Engineering stem cell cardiac patch with microvascular features representative of native myocardium

Abstract

The natural myocardium is a highly aligned tissue with an oriented vasculature. Its characteristic cellular as well as nanoscale extracellular matrix (ECM) organization along with an oriented vascular network ensures appropriate blood supply and functional performance. Although significant efforts have been made to develop anisotropic cardiac structure, currently neither an ideal biomaterial nor an effective vascularization strategy to engineer oriented and high-density capillary-like microvessels has been achieved for clinical cardiovascular therapies. A naturally derived oriented ECM nanofibrous scaffold mimics the physiological structure and components of tissue ECM and guides neovascular network formation. The objective of this study was to create an oriented and dense microvessel network with physiological myocardial microvascular features. Methods: Highly aligned decellularized human dermal fibroblast sheets were used as ECM scaffold to regulate physiological alignment of microvascular networks by co-culturing human mesenchymal stem cells (hMSCs) and endothelial cells (ECs). The influence of topographical features on hMSC and EC interaction was investigated to understand underlying mechanisms of neovasculature formation. Results: Results demonstrate that the ECM topography can be translated to ECs via CD166 tracks and significantly improved hMSC-EC crosstalk and vascular network formation. The aligned ECM nanofibers enhanced structure, length, and density of microvascular networks compared to randomly organized nanofibrous ECM. Moreover, hMSC-EC co-culture promoted secretion of pro-angiogenic growth factors and matrix remodeling via metalloprotease-2 (MMP-2) activation, which resulted in highly dense vascular network formation with intercapillary distance (20 μm) similar to the native myocardium. Conclusion: HMSC-EC co-culture on the highly aligned ECM generates physiologically oriented and dense microvascular network, which holds great potential for cardiac tissue engineering.

miR-27a regulates vascular remodeling by targeting endothelial cells' apoptosis and interaction with vascular smooth muscle cells in aortic dissection

“…EC dysfunction within the walls of large arteries is an important contributor to inflammation, barrier dysfunction, blood clotting, hypertension and vascular structural changes 40-45. Various mechanisms induce EC injury and death, which may lead to the detachment of ECs from the vascular wall and thereby cause vascular remodeling 46. Jia et al reported that endothelial dysfunction plays a role in AD development by endoplasmic reticulum stress dependent microparticles derived from smooth muscle cells 47.…”

Bladder reconstruction using autologous smooth muscle cell sheets grafted on a pre-vascularized capsule

“…The field of tissue engineering has progressed rapidly, but poor vascularization remains a major obstacle in bioengineering cell-dense tissues, limiting the viable size of constructs due to hypoxia, nutrient insufficiency, and waste accumulation. Prior classical vascularization strategies focused on stimulating vascular ingrowth into tissue constructs, which can be achieved by incorporating growth factors or endothelial cells 26 - 28 . However, these so-called angiogenic approaches are inadequate because the average growth rate of newly developing micro-vessels is only ~5 μm/h 7 , 29 .…”

Advances in 3D bioprinting technology for cardiac tissue engineering and regeneration

“…With the continuous improvement of the production process and formulation, the preparation of the dECM has gradually developed from traditional methods such as lyophilized powder and acid digestion to today's higher fidelity methods such as ultrasonic homogenization, which allows its natural protein structure and function to be better retained [ 100 , 101 ]. More importantly, proteomic explorations of the physiological and pathological dECM of the cardiovascular system will help extract more functional factors such as the VEGF [ 102 ] and MMP2 [ 103 ], which offer critical support for the generation of a more standardized and opulent preparation of 3D-CTE bioink [ 104 , 105 ].…”