title: RNA-Mediated Reprogramming of Primary Adult Human Dermal Fibroblasts into c-kit(+) Cardiac Progenitor Cells.
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.
authors.affiliation: Department of Surgery, Duke University Medical Center , Durham, North Carolina.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Pratico
authors.affiliation: Department of Surgery, Duke University Medical Center , Durham, North Carolina.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Feger
authors.affiliation: Department of Surgery, Duke University Medical Center , Durham, North Carolina.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Watson
authors.affiliation: Department of Surgery, Duke University Medical Center , Durham, North Carolina.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Sullenger
authors.affiliation: Department of Surgery, Duke University Medical Center , Durham, North Carolina.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Bowles
authors.affiliation: Department of Surgery, Duke University Medical Center , Durham, North Carolