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Recent studies suggest that vascular cells and a vascular network may have regenerative effects on implanted cardiomyocytes (CM) and nearby heart tissue separate from perfusion of oxygen and nutrients. The goal of this study was to test whether vascular cells or a formed vascular network in a fibrin\u2010based hydrogel would alter the proliferation of human iPSC\u2010derived CM. First, vascular network formation in a slowly degrading PEGylated fibrin hydrogel was optimized by altering the cell ratio of human umbilical vein endothelial cells to human dermal fibroblasts, the inclusion of growth factors, and the total cell concentration. An endothelial to fibroblast ratio of 5:1 and a total cell concentration of 1.1\u2009\u00d7\u200910<jats:sup>6<\/jats:sup> cells\/mL without additional growth factors generated robust vascular networks while minimizing the number of cells required. Using this optimized system, human iPSC\u2010derived CM were cultured on hydrogels without vascular cells, hydrogels with unorganized encapsulated vascular cells, or hydrogels with encapsulated vascular cells organized into networks for 7\u2009days. CM proliferation and gene expression were assayed following 7\u2009days of culture on the hydrogels. The presence of vascular cells in the hydrogel, whether unorganized or in vascular networks, significantly increased CM proliferation compared to an acellular hydrogel. Hydrogels with unorganized vascular cells resulted in lower CM maturity evidenced by decreased expression of cardiac troponin t (TNNT2), myosin light chain 7, and phospholamban compared to hydrogels without vascular cells and hydrogels with vascular networks. Altogether, this study details a robust method of forming rudimentary vascular networks in a fibrin\u2010based hydrogel and shows that a hydrogel containing endothelial cells and fibroblasts can induce proliferation in adjacent CM, and these cells do not hinder CM gene expression when organized into a vascular network.<\/jats:p>","DOI":"10.1002\/jbm.a.37662","type":"journal-article","created":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T06:49:46Z","timestamp":1703832586000},"page":"625-634","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Vascularization of <scp>PEGylated<\/scp> fibrin hydrogels increases the proliferation of human <scp>iPSC<\/scp>\u2010cardiomyocytes"],"prefix":"10.1002","volume":"112","author":[{"given":"Ethan J.","family":"Vanderslice","sequence":"first","affiliation":[{"name":"Department of Bioengineering University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Staunton G. 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