Chromosomal instability in human trophoblast stem cells and placentas DOI Creative Commons
Danyang Wang,

Andrew Cearlock,

Katherine Lane

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 25, 2025

The human placenta, a unique tumor-like organ, is thought to exhibit rare aneuploidy associated with adverse pregnancy outcomes. Discrepancies in reported prevalence placentas stem from limitations modeling and detection methods. Here, we use isogenic trophoblast cells (TSCs) derived both naïve primed pluripotent (hPSCs) reveal the spontaneous occurrence of aneuploidy, suggesting chromosomal instability (CIN) as an inherent feature lineage. We identify potential pathways contributing tolerance CIN, such autophagy, which may support survival aneuploid cells. Despite extensive abnormalities, TSCs maintain their proliferative differentiation capacities. These findings are further validated placentas, where observe high heterogeneous across trophoblasts, particularly invasive extravillous trophoblasts. Our study challenges traditional view placenta provides insights into implications CIN placental function.

Language: Английский

Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial DOI Creative Commons
Antonio Capalbo, Maurizio Poli, Laura Rienzi

et al.

The American Journal of Human Genetics, Journal Year: 2021, Volume and Issue: 108(12), P. 2238 - 2247

Published: Nov. 18, 2021

Chromosome imbalance (aneuploidy) is the major cause of pregnancy loss and congenital disorders in humans. Analyses small biopsies from human embryos suggest that aneuploidy commonly originates during early divisions, resulting mosaicism. However, developmental potential mosaic remains unclear. We followed distribution aneuploid chromosomes across 73 unselected preimplantation 365 biopsies, sampled four multifocal trophectoderm (TE) samples inner cell mass (ICM). When mosaicism impacted fewer than 50% cells one TE biopsy (low-medium mosaicism), only 1% aneuploidies affected other portions embryo. A double-blinded prospective non-selection trial (NCT03673592) showed equivalent live-birth rates miscarriage 484 euploid, 282 low-grade mosaic, 131 medium-grade embryos. No instances or uniparental disomy were detected ensuing pregnancies newborns, obstetrical neonatal outcomes similar between study groups. Thus, low-medium mostly arises after ICM differentiation, such have as fully euploid ones.

Language: Английский

Citations

178
A body map of somatic mutagenesis in morphologically normal human tissues DOI
Ruoyan Li,

Lin Di,

Jie Li

et al.

Nature, Journal Year: 2021, Volume and Issue: 597(7876), P. 398 - 403

Published: Aug. 25, 2021

Language: Английский

Citations

146
Extensive phylogenies of human development inferred from somatic mutations DOI Creative Commons
Tim H. H. Coorens, Luiza Moore, Philip S. Robinson

et al.

Nature, Journal Year: 2021, Volume and Issue: 597(7876), P. 387 - 392

Published: Aug. 25, 2021

Starting from the zygote, all cells in human body continuously acquire mutations. Mutations shared between different imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues three adult individuals using whole-genome sequencing 511 laser capture microdissections. Reconstructed embryonic progenitors same generation phylogeny often contribute to extents body. The degree this asymmetry varies individuals, with ratios two reconstructed daughter zygote ranging 60:40 93:7. Asymmetries pervade subsequent generations can differ individual. resolve spatial patterning tissues, revealing contiguous patches of, on average, 301 crypts colonic epithelium derived most recent cell also effect brain development. Using data ten additional men, investigated developmental split soma germline, results suggesting an extraembryonic contribution primordial germ cells. This research demonstrates that, despite reaching ultimate tissue patterns, early bottlenecks commitments lead substantial variation patterns both within individuals. Somatic mutations obtained microdissected biopsies used these back zygote.

Language: Английский

Citations

129
Effects of aneuploidy on cell behaviour and function DOI
Rong Li,

Jin Zhu

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(4), P. 250 - 265

Published: Jan. 5, 2022

Language: Английский

Citations

103
A spatially resolved timeline of the human maternal–fetal interface DOI Creative Commons
Shirley Greenbaum, Inna Averbukh, Erin Soon

et al.

