Abstract
Tissue engineering approaches to regenerate myocardial tissue after disease or injury is promising. Integration with the host vasculature is critical to the survival and therapeutic efficacy of engineered myocardial tissues. To create more physiologically oriented engineered myocardial tissue with organized cellular arrangements and endothelial interactions, randomly oriented or parallel-aligned microfibrous polycaprolactone scaffolds were seeded with human pluripotent stem cell-derived cardiomyocytes (iCMs) and/or endothelial cells (iECs). The resultant engineered myocardial tissues were assessed in a subcutaneous transplantation model and in a myocardial injury model to evaluate the effect of scaffold anisotropy and endothelial interactions on vascular integration of the engineered myocardial tissue. Here we demonstrated that engineered myocardial tissue composed of randomly oriented scaffolds seeded with iECs promoted the survival of iECs for up to 14 days. However, engineered myocardial tissue composed of aligned scaffolds preferentially guided the organization of host capillaries along the direction of the microfibers. In a myocardial injury model, epicardially transplanted engineered myocardial tissues composed of randomly oriented scaffolds seeded with iCMs augmented microvessel formation leading to a significantly higher arteriole density after 4 weeks, compared to engineered tissues derived from aligned scaffolds. These findings that the scaffold microtopography imparts differential effect on revascularization, in which randomly oriented scaffolds promote pro-survival and pro-angiogenic effects, and aligned scaffolds direct the formation of anisotropic vessels. These findings suggest a dominant role of scaffold topography over endothelial co-culture in modulating cellular survival, vascularization, and microvessel architecture.
Highlights
Cardiovascular disease is the leading cause of death in the US, with over 16 million people suffering from coronary heart disease and 0.7 million new myocardial infarcts per year (Benjamin et al, 2018)
The randomly oriented scaffolds were composed of microfibers with arbitrarily organization, whereas the aligned scaffolds consisted of microfibers arranged about a single axis (Figures 1D,E). These observations were confirmed by Fast Fourier Transform (FFT) analysis, in which the pixelsin the frequency plot of the aligned scaffold (Figure 1E, inset) depicted a principal angle of orientation about the central origin that is consistent with anisotropy, whereas the pixels in the frequency plot of the randomly oriented scaffold (Figure 1D, inset) lacked any principal angle of orientation and was consistent with of isotropy
The salient findings of this study are that (1) anisotropic scaffolds can guide the organization of iCMs and iECs along the direction of the aligned microfibers in vitro (Figure 2); (2) in a subcutaneous transplantation model, engineered myocardial tissue composed of randomly oriented scaffolds seeded with iECs promoted the survival of iECs for up to 14 days (Figure 3), the engineered myocardial tissues derived from aligned scaffolds preferentially guided the formation of capillaries along the direction of the microfibers (Figure 4); and (3) in a myocardial injury model, the engineered myocardial tissues composed of randomly oriented scaffolds seeded with iCMs promoted a higher arteriole density, compared to those composed of aligned scaffolds (Figure 6)
Summary
Cardiovascular disease is the leading cause of death in the US, with over 16 million people suffering from coronary heart disease and 0.7 million new myocardial infarcts per year (Benjamin et al, 2018). An important component of engineered tissues is the extracellular matrix (ECM), a scaffolding structure that provides signaling cues to cells through properties such as spatial patterning, stiffness, and cell binding domains. It is well-established that the myocardium has highly organized physiological structure and ordered cellular orientation. The cells transplanted into the myocardium by mere injection are disarrayed in organization do not resemble the physiological orientation of native cardiac tissue. To better reflect native cellular organization, parallel-aligned (anisotropic) scaffolds have been capable of providing provide spatial guidance cues that direct cellular rearrangement. Among the various spatial patterning techniques, electrospinning is amenable to the fabrication of three-dimensional scaffolds over large areas with controllable nano-to-micro fibrous structure
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