Cardiac fibrosis inhibitor CTPR390 prevents structural and morphological changes in collagen and fibroblasts of engineered human connective tissue

Maestro, D.; Palanca, A.; Llarena, I.; DeGrave, A. N.; Guedes, G.; de Oliveira, G. H.; Coelho Conceicao, A. L.; Mieites, V.; Icardo De La Escalera, J. M.; Sanchez-Cano, C.; Conde, O. M.; Lutz, S.; Cortajarena, A. L.; Villar, A. V.

doi:10.1101/2025.01.15.633162

bioRxiv · 10.1101/2025.01.15.633162

Cardiac fibrosis inhibitor CTPR390 prevents structural and morphological changes in collagen and fibroblasts of engineered human connective tissue

Maestro, D.·Palanca, A.·Llarena, I.·DeGrave, A. N.·Guedes, G.·de Oliveira, G. H.·Coelho Conceicao, A. L.·Mieites, V.·Icardo De La Escalera, J. M.·Sanchez-Cano, C.·Conde, O. M.·Lutz, S.·Cortajarena, A. L.·Villar, A. V.

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Abstract

Cardiac fibrosis is a key characteristic of heart failure, with no effective treatment available. Using three-dimensional human models and cutting-edge biotechnology to evaluate new therapies offers a significant advancement. CTPR390, an experimental anti-fibrotic inhibitor targeting Hsp90, has shown success in animal models, but remains unexplored in human cardiac models. This study evaluated a cardiac three-dimensional engineered connective tissue (ECT) model treated with CTPR390, focusing on changes in the extracellular matrix and fibroblasts. Results showed that CTPR390 prevented architectural changes in TGF{beta}1-activated ECT, preserving tissue perimeter, collagen fibers alignment while reducing percentage of structured areas and degree of collagen structuration. Additionally, the treatment reduced cell area of elongated fibroblasts under tension, without changes in the internal rounded cells devoid of tension. Fibroblast recruitment to tension areas was diminished, showing biomechanical behavior similar to control ECT. This treatment also lowered the gene and protein expression of key pro-fibrotic markers. For the first time, advanced biotechnology was employed to detect the detailed structure of tissue fibrosis reduction after administering CTPR390, representing a significant advancement toward clinical application for cardiac fibrosis treatment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=56 SRC="FIGDIR/small/633162v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1f84961org.highwire.dtl.DTLVardef@19999eeorg.highwire.dtl.DTLVardef@1491286org.highwire.dtl.DTLVardef@5f2968_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Maestro, D., Palanca, A., Llarena, I., DeGrave, A. N., Guedes, G., de Oliveira, G. H., Coelho Conceicao, A. L., Mieites, V., Icardo De La Escalera, J. M., Sanchez-Cano, C., Conde, O. M., Lutz, S., Cortajarena, A. L., Villar, A. V.. 2025-01-17. Cardiac fibrosis inhibitor CTPR390 prevents structural and morphological changes in collagen and fibroblasts of engineered human connective tissue. https://doi.org/10.1101/2025.01.15.633162

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