Nature, Journal Year: 2023, Volume and Issue: 619(7970), P. 595 - 605

Published: July 19, 2023

Abstract Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with maternal decidua promote a tissue microenvironment conducive artery remodelling (SAR) 1–3 . However, it remains matter of debate regarding which immune stromal cells participate these interactions this evolves respect gestational age. Here we used multiomics approach, combining strengths spatial proteomics transcriptomics, construct spatiotemporal atlas human maternal–fetal interface half pregnancy. We multiplexed ion beam imaging by time-of-flight 37-plex antibody panel analyse around 500,000 588 arteries within intact from 66 individuals between 6 20 weeks gestation, integrating dataset co-registered transcriptomics profiles. Gestational age substantially influenced frequency cells, tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 IDO-1 becoming increasingly enriched colocalized at later time points. By contrast, SAR progression preferentially correlated EVT invasion was transcriptionally defined 78 gene ontology pathways exhibiting distinct monotonic biphasic trends. Last, developed an integrated model whereby is accompanied upregulation pro-angiogenic, immunoregulatory programmes that vascular endothelium while avoiding activation cells.

Language: Английский

Citations

85
Replication stress impairs chromosome segregation and preimplantation development in human embryos DOI Creative Commons
Katherine L. Palmerola, Selma Amrane, Alejandro De Los Angeles

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(16), P. 2988 - 3007.e20

Published: July 19, 2022

Human cleavage-stage embryos frequently acquire chromosomal aneuploidies during mitosis due to unknown mechanisms. Here, we show that S phase at the 1-cell stage shows replication fork stalling, low speed, and DNA synthesis extending into G2 phase. damage foci consistent with collapsed forks, DSBs, incomplete form in an ATR- MRE11-dependent manner, followed by spontaneous chromosome breakage segmental aneuploidies. Entry results breakage, whole errors, micronucleation, fragmentation, poor embryo quality. Sites of are concordant sites phase, locating gene-poor regions long neural genes, which transcriptionally silent this development. Thus, stress mammalian preimplantation predisposes fragility, particular human embryo, formation aneuploidies, impairing developmental potential.

Language: Английский

Citations

79
Early human trophoblast development: from morphology to function DOI Creative Commons
Martin Gauster, Gerit Moser, Stefan Wernitznig

et al.

Cellular and Molecular Life Sciences, Journal Year: 2022, Volume and Issue: 79(6)

Published: June 1, 2022

Human pregnancy depends on the proper development of embryo prior to implantation and into uterine wall. During pre-implantation phase, formation morula is followed by internalization blastomeres that differentiate pluripotent inner cell mass lineage, while cells surface undergo polarization trophectoderm blastocyst. The mediates apposition adhesion blastocyst epithelium. These processes lead a stable contact between embryonic maternal tissues, resulting in new organ, placenta. implantation, start form basis for multiple specialized trophoblast subpopulations, all which fulfilling specific key functions placentation. They either polar serving typical epithelial functions, or apolar invasive adapt wall progressing pregnancy. composition these subpopulations crucial human placenta alterations are suggested result placenta-associated pathologies. This review article focuses what known about very early reproduction emphasizes morphological functional aspects differentiation subpopulations.

Language: Английский

Citations

76
The first two blastomeres contribute unequally to the human embryo DOI Creative Commons
Sergi Junyent, Maciej Meglicki, Roman Vetter

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(11), P. 2838 - 2854.e17

Published: May 1, 2024

Retrospective lineage reconstruction of humans predicts that dramatic clonal imbalances in the body can be traced to 2-cell stage embryo. However, whether and how such asymmetries arise embryo is unclear. Here, we performed prospective tracing human embryos using live imaging, non-invasive cell labeling, computational predictions determine contribution each blastomere epiblast (body), hypoblast (yolk sac), trophectoderm (placenta). We show majority cells originate from only one observe three become internalized at 8-to-16-cell transition. Moreover, these are more frequently derived first divide stage. propose division dynamics a internalization bottleneck early establish asymmetry composition future body.

Language: Английский

Citations

29
Genetic variation across and within individuals DOI
Zhi Yu, Tim H. H. Coorens, Md Mesbah Uddin

et al.

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(8), P. 548 - 562

Published: March 28, 2024

Language: Английский

Citations

23
Mechanics of human embryo compaction DOI
Julie Firmin,

Nicolas Ecker,

Diane Rivet-Danon

et al.

Nature, Journal Year: 2024, Volume and Issue: 629(8012), P. 646 - 651

Published: May 1, 2024

Language: Английский

Citations

23