Proud moment! My First, First Author paper is finally published! Happy Monday News! 🥳
An organ-on-chip model of pulmonary arterial hypertension identifies a BMPR2-SOX17-prostacyclin signalling axis ➡️nature.com/articles/s4200… @CommsBio #PAH #PhD #PhDChat
Here's the Tweetorial👇
Inspired by #OrganOnChip technology, we sought to create a model of the pulmonary vascular wall in order to investigate the underlying mechanisms of vascular remodelling in Pulmonary Arterial Hypertension (#PAH).
All of our chips were produced in-house from raw materials.
We created an endothelial-smooth muscle cell interface on our chips and applied laminar fluid shear stress (6 dynes/cm^2) over the endothelial monolayer which enhanced barrier function when compared to static controls.
Bone Morphogenetic Protein Receptor 2 (BMPR2) expression and function is commonly affected in PAH patients.
To investigate PAH, we reduced the expression level of the BMPR2 gene in the primary endothelial cells in our chip.
The smooth muscle cells (SMCs) were unmodified.
Another major factor in PAH progression is low oxygen levels (hypoxia).
Individually, BMPR2 reduction and hypoxia had minimal effects on SMC proliferation.
The *combination* of a BMPR2-deficient endothelium AND hypoxia caused excessive proliferation of healthy SMCs in our chips
Moving forward with this "two hit" combination model, we found a unique set of genes and pathways associated with PAH via transcriptomics (Bulk RNAseq).
The excessive SMC proliferation was able to be treated using Imatinib - an experimental drug for PAH.
To further validate our model for potential use in personalised medicine, BMPR2-deficient HPAECs were substituted for Endothelial Colony Forming Cells (ECFCs) derived from PAH patients.
ECFCs were subjected to the "two hit" model & again we saw an increase in SMC proliferation
PAH ECFCs were analysed by RNAseq, finding another set of unique genes and pathways associated with PAH.
Dataset comparisons revealed many common changes.
A striking observation in both models was: BMPR2⏬ led to SOX17⏬
Using tissue sections from an in vivo BMPR2 model (C118W) we were able to corroborate our BMPR2-SOX17 finding, demonstrating the potential utility of organs-on-chips as proxies for animal models in PAH pathway/mechanism discovery research.
Endothelial SOX17 overexpression in our "two hit" HPAEC model abrogated excessive SMC proliferation.
Separately, by proteomics, we found prostacyclin synthase (PTGIS) to be⏫with endothelial SOX17 overexpression
A prostacyclin inhibitor blocked the protective SOX17 effect in our two hit HPAEC model, where increased SMC proliferation was observed.
This led to our finding of a BMPR2-SOX17-Prostacyclin signalling axis
Huge thank you to:
- My PhD supervisors @BwsLab @EdelResearch
- @TheBHF for funding my MRes/PhD Scholarship
- @imperialcollege @ImperialMed @ImperialNHLI & @impchemistry
- My amazing co-authors (on twitter) @HaenselMaike @AdamFellows92 @HelpMyBreathing (+ the twitterless!)
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