Abstract
Cardiovascular disease is the leading cause of death in the United States. Heart failure is a common, costly, and potentially fatal condition that is inadequately managed by pharmaceuticals. Cardiac repair therapies are promising alternative options. A potential cardiac repair therapy involves reprogramming human fibroblasts toward an induced cardiac progenitor-like state. We developed a clinically useful and safer reprogramming method by nonintegrative delivery of a cocktail of cardiac transcription factor-encoding mRNAs into autologous human dermal fibroblasts obtained from skin biopsies. Using this method, adult and neonatal dermal fibroblasts were reprogrammed into cardiac progenitor cells (CPCs) that expressed c-kit, Isl-1, and Nkx2.5. Furthermore, these reprogrammed CPCs differentiated into cardiomyocytes (CMs) in vitro as judged by increased expression of cardiac troponin T, α-sarcomeric actinin, RyR2, and SERCA2 and displayed enhanced caffeine-sensitive calcium release. The ability to reprogram patient-derived dermal fibroblasts into c-kit(+) CPCs and differentiate them into functional CMs provides clinicians with a potential new source of CPCs for cardiac repair from a renewable source and an alternative therapy in the treatment of heart failure.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actinin / genetics
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Actinin / metabolism
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Adult Stem Cells / cytology*
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Adult Stem Cells / metabolism
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Cell Line
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Cellular Reprogramming*
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Fibroblasts / cytology*
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Fibroblasts / metabolism
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Homeobox Protein Nkx-2.5
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / metabolism
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Humans
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LIM-Homeodomain Proteins / genetics*
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LIM-Homeodomain Proteins / metabolism
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Myocytes, Cardiac / cytology*
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Myocytes, Cardiac / metabolism
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism
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RNA, Messenger / genetics*
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Ryanodine Receptor Calcium Release Channel / genetics
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Ryanodine Receptor Calcium Release Channel / metabolism
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Troponin T / genetics
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Troponin T / metabolism
Substances
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Homeobox Protein Nkx-2.5
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Homeodomain Proteins
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LIM-Homeodomain Proteins
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NKX2-5 protein, human
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RNA, Messenger
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Ryanodine Receptor Calcium Release Channel
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Transcription Factors
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Troponin T
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insulin gene enhancer binding protein Isl-1
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Actinin
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Proto-Oncogene Proteins c-kit
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Sarcoplasmic Reticulum Calcium-Transporting ATPases