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Tissue Eng Part A. 2016 Apr;22(7-8):633-44. doi: 10.1089/ten.TEA.2015.0482. Epub 2016 Mar 31.

Stromal Cells in Dense Collagen Promote Cardiomyocyte and Microvascular Patterning in Engineered Human Heart Tissue.

Roberts MA1,2,3, Tran D1, Coulombe KL2,3,4, Razumova M1,2,3, Regnier M1,2,3, Murry CE1,2,3,4,5, Zheng Y1,2,3.

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1 Department of Bioengineering, University of Washington , Seattle, Washington.
2 Center for Cardiovascular Biology, University of Washington , Seattle, Washington.
3 Institute for Stem Cell and Regenerative Medicine, University of Washington , Seattle, Washington.
4 Department of Pathology, University of Washington , Seattle, Washington.
5 Department of Medicine/Cardiology, University of Washington , Seattle, Washington.


Cardiac tissue engineering is a strategy to replace damaged contractile tissue and model cardiac diseases to discover therapies. Current cardiac and vascular engineering approaches independently create aligned contractile tissue or perfusable vasculature, but a combined vascularized cardiac tissue remains to be achieved. Here, we sought to incorporate a patterned microvasculature into engineered heart tissue, which balances the competing demands from cardiomyocytes to contract the matrix versus the vascular lumens that need structural support. Low-density collagen hydrogels (1.25 mg/mL) permit human embryonic stem cell-derived cardiomyocytes (hESC-CMs) to form a dense contractile tissue but cannot support a patterned microvasculature. Conversely, high collagen concentrations (density ≥6 mg/mL) support a patterned microvasculature, but the hESC-CMs lack cell-cell contact, limiting their electrical communication, structural maturation, and tissue-level contractile function. When cocultured with matrix remodeling stromal cells, however, hESC-CMs structurally mature and form anisotropic constructs in high-density collagen. Remodeling requires the stromal cells to be in proximity with hESC-CMs. In addition, cocultured cardiac constructs in dense collagen generate measurable active contractions (on the order of 0.1 mN/mm(2)) and can be paced up to 2 Hz. Patterned microvascular networks in these high-density cocultured cardiac constructs remain patent through 2 weeks of culture, and hESC-CMs show electrical synchronization. The ability to maintain microstructural control within engineered heart tissue enables generation of more complex features, such as cellular alignment and a vasculature. Successful incorporation of these features paves the way for the use of large scale engineered tissues for myocardial regeneration and cardiac disease modeling.

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