1. Development of a vascularized human placental barrier on-chip (MiVPChip, #PID2020-116745GA-I00)

Funding Body: Agencia Estatal de Investigación – Proyectos de I+D de GENERACIÓN DE CONOCIMIENTO

Project summary

The placenta acts as the primary source of nutrients and oxygen, as well as a first line of defence between fetus and exposure to toxic substances, bacteria and viruses from maternal blood. Models aimed at studying this unique organ typically include difficult-to-culture placental explants and animal models with mismatched placental physiology; thus, there is a strong need for the development of humanized in vitro tools. We have recently developed a model of fetal vasculature that demonstrated sensitivity to exogenous perfusion of inflammatory cytokines and perfusion with immune cells. This proposal aims to combine perfusable 3D fetal vessels with a stable trophoblast layer in order to generate a physiologic human placental interface system. Our model possesses the unique ability to perfuse both the maternal and fetal components, to distinctly regulate hemodynamics on-chip.

We aim to demonstrate a functional placental barrier – including resistance to transport of large proteins, and perfusion of small molecules (including hormones). We will employ the system to highlight key changes in both the secretome and transcriptome of fetal vasculature in response to anti-angiogenic markers upregulated in pre-eclampsia. Moreover, we will use our model to examine the understudied effect of pregnancy-specific glycoproteins (PSG-1) on the maternal-fetal interface, and examine their pro-angiogenic potential. The MiVPChip project aims to generate a human placental maternal-fetal interface on-chip, as a unique tool for investigating dysfunction of both the trophoblasts and vascular components of the placenta.  This model will provide insight into placental dysfunction and will serve as a platform to investigate xenobiotics transfer across the maternal-fetal interface.

2. Development of novel 3D vascularized cardiac models to investigate Coronary Microvascular Disease

Funding Body: ERC StG (3DVasCMD, project number 101040977)

Project summary

Coronary microvascular disease (CMD) is a significant healthcare challenge, contributing to ischemic heart disease, the number one global cause of human mortality. CMD is associated with dysfunction of small coronary vessels, due to ageing, obesity and metabolic disease, that reduces blood flow and oxygenation in the heart. Despite its widespread impact on health, our understanding is limited to animal studies, which do not recapitulate the pathophysiology in humans, nor can they be used to reveal cellular crosstalk in a controlled manner. Thus, there is a critical need to develop a humanized in vitro model to mimic CMD. Advances in organ-on-chip and induced pluripotent stem cell (iPSC) technologies, together with our state-of-the-art 3D humanized vascular models, provide new opportunities to investigate CMD. 3DVasCMD builds on our expertise to develop a complex vascularized cardiac model, to reveal pathological mechanisms and novel therapeutic targets of CMD. By combining cutting-edge tissue-engineering approaches we will: 1) Develop and characterize a 3D vascularized cardiac model, 2) Determine the impact of known risk factors on the pathophysiology of CMD; 3) Develop a high-throughput system for cardiovascular drug screening. Our model will reveal cardiac tissue-vessel crosstalk by combining autologously-differentiated iPSCs in a controlled fluidic environment. This model will enable unprecedented study of ischemia, diabetes, and sex-hormone contributions to CMD using 3D in vitro tissues. Ultimately, a high-throughput version of our model, combined with machine learning, will predict the efficacy of therapeutic targets. Using an interdisciplinary approach, 3DVasCMD will impact our understanding of how microenvironmental and heritable risk-factors contribute to CMD. This model has the potential to study multiple facets of vascular disease and can be further developed into a preclinical tool, which will be a breakthrough for cardiovascular biology and medicine