Immunosuppressants Tacrolimus and Sirolimus revert the cardiac antifibrotic properties of p38-MAPK inhibition in 3D-multicellular human iPSC-heart organoids

Abstract

Cardiac reactive fibrosis is a fibroblast-derived maladaptive process to tissue injury that exacerbates an uncontrolled deposition of large amounts of extracellular matrix (ECM) around cardiomyocytes and vascular cells, being recognized as a pathological entity of morbidity and mortality. Cardiac fibrosis is partially controlled through the sustained activation of TGF-β1 through IL-11 in fibroblasts. Yet, preclinical studies on fibrosis treatment require human physiological approaches due to the multicellular crosstalk between cells and tissues in the heart. Here, we leveraged an iPSC-derived multi-lineage human heart organoid (hHO) platform composed of different cardiac cell types to set the basis of a preclinical model for evaluating drug cardiotoxicity and assessing cardiac fibrosis phenotypes. We found that the inhibition of the p38-MAPK pathway significantly reduces COL1A1 depositions. Yet, concomitant treatment with organ-rejection immunosuppressant drugs Tacrolimus or Sirolimus reverts this effect, opening new questions on the clinical considerations of combined therapies in reducing fibrosis after organ transplantation.

Immunosuppressive Agents—Effects on the Cardiovascular System and Selected Metabolic Aspects: A Review

“…It had an inhibitory effect on the synthesis of α-smooth muscle actin, transforming growth factor-β, metalloproteinase-9, and tumor necrotic factor [41]. However, in cell cultures, FK-506 and RAP have been shown to reverse the inhibitory effect of the p38-MAPK pathway, resulting in increased collagen deposition in the heart and increased fibrosis [42]. More research on this topic is needed to accurately understand the effects of FK-506 on cardiac remodeling and its profibrotic properties.…”

Cardiac organoid: multiple construction approaches and potential applications

“…Although hCOs are powerful tools for testing drugs, they are still far from a natural heart. 93 The reliability of drug screening can be improved by increasing the structural and functional similarity of organoids to the natural heart, and by exploring the influence of the cardiac microenvironment and other organs on cardiac drug toxicity.…”