Biology subjects

Calvi, I.

Publications and source records attributed to Calvi, I..

4 recordsLinked to original sources

bioRxiv2025

Low oxygen promotes extravillous trophoblast progenitor expansion but restrains maturation

Placental development occurs in a low oxygen environment, yet how oxygen tension instructs differentiation of progenitor cytotrophoblasts (CTB) along the extravillous versus villous pathways remains incompletely understood. In particular, the role of low oxygen in early extravillous trophoblast (EVT) progenitor expansion and subsequent maturation has been difficult to assess due to the lack of models allowing sequential, high-resolution characterization. Using human trophoblast organoids and single-cell transcriptomics, we examined the effects of ambient (21%) and physiological (2-3%, 8%) oxygen on EVT and SCT differentiation. We show that low oxygen promotes the initial expansion of column CTB-like progenitors but restricts terminal EVT maturation. Conversely, we show that ambient oxygen drives the formation of EVT and syncytiotrophoblast. Stabilization of HIF-1 partially recapitulates the EVT maturation block but does not contribute to EVT progenitor expansion, indicating HIF-dependent and-independent contributions. These findings clarify how oxygen shapes EVT lineage progression and define HIF-1s role in coordinating progenitor expansion versus maturation.

developmental biology↗

bioRxiv2025

A model of apical-out human first trimester trophoblast organoids to study regeneration after syncytial damage

The villous syncytiotrophoblast in humans is the interface between maternal blood and the placenta and its functions are essential for a successful pregnancy. The syncytium can be damaged in vivo focally by high-velocity and turbulent maternal blood flow, or more globally by oxidative stress. It then quickly regenerates, a process critical for the maintenance of placental functions including nutrient transfer and protection from infections. To investigate this process, we developed apical-out trophoblast organoids from first-trimester placentas and induced mechanical damage to the syncytium. We observed spontaneous regeneration of syncytiotrophoblast both morphologically and functionally. TNFRSF12A, the TWEAK receptor, was identified as a potential enhancer of syncytiotrophoblast regeneration. Supplementation with recombinant TWEAK in organoids increased the expression of cell proliferation and fusion markers, promoting syncytiotrophoblast formation. The source of TWEAK was found to be macrophages derived from maternal blood monocytes that adhere to sites of syncytiotrophoblast damage in vivo. This in vitro model that allows the exploration of syncytial biology has relevance for important pregnancy disorders including pre-eclampsia, where breaks occur more often, and vertical infections, where maternal monocytes could be a source of transmission.

developmental biology↗

bioRxiv2025

SDS-22 stabilizes the PP1 catalytic subunits GSP-1/-2 contributing to polarity establishment in C. elegans embryos

In many cells, cell polarity depends on the asymmetric distribution of the conserved PAR proteins, maintained by a balanced activity between kinases and phosphatases. The C. elegans one-cell embryo is polarized along the anterior-posterior axis, with the atypical protein kinase C PKC-3 enriched in the anterior, and the ring finger protein PAR-2 in the posterior. PAR-2 localization is regulated by PKC-3 and the PP1 phosphatases GSP-1/-2. Here, we find that, similar to GSP-2 depletion, depletion of the conserved PP1 interactor SDS-22 results in a partial rescue of the polarity defects of a pkc-3 temperature-sensitive mutant. Consistent with the rescue, SDS-22 depletion or mutation results in reduced GSP-1/-2 protein levels and activity. The decreased levels of GSP-1/-2 can be rescued by reducing proteasomal activity. Our data suggest that SDS-22 contributes to polarity by protecting the GSP-1 and GSP-2 catalytic subunits from proteasome-mediated degradation, supporting recent data in human cells showing the SDS22 is required to stabilize nascent PP1.

cell biology↗

bioRxiv2022

PP1 phosphatases control PAR-2 localization and polarity establishment in C. elegans embryos

Cell polarity relies on the asymmetric distribution of the conserved PAR proteins, which is regulated by phosphorylation/dephosphorylation reactions. While the kinases involved have been well studied, the role of phosphatases remains poorly understood. In C. elegans zygotes, phosphorylation of the posterior PAR-2 protein by the atypical protein kinase PKC-3 inhibits PAR-2 cortical localization. Polarity establishment depends on loading of PAR-2 at the posterior cortex. We show that the PP1 phosphatases GSP-1 and GSP-2 are required for polarity establishment in embryos. We find that co-depletion of GSP-1 and GSP-2 abrogates the cortical localization of PAR-2 and that GSP-1 and GSP-2 interact with PAR-2 via a PP1 docking motif in PAR-2. Mutating this motif in vivo, to prevent binding of PAR-2 to PP1, abolishes cortical localization of PAR-2, while optimizing this motif extends PAR-2 cortical localization. Our data suggest a model in which GSP-1/-2 counteract PKC-3 phosphorylation of PAR-2 allowing its cortical localization at the posterior and polarization of the one-cell embryo. SUMMARYCalvi et al. identify PP1 protein phosphatases as regulators of cell polarity in C. elegans embryos. Their results show that two redundant phosphatases, GSP-1 and GSP-2, interact with the polarity protein PAR-2 and control its localization and polarity establishment.

cell biology↗