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Theranostics 2019; 9(8):2143-2157. doi:10.7150/thno.29552 This issue Cite

Research Paper

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

Zichen Qian¹, Dhavan Sharma¹, Wenkai Jia¹, Daniel Radke¹, Timothy Kamp², Feng Zhao^1✉

1. Department of Biomedical Engineering, Michigan Technological University, Houghton, MI 49931, USA;
2. Stem Cell and Regenerative Medicine Center, University of Wisconsin, Madison, WI 53705, USA.

✉ Corresponding author: Feng Zhao, Department of Biomedical Engineering, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, U.S. Tel: 906-487-2852 Fax: 906-487-1717 Email: fengzhaoedu

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.

Keywords: Extracellular matrix nanofibers, prevascularization, vascular density, vascular maturation, vascular orientation

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