Delta-1 functionalized hydrogel promotes hESC-cardiomyocyte graft proliferation and maintains heart function post-injury
Current cell transplantation techniques are hindered by small graft size, requiring high cell doses to achieve therapeutic cardiac remuscularization. Enhancing the proliferation of transplanted human stem cell-derived cardiomyocytes (hESC-CMs) could address this, allowing an otherwise subtherapeutic cell dose to prevent disease progression after myocardial infarction. Here, we designed a hydrogel that activates Notch signaling through 3D presentation of the Notch ligand Delta-1 to use as an injectate for transplanting hESC-CMs into the infarcted rat myocardium. After four weeks, hESC-CM proliferation increased 2-fold and resulted in a 3-fold increase in graft size with the Delta-1 hydrogel compared to controls. To stringently test the effect of Notch-mediated graft expansion on long-term heart function, a normally subtherapeutic dose of hESC-CMs was implanted into the infarcted myocardium and cardiac function was evaluated by echocardiography. Transplantation of the Delta-1 hydrogel + hESC-CMs augmented heart function and was significantly higher at three months compared to controls. Graft size and hESC-CM proliferation were also increased at three months post-implantation. Collectively, these results demonstrate the therapeutic approach of a Delta-1 functionalized hydrogel to reduce the cell dose required to achieve functional benefit after myocardial infarction by enhancing hESC-CM graft size and proliferation.
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Kaytlyn A Gerbin (edit)
Katie A Mitzelfelt (add twitter)
Xuan Guan (add twitter)
Amy M Martinson (add twitter)
Charles E Murry (edit)
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Bioengineering

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09/14/19 01:02AM
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biorxivpreprint: Delta-1 functionalized hydrogel promotes hESC-cardiomyocyte graft proliferation and maintains heart function post-injury https://t.co/N4TwtC1wJ1 #bioRxiv
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