiation capacity to derivates three germ layers, leading miss-specification cranial placode and non-neural ectoderm during neuroectoderm by poorer expression lineage specific markers hepatoblasts cardiac progenitors. Competition assays cells retain their selective advantage differentiation, which is mediated higher MDM4 , gene located common...

Abstract We identified a human embryonic stem cell subline that fails to respond the differentiation cues needed obtain endoderm derivatives, differentiating instead into extra-embryonic mesoderm. RNA-sequencing analysis showed has hyperactivation of WNT and BMP4 signalling. Modulation these pathways with small molecules confirmed them as cause impairment. While activation in control cells resulted loss induction mesoderm markers, inhibition restored its ability differentiate. Karyotyping...

Humans present remarkable diversity in their mitochondrial DNA (mtDNA) terms of variants across individuals as well tissues and even cells within one person. We have investigated the timing first appearance this variant-driven mosaicism. For this, we deep-sequenced mtDNA 254 oocytes from 85 donors, 158 single blastomeres 25 day-3 embryos, 17 inner cell mass trophectoderm samples 7 day-5 blastocysts, 142 bulk 68 different adult tissues. found that embryos carry only detected cell, showing...

Summary Though gains of chromosome 12p13.31 are highly recurrent in hPSC, their impact on differentiation is poorly understood. We identify a reduction capacity towards all three germ layers and subpopulation residual pluripotent cells that appear during hepatic specification. These form as result the overexpression NANOG GDF3, whereby primary driver delays activation WNT signaling, partly direct physical interaction with TCF7. Entry into state determined by cell cycle position at onset...

Abstract Human pluripotent stem cell (hPSC) cultures are prone to genetic drift, as cells that have acquired specific abnormalities experience a selective advantage in vitro. These highly recurrent hPSC lines worldwide, but currently their functional consequences differentiating scarcely described. An accurate assessment of the risk associated with these variants both research and clinical settings is therefore lacking. In this work, we established one abnormalities, loss chromosome 18q,...

About 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic blastocysts can implant and lead healthy new-borns with normal karyotypes. Studies mouse gastruloids showed that aneuploid cells are eliminated from the epiblast by p53-mediated apoptosis while being tolerated trophectoderm. These observations suggest a selective loss embryos, but underlying mechanisms not yet fully understood. Here, we investigated cellular consequences...

<title>Abstract</title> In this study, we show that undirected differentiation of human embryonic stem cells (hESC) to retinal pigment epithelium (RPE) acts as a selective barrier against aneuploid cells. Large-scale omics analysis reveals 3–6% genetically normal hESC cultures are aneuploid, none which progresses through RPE except for with gain 1q. We while all homogeneously lines carrying an array different abnormalities have impaired differentiation, co-culture specifically rescues the...

Abstract Chromosomal abnormalities acquired during cell culture can compromise the differentiation potential of human pluripotent stem cells (hPSCs). In this work, we identified a diminished capacity to retinal progenitor in embryonic (hESCs) with loss chromosome 18q. Time-course gene-expression analysis spontaneous and single-cell RNA sequencing found that these variant lines poorly specified into anterior neuroectoderm, and, when progressing through differentiation, they yielded pigmented...

Abstract Gain of 1q is a highly recurrent chromosomal abnormality in human pluripotent stem cells. In this work, we show that gains impact the differentiation capacity to derivates three germ layers, leading mis-specification cranial placode and non-neural ectoderm during neuroectoderm differentiation. Also, found weaker expression lineage-specific markers hepatoblasts cardiac progenitors. Competition assays cells retain their selective advantage differentiation, which mediated by higher...

About 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic blastocysts can implant and lead healthy new-borns with normal karyotypes. Studies mouse gastruloids have shown that aneuploid cells proteotoxic stress, autophagy p53 activation they are eliminated from the epiblast by apoptosis while being tolerated trophectoderm. These observations suggest a selective loss embryos, but underlying mechanisms not yet fully understood. In...

About 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic blastocysts can implant and lead healthy new-borns with normal karyotypes. Studies mouse gastruloids showed that aneuploid cells are eliminated from the epiblast by p53-mediated apoptosis while being tolerated trophectoderm. These observations suggest a selective loss embryos, but underlying mechanisms not yet fully understood. Here, we investigated cellular consequences...

Is there an association between different mitochondrial DNA (mtDNA) genotypes and female infertility or ovarian response, is the appearance of variants in oocytes favored by medically assisted reproduction (MAR) techniques? Ovarian response was negatively associated with global non-synonymous protein-coding homoplasmic but positively haplogroup K; number retrieved a cycle correlates heteroplasmic oocytes, principally located hypervariable (HV) region rRNA loci, as well variants. Several...

Abstract About 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic blastocysts can implant and lead healthy new-borns with normal karyotypes. Studies mouse gastruloids have shown that aneuploid cells proteotoxic stress, autophagy p53 activation they are eliminated from the epiblast by apoptosis while being tolerated trophectoderm. These observations suggest a selective loss embryos, but underlying mechanisms not yet fully...

Though gains of chromosome 12p13.31 are highly recurrent in hPSC, their impact on differentiation is poorly understood. We identify a reduction capacity towards all three germ layers and subpopulation residual pluripotent cells that appear during hepatic specification. These form as result the overexpression NANOG GDF3, whereby primary driver delays activation WNT signaling, partly direct physical interaction with TCF7. Entry into state determined by cell cycle position at onset maintained...

ABSTRACT Humans present remarkable mitochondrial DNA (mtDNA) variant mosaicism, not only across tissues but even individual cells within one person. The timing of the first appearance this mosaicism has yet been established. In study, we hypothesized it occurs during preimplantation development. To investigate this, deep-sequenced mtDNA 254 oocytes from 85 donors, 158 single blastomeres 25 day-3 embryos, 17 inner cell mass and trophectoderm samples 7 day-5 blastocysts, 142 bulk 68 different...

Aneuploidy is present in about 80% of human cleavage-stage embryos and thought to largely explain our relatively low fertility. However, the percentage aneuploid cells decreases gradually chromosomally mosaic blastocysts have been shown result healthy newborns with normal karyotypes. These observations imply a selective loss cells, but underlying mechanisms are not yet fully understood. Here, we show that, while had lower cell numbers both trophectoderm inner-cell-mass, effect aneuploidy was...