Receptor tyrosine kinase inhibitors negatively impact on pro-reparative characteristics of human cardiac progenitor cells

Article


Smith, A. J., Ruchaya, P. J., Walmsley, R., Wright, K. E., Lewis-McDougall, F. C., Bond, J. and Ellison-Hughes, G. M. 2022. Receptor tyrosine kinase inhibitors negatively impact on pro-reparative characteristics of human cardiac progenitor cells. Scientific Reports. 12 (Art. 10132). https://doi.org/https://doi.org/10.1038/s41598-022-13203-3
AuthorsSmith, A. J., Ruchaya, P. J., Walmsley, R., Wright, K. E., Lewis-McDougall, F. C., Bond, J. and Ellison-Hughes, G. M.
Abstract

Receptor tyrosine kinase inhibitors improve cancer survival but their cardiotoxicity requires investigation. We investigated these inhibitors' effects on human cardiac progenitor cells in vitro and rat heart in vivo. We applied imatinib, sunitinib or sorafenib to human cardiac progenitor cells, assessing cell viability, proliferation, stemness, differentiation, growth factor production and second messengers. Alongside, sunitinib effects were assessed in vivo. Inhibitors decreased (𝘱 < 0.05) cell viability, at levels equivalent to 'peak' (24 h; imatinib: 91.5 ± 0.9%; sunitinib: 83.9 ± 1.8%; sorafenib: 75.0 ± 1.6%) and 'trough' (7 days; imatinib: 62.3 ± 6.2%; sunitinib: 86.2 ± 3.5%) clinical plasma levels, compared to control (100% viability). Reduced (𝘱 < 0.05) cell cycle activity was seen with imatinib (29.3 ± 4.3% cells in S/G2/M-phases; 50.3 ± 5.1% in control). Expression of PECAM-1, Nkx2.5, Wnt2, linked with cell differentiation, were decreased (𝘱 < 0.05) 2, 2 and 6-fold, respectively. Expression of HGF, p38 and Akt1 in cells was reduced (𝘱 < 0.05) by sunitinib. Second messenger (p38 and Akt1) blockade affected progenitor cell phenotype, reducing c-kit and growth factor (HGF, EGF) expression. Sunitinib for 9 days (40 mg/kg, i.p.) in adult rats reduced (𝘱 < 0.05) cardiac ejection fraction (68 ± 2% 𝘷𝘴. baseline (83 ± 1%) and control (84 ± 4%)) and reduced progenitor cell numbers. Receptor tyrosine kinase inhibitors reduce cardiac progenitor cell survival, proliferation, differentiation and reparative growth factor expression.

JournalScientific Reports
Journal citation12 (Art. 10132)
ISSN2045-2322
Year2022
PublisherNature Publishing Group
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Supplemental file
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Digital Object Identifier (DOI)https://doi.org/https://doi.org/10.1038/s41598-022-13203-3
Publication dates
Online16 Jun 2022
Publication process dates
Accepted23 May 2022
Deposited13 Jun 2023
Funder Heart Research UK
Rosetrees Trust
Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Copyright holder© 2022, The Author(s)
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