Editors' ChoiceCELL THERAPY

Placing skin cells on the assembly line for cardiac repair

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Science Translational Medicine  04 Sep 2019:
Vol. 11, Issue 508, eaaz0306
DOI: 10.1126/scitranslmed.aaz0306

Abstract

Human skin fibroblasts engineered to enhance β-catenin and Gata4 expression secrete vesicles that repair cardiac and skeletal muscle injuries in mice.

Transplanting cells or cell-secreted vesicles into the heart is an emerging therapeutic approach to repair cardiac injury. Vesicles are advantageous because they are more stable and less immunogenic than cells. Clinical trials are now under way to establish the safety and efficacy of delivering cardiosphere-derived cells (CDCs), a type of cardiac progenitor cell, or vesicles secreted by CDCs to injured hearts. However, in preclinical testing and clinical trials, these approaches have shown inconsistent therapeutic efficacy, due in part to batch-dependent differences in the potency of CDCs.

Ibrahim et al. sought to identify the underlying source of variability in CDC efficacy by comparing the transcriptomes of low-potency and high-potency CDCs. Their data revealed that the Wnt/β-catenin signaling pathway is more active in high-potency CDCs. Based on this information, the authors successfully boosted the efficacy of low-potency CDCs by treating them with a drug that increases β-catenin. The authors then investigated whether they could change a nontherapeutic cell into a therapeutic cell by manipulating β-catenin. To test this, they overexpressed β-catenin and Gata4, a cardiac transcription factor, in human skin fibroblasts. When transplanted into mouse hearts after a heart attack, unmodified fibroblasts had deleterious effects. In contrast, transplanting engineered fibroblasts improved survival and cardiac function. Similar results were seen in animals treated with the vesicles secreted by engineered fibroblasts. These vesicles also had therapeutic effects when transplanted into one of the leg muscles in a mouse model of Duchenne muscular dystrophy, indicating similar benefits for repairing skeletal muscle injury.

Collectively, this is an important advancement because CDCs are rare and must be harvested from adult hearts, which are limited in supply. In contrast, skin fibroblasts are abundant and easy to acquire from patients. Likely due to the overexpression of Gata4, the engineered fibroblasts were also resistant to senescence. Thus, these cells can be grown and expanded relatively easily, a feature that is desirable from a manufacturing perspective. However, the long-term safety and efficacy of these engineered fibroblasts and their vesicles must still be thoroughly tested in both preclinical models and clinical trials.

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