Trophoblast–endothelium signaling involves angiogenesis and apoptosis in a dynamic bioprinted placenta model

Abstract

Trophoblast invasion and remodeling of the maternal spiral arteries are required for pregnancy success. Aberrant endothelium-trophoblast crosstalk may lead to preeclampsia, a pregnancy complication that has serious effects on both the mother and the baby. However, our understanding of the mechanisms involved in this pathology remains elementary because current in vitro models cannot describe trophoblast-endothelium interactions under dynamic culture. In this work, we developed a dynamic 3D placenta model by bioprinting trophoblasts and an endothelialized lumen in a perfusion bioreactor. We found the perfusion bioreactor system significantly augmented responses of endothelial cells by encouraging network formations and expressions of angiogenic markers CD31, MMP2, MMP9, and VEGFA. Bioprinting favored colocalization trophoblasts with endothelial cells, similar to in vivo observations. Additional analysis revealed that trophoblasts reduced the angiogenic responses by reducing network formation and motility rates while inducing apoptosis of endothelial cells. Moreover, presence of endothelial cells appeared to inhibit trophoblast invasion rates. These results clearly demonstrated the utility and potential of bioprinting and perfusion bioreactor system to model trophoblast-endothelium interactions in vitro. Our bioprinted placenta model represents a crucial step to develop advanced research approach that will expand our understanding and treatment options of preeclampsia and other pregnancy-related pathologies.

Immune Cells in the Uterine Remodeling: Are They the Target of Endocrine Disrupting Chemicals?

“…By using a threedimensional bioprinted placenta model, Kuo et al performed impressive trophoblast-endothelium interaction studies. They reported that the co-culture of trophoblasts with endothelial cells significantly reduced the outgrowth and network formation of endothelial cells and induced endothelial cell apoptosis, shown by a significant upregulation of apoptosis marker (35). Trophoblast invasion is temporally and spatially regulated by autocrine (trophoblastic) and paracrine (uterine) factors as well as cell-to-cell and cell-to-matrix interactions (36).…”

3D Printing Techniques and Their Applications to Organ-on-a-Chip Platforms: A Systematic Review

“…This is characterized by elevated blood pressure and also a noteworthy quantity of protein present in the urine of pregnant women due to reduced trophoblast invasion of maternal spiral arteries. Nevertheless, there are few biomodels able to reproduce this pathology [ 23 , 55 , 57 ]. A promising model was proposed by Kuo and co-workers [ 55 ].…”

Trophoblast attachment to the endometrial epithelium elicits compartment-specific transcriptional waves in an in-vitro model

“…Interestingly, trophoblast inflammatory response was up-regulated after 24 h but not before; it is postulated that, once the epithelium is breached, inflammation could act as a regulatory mechanism to prevent excessive invasion. Interestingly, angiogenesis was continuously increased along the 24 h of co-culture; if extrapolated to the in-vivo situation, the transcriptional up-regulation during this early time could trigger signalling required for remodelling of the maternal vasculature needed for placental development (Kuo et al, 2019;Zhou et al, 2003). Regulation of the unfolded protein response, which is linked to endoplasmic reticulum stress, has been related to placental development (Burton and Yung, 2011;Yung et al, 2014).…”