Editors' ChoiceRegenerative Medicine

A homestay for your heart

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Science Translational Medicine  20 Dec 2017:
Vol. 9, Issue 421, eaar4437
DOI: 10.1126/scitranslmed.aar4437

Abstract

Heart-injectable hydrogels containing microRNA promote cardiomyocyte proliferation in mice after myocardial infarction.

Traveling offers opportunities to see new sites and cultures, but finding the right base to explore from can be challenging. It’s not surprising then that homestays, Airbnb, and other private lodging have exploded in popularity. These options provide travelers with temporary homes in hard-to-reach sites and all the amenities to thrive. Now these same principles are being applied to rejuvenate cardiomyocytes after heart attack by creating intercardiac scaffolds installed with specific molecular amenities. Heart attacks occur when the heart’s blood supply is compromised, causing cardiomyocyte death and replacement with noncontractile fibrotic tissue. Because adult cardiomyocytes are largely nonproliferative, many strategies aim to deliver proliferative cues. However, getting these signals to the heart—and keeping them there—presents a tremendous challenge.

Wang and colleagues tackled this problem by designing hydrogels functionalized with cyclodextrin and adamantane, molecules that form host/guest complexes. These interactions stabilize resting gels but allow flow during injection because of temporary disassociation under syringe shear. Next, a microRNA (miRNA) known to induce cardiomyocyte proliferation was modified with cholesterol. This modification increased miRNA uptake and activity in neonatal cardiomyocytes and allowed miRNA incorporation in hydrogels through complexation with cyclodextrin. Upon injection into hearts of adult mice immediately after myocardial infarction (MI), fluorescent hydrogels were observed for up to 28 days, while expression of the microRNA targets decreased over this interval. Proliferation of cardiomyocytes also increased significantly compared with miRNA lacking gels or gels containing a nonspecific miRNA. Importantly, studies in fluorescent confetti mice revealed proliferation of new, clonally expanded cardiomyocytes after treatment of MI. Last, in wild-type mice treated with the hydrogels after MI, cardiac function tests (e.g., minimum and maximum blood volumes during contraction, infarct size) were significantly improved at four weeks. This improvement made many values indistinguishable from healthy mice without MI, whereas treatment with PBS or gels containing nonspecific miRNA had no effect.

In these studies, miRNA was released from hydrogels over about a week. Moving forward, understanding the kinetics and routes for tuning release in larger animals will be important to assess the clinical utility. Even so, providing cardiomyocytes the local cues they need to recharge after a heart attack might keep patients traveling for many years to come.

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