Pro-angiogenic Potential of Mesenchymal Stromal Cells Regulated by Matrix Stiffness and Anisotropy Mimicking Right Ventricles

Abstract

Capillary rarefaction is a hallmark of right ventricle (RV) failure. Mesenchymal stromal cell (MSC)-based therapy offers a potential treatment due to its pro-angiogenic function. However, the impact of RV tissue mechanics on MSC behavior is unclear, especially when referring to RV end-diastolic stiffness and mechanical anisotropy. In this study, we assessed MSC behavior on electrospun scaffolds with varied stiffness (normal vs failing RV) and anisotropy (isotropic vs anisotropic). In individual MSCs, we observed the highest vascular endothelial growth factor (VEGF) production and total tube length in the failing, isotropic group (2.00 ± 0.37, 1.53 ± 0.24), which was greater than the normal, isotropic group (0.70 ± 0.15, 0.55 ± 0.07; p < 0.05). The presence of anisotropy led to trends of increased VEGF production on normal groups (0.75 ± 0.09 vs 1.20 ± 0.17), but this effect was absent on failing groups. Our findings reveal synergistic effects of RV-like stiffness and anisotropy on MSC pro-angiogenic function and may guide MSC-based therapies for heart failure.

Recent Advances in Tissue-Engineered Cardiac Scaffolds—The Progress and Gap in Mimicking Native Myocardium Mechanical Behaviors

“…We recently reported different MSC responses to varied matrix stiffness and anisotropy degrees using PEUU scaffolds mimicking healthy and diseased right ventricles. The biaxial elastic behavior was measured in the main fiber and cross-fiber directions, and anisotropic elastic behavior was confirmed [97]. A re-examination of the two anisotropic scaffold groups that represent healthy (soft) and diseased (stiff) right ventricle elasticities was performed via stress relaxation tests.…”

“…Matrix anisotropy has been shown to play a role in MSC morphology, differentiation fate, and other paracrine functions [110][111][112][113][114][115][116]. Recently, Nguyen-Truong et al [97] examined the effect of RV tissue mechanics on the pro-angiogenic paracrine function of MSCs, concentrating on the combined effect of RV-like tissue stiffness and anisotropy. Using random and aligned PEUU electrospun scaffolds with the stiffness of normal RVs, they found that the MSCs cultured on the anisotropic group consistently exhibited a higher pro-angiogenic function than those cultured on the isotropic group, showing a positive influence of anisotropy on MSC paracrine function.…”

“…Therefore, it is possible that the existing cardiac scaffolds present viscoelastic properties, although this behavior has been ignored. Viscoelastic properties of the previously reported anisotropic elastic scaffolds that mimic the stiffness of healthy (soft and anisotropic) and diseased (stiff and anisotropic) right ventricles [97]. Viscoelastic properties were measured by equibiaxial stress relaxation at the maximal strain of 15%.…”