Key result
Mesenchymal stromal cell-derived extracellular vesicles improve calcium handling and cut relaxation time ~42% in HFpEF microtissues.
Why the study?
HFpEF still requires therapeutic improvements, but animal models with translational relevance remain limited, motivating evaluation of human mesenchymal stromal cell-derived extracellular vesicles in a multi-cell-type human cardiac microtissue model emulating HFpEF.
Do extracellular vesicles derived from human mesenchymal stromal cells mitigate functional and structural abnormalities in a 3D human cardiac microtissue model of HFpEF?
Do extracellular vesicles derived from human mesenchymal stromal cells mitigate functional and structural abnormalities in a 3D human cardiac microtissue model of HFpEF?
Human mesenchymal stromal cell-derived extracellular vesicles normalized relaxation and calcium handling abnormalities and blunted fibrosis gene expression in a 3D human cardiac microtissue model of HFpEF, demonstrating their potential as a therapeutic adjunct and the utility of the model for drug screening.
Hypothesis-generating for extracellular vesicle therapy in HFpEF; extends microtissue models for preclinical screening but leaves clinical translation open.
Background Heart failure with preserved ejection fraction (HFpEF) is a syndrome with an increased prevalence, which still requires therapeutic improvements, but for which the animal models with translational relevance remain limited. To address this issue, a human cardiac microtissue model composed exclusively of cardiomyocytes (CM) and subjected to conditions mimicking the main comorbidities leading to HFpEF has been developed. Purpose The present study first leveraged this model by incorporating fibroblasts (FB) and endothelial cells (EC). Then, based on the recognition that microvascular inflammation is a key feature of HFpEF, it assessed whether extracellular vesicles (EV) derived from human mesenchymal stromal cells (MSC) could mitigate the functional and structural abnormalities featured by these HFpEF-emulating 3D constructs. Materials and Methods Cardiac microtissues (CMT) were generated by mixing human induced pluripotent stem cell-derived CM, human ventricular cardiac FB, and human coronary artery EC (70%:15%:15%). Once the CMTs were formed and homogeneously contracting, they were subjected to HFpEF-mimicking conditions: interleukin-1β, 10 ng/mL, and interferon-γ, 100 ng/mL, to simulate obesity-related inflammation; high glucose concentration, 11.1 mmol/L, without insulin for diabetic conditions; angiotensin II, 10 ng/mL, and endothelin-1, 10 ng/mL, to emulate hypertension. EV (1 x 1010 particles) from human Wharton’s jelly umbilical cord MSC were added to the medium from the onset of HFpEF treatment and again two days later. Results After 5 days, calcium transient analysis (Fluo-4 calcium dye measurements after a 5-minute electrical stimulation period of the CMT) showed that the mean decay time was significantly prolonged in HFpEF CMT compared with healthy controls (763 ± 77 ms vs 705 ± 17 ms; p = 0.001), an effect which was largely prevented by HFpEF EV-treated CMT (687 ± 74 ms, p < 0.0001 vs HFpEF CMT, n = 15–20 CMT per group). Contractility assays showed a significant increase in mean relaxation time after exposure to HFpEF inducers in comparison to healthy CMT (597 ± 212 ms vs. 287 ± 212 ms; p < 0.0001), but was almost fully normalized by EV treatment (347 ± 31 ms, p < 0.0001 vs HFpEF CMT). Likewise, compared with healthy controls, HFpEF CMT demonstrated increased expression of fibrosis-associated genes (COL1A1, MMP2), which was fully blunted by exposure to EV. These data will be correlated with those of an ongoing study of EV treatment in a mouse HFpEF model. Conclusion This study suggests that human CMT represent a useful platform for screening HFpEF therapeutics, among which EV might be a promising adjunct to current therapies.
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Mathioudaki et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF). Extracellular vesicles from human Wharton's jelly umbilical cord mesenchymal stromal cells vs. Untreated HFpEF-mimicking cardiac microtissues and healthy controls was evaluated on Mean calcium transient decay time (ms) and mean relaxation time (ms) (p=<0.0001). Mesenchymal stromal cell-derived extracellular vesicles normalized calcium transient decay (687 vs 763 ms; p<0.0001) and relaxation time (347 vs 597 ms; p<0.0001) in HFpEF cardiac microtissues.
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