Study of Human T21 Placenta Suggests a Potential Role of Mesenchymal Spondin-2 in Placental Vascular Development

Abstract

Placental development is particularly altered in trisomy of chromosome 21 (T21)–affected pregnancies. We previously described in T21-affected placentae an abnormal paracrine crosstalk between the villus mesenchymal core and villus trophoblasts. T21-affected placentae are known to be characterized by their hypovascularity. However, the causes of this anomaly remain not fully elucidated. Therefore, the hypothesis of an abnormal paracrine crosstalk between fetal mesenchymal core and placental endothelial cells (PLECs) was evocated. Villus mesenchymal cells from control (CMCs) and T21 placentae (T21MCs) were isolated and grown in culture to allow their characterization and collection of conditioned media for functional analyses (CMC-CM and T21MC-CM, respectively). Interestingly, PLEC proliferation and branching ability were less stimulated by T21MC-CM than by CMC-CM. Protein array analysis identified secreted proangiogenic growth factors in CMC-CM, which were reduced in T21MC-CM. Combined mass spectrometry and biochemical analysis identified spondin-2 as a factor decreased in T21MC-CM compared with CMC-CM. We found that exogenous spondin-2 stimulated PLEC proliferation and established that T21MC-CM supplemented with spondin-2 recovered conditioned media ability to induce PLEC proliferation and angiogenesis. Hence, this study demonstrates a crosstalk between villus mesenchymal and fetal endothelial cells, in which spondin-2 secreted from mesenchymal cells plays a central role in placental vascular functions. Furthermore, our results also suggest that a reduction in spondin-2 secretion may contribute to the pathogenesis of T21 placental hypovascularity.

Fetal hemodynamics and placental histopathology in Down syndrome

“…However, the cause of this anomaly has not yet been fully elucidated. Gerbaud et al 24 suggested that the hypovascularization was a multifactorial process related, in part, to an imbalance between pro‐angiogenic and antiangiogenic factors. Kuhlmann et al 25 believe that the hypovascularization is the result of defective or slow angiopoiesis, which may be intensified by late vascular obliteration culminating in what they described as placental immaturity.…”

The biological functions and related signaling pathways of SPON2

“…Gerbaud P et al. reported that exogenous SPON2 promotes the proliferation of placental endothelial cells, while decreased secretion of SPON2 may impair placental vascular function in trisomy 21 syndrome ( 91 ).…”

“…SPON2 exerts a promotive influence on vascular regeneration and hematopoietic reconstitution (90). Gerbaud P et al reported that exogenous SPON2 promotes the proliferation of placental endothelial cells, while decreased secretion of SPON2 may impair placental vascular function in trisomy 21 syndrome (91).…”

Exploring maternal-fetal interface with in vitro placental and trophoblastic models

“…These CTB stem cells demonstrated self-renewal capacity and the potential to differentiate into STB and EVT cells, as confirmed by marker expression, hormone secretion, and invasive capacity. To evaluate the applicability of hPSCs-derived CTBs, the researchers successfully replicated the delayed CTB maturation and impaired STB differentiation observed in trisomy 21 syndrome (T21) ( Gerbaud et al, 2019 ) hPSCs. Overall, their study emphasizes that hPSCs provide a reliable model for studying human trophoblast development and accurately replicating trophoblast cell differentiation defects.…”