Developing Vasculature and Stroma in Engineered Human Myocardium

• Published in: Tissue engineering. Part A Vol. 17; no. 9-10; pp. 1219 - 1228
• Main Authors: Kreutziger, Kareen L., Muskheli, Veronica, Johnson, Pamela, Braun, Kathleen, Wight, Thomas N., Murry, Charles E.
• Format: Journal Article
• Language: English
• Published: United States Mary Ann Liebert, Inc 01.05.2011
• Subjects: Angiogenesis; Animals; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Cardiomyocytes; Cells, Cultured; Cellular biology; Collagen; Coronary Vessels; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - transplantation; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelial Cells - transplantation; Extracellular Matrix Proteins - biosynthesis; Heart muscle; Humans; Myocardium; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - transplantation; Original; Original Articles; Physiological aspects; Rats; Rats, Nude; Rats, Sprague-Dawley; Stem Cell Transplantation; Stem cells; Stromal Cells - cytology; Stromal Cells - metabolism; Stromal Cells - transplantation; Tissue engineering; Tissue Engineering - methods; Transplantation, Heterologous; United States
• ISSN: 1937-3341; 1937-335X
• DOI: 10.1089/ten.tea.2010.0557

We recently developed a scaffold-free patch of human myocardium with human embryonic stem cell-derived cardiomyocytes and showed that stromal and endothelial cells form vascular networks in vitro and improve cardiomyocyte engraftment. Here, we hypothesize that stromal cells regulate the angiogenic phenotype by modulating the extracellular matrix (ECM). Human marrow stromal cells (hMSCs) support the greatest degree of endothelial cell organization, at 1.3- to 2.4-fold higher than other stromal cells tested. Stromal cells produce abundant ECM components in patches, including fibrillar collagen, hyaluronan, and versican. We identified two clonal hMSC lines that supported endothelial networks poorly and robustly. Interestingly, the pro-angiogenic hMSCs express high levels of versican, a chondroitin sulfate proteglycan that modulates angiogenesis and wound healing, whereas poorly angiogenic hMSCs produce little versican. When transplanted onto uninjured athymic rat hearts, patches with proangiogenic hMSCs develop ∼50-fold more human vessels and form anastomoses with the host circulation, resulting in chimeric vessels containing erythrocytes. Thus, stromal cells play a key role in supporting vascularization of engineered human myocardium. Different stromal cell types vary widely in their proangiogenic ability, likely due in part to differences in ECM synthesis. Comparison of these cells defines an in vitro predictive platform for studying vascular development.