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bioRxiv · 10.1101/768226

Delta-1 functionalized hydrogel promotes hESC-cardiomyocyte graft proliferation and maintains heart function post-injury

Gerbin, K. A.·Mitzelfelt, K. A.·Guan, X.·Martinson, A. M.·Murry, C. E.
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Abstract

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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Gerbin, K. A., Mitzelfelt, K. A., Guan, X., Martinson, A. M., Murry, C. E.. 2019-09-14. Delta-1 functionalized hydrogel promotes hESC-cardiomyocyte graft proliferation and maintains heart function post-injury. https://doi.org/10.1101/768226

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