Poster #075, Cedars-Sinai Medical Center
Identification of Cytokine Regulators of Fibrosis in iPSC-Derived Intestinal Mesenchymal Cells from Crohn’s Disease Patients
Mentors: Christian Wong Valencia, PhD and Robert Barrett, PhD
Crohn’s disease (CD) is a form of inflammatory bowel disease that affects over 1 million individuals in the US alone. Furthermore, 30–50% of patients develop fibrosis, a complication characterized by a buildup of excess extracellular matrix (ECM) proteins within the small intestine. It is understood that cytokines secreted by surrounding cells play a key role in regulating fibrosis. Most research and potential therapies have focused on TNF-α as proinflammatory and TGF-β as a fibrogenic driver. However, the impact of additional cytokines on fibrosis has been largely overlooked. Therefore, the goal of this study was to evaluate the role of multiple cytokines in the fibrotic response via a fluorescence microscopy-based screening. Using mesenchymal cells derived from induced pluripotent stem cells (iPSCs) from CD patients with fibrosis, we screened a panel of 76 cytokines associated with fibrotic CD to identify regulators of ECM production beyond TNF-α/TGF-β. To evaluate whether the effect on fibrosis from the cytokine panel depended on surrounding TNF-α/TGF-β, the mesenchymal cells were prepared under four background conditions: basal, TNF-α, TGF-β, or combined TNF-α/TGF-β. We identified PDGF-BB as the only cytokine sufficient to independently increase ECM production in all experimental groups; however, its profibrotic effect was less potent than TGF-β alone. Moreover, we found that multiple inflammatory cytokines associated with fibrotic CD exhibited antifibrotic effects, namely IL-4, IL-13, IFN-γ, IL-17A, IL-1α, and IL-1β. In the future, more research is needed to determine whether PDGF-BB drives fibrosis directly or through downstream TGF-β activation. Additionally, more research is needed to understand the mechanism by which inflammatory cytokines exhibit antifibrotic effects. Further investigation into these results will provide novel insight into the mechanisms driving fibrosis in CD patients and ultimately serve in the development of new therapeutics.