ArticleTranslational pediatrics2026
Stage-associated differences in injury and stress responses of hiPSC-derived cardiomyocytes under macrophage-derived inflammatory stimulation.
Article in Translational pediatrics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Macrophage-driven inflammation contributes to myocardial injury in pediatric myocarditis, but the extent to which cardiomyocyte maturation status influences responses to inflammatory stimulation remains unclear. This study aimed to investigate stage-associated differences in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to THP-1 macrophage-derived conditioned media and to explore the involvement of stress-response pathways. Methods: A macrophage-derived inflammatory microenvironment was modeled using THP-1-derived macrophage conditioned media (M0-CM and M1-CM). hiPSC-CMs at day 7 (D7) and day 21 (D21) were used as early-stage and relatively more mature in vitro stages, respectively. Cell viability was assessed using Cell Counting Kit-8 (CCK-8), and lactate dehydrogenase (LDH) release and cardiac troponin I (cTnI) levels were measured to evaluate injury. C/EBP homologous protein (CHOP) expression was analyzed by Western blot, and mitochondrial membrane potential (ΔΨm) was determined using tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining following small interfering RNA (siRNA)-mediated CHOP knockdown. Results: M1-CM significantly increased tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels compared with M0 and control groups (P<0.001), along with upregulation of inducible nitric oxide synthase (iNOS) (P<0.001). Under inflammatory stimulation, D7 hiPSC-CMs showed greater decreases in viability and greater LDH and cTnI release than D21 hiPSC-CMs in the stage-stratified analyses. CHOP expression was induced by M1-CM (P<0.001), and CHOP knockdown decreased LDH release (P<0.001) and partially restored ΔΨm (P<0.05). Conclusions: Early-stage hiPSC-CMs showed greater vulnerability to THP-1 macrophage-derived inflammatory stimulation than relatively more mature D21 cells in this
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