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Sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischaemic injury

Nature Biomedical Engineering volume 1, pages 983–992 (2017)Cite this article

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Abstract

MicroRNA-based therapies that target cardiomyocyte proliferation have great potential for the treatment of myocardial infarction. In previous work, we showed that the miR-302/367 cluster regulates cardiomyocyte proliferation in the prenatal and postnatal heart. Here, we describe the development and application of an injectable hyaluronic acid hydrogel for the local and sustained delivery of miR-302 mimics to the heart. We show that the miR-302 mimics released in vitro promoted cardiomyocyte proliferation over one week, and that a single injection of the hydrogel in the mouse heart led to local and sustained cardiomyocyte proliferation for two weeks. After myocardial infarction, gel–miR-302 injection caused local clonal proliferation and increased cardiomyocyte numbers in the border zone of a Confetti mouse model. Gel–miR-302 further decreased cardiac end-diastolic (39%) and end-systolic (50%) volumes, and improved ejection fraction (32%) and fractional shortening (64%) four weeks after myocardial infarction and injection, compared with controls. Our findings suggest that biomaterial-based miRNA delivery systems can lead to improved outcomes via cardiac regeneration after myocardial infarction.

Heart disease is the leading cause of mortality across the world—in the United States and Europe, heart disease contributes to 600,000 and 4,000,000 deaths each year, respectively1,2. Myocardial infarctions (MIs), or heart attacks, are individually linked to at least 50% of deaths2. During MI, blood supply to cardiac tissue is compromised, initiating a tissue remodelling response. Central to this process is the permanent loss of contractile cardiomyocytes, the native muscle cells in the heart, and the replacement of healthy tissue with non-contractile, fibrotic tissue. Improved management of acute MI through medical and surgical intervention has allowed up to 95% of patients to survive hospitalization2; however, many of these patients will develop chronic heart failure, resulting in a 50% mortality rate at five years post-MI2.

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Acknowledgements

The authors thank C. Loebel for assistance with manuscript revisions, C. Chen, C. Venkataraman, A. Trubelja, S. Zaman, J. Gordon and F. Arisi for assistance with mouse surgeries and histology, J. Galarraga and C. Rodell for material contribution and helpful discussion, S. Schultz of the Penn Small Animal Imaging Facility for assistance with echocardiography, and the Penn Histology and Gene Expression Core. This work was made possible by financial support from the American Heart Association through an established investigator award (J.A.B.) and predoctoral fellowship (L.L.W.), and the National Institutes of Health (F30 HL134255, UO1 HL100405, U01 HL134745).

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  1. Leo L. Wang and Ying Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    Leo L. Wang & Jason A. Burdick

  2. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Ying Liu, Tao Wang, Minmin Lu, Christina A. Cavanaugh, Su Zhou & Edward E. Morrisey

  3. Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA

    Jennifer J. Chung, Ann C. Gaffey, Rahul Kanade & Pavan Atluri

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Contributions

L.L.W. and Y.L. contributed equally to this work. L.L.W., Y.L., E.E.M. and J.A.B. conceived the ideas and designed the experiments. L.L.W., Y.L., J.J.C., T.W., A.C.G., M.L., C.A.C., S.Z. and R.K. conducted the experiments and analysed the data. L.L.W., Y.L., P.A., E.E.M. and J.A.B. interpreted the data and wrote the manuscript. All authors have given approval to the final version of the manuscript.

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Correspondence to Edward E. Morrisey or Jason A. Burdick.

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Wang, L.L., Liu, Y., Chung, J.J. et al. Sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischaemic injury. Nat Biomed Eng 1, 983–992 (2017). https://doi.org/10.1038/s41551-017-0157-y

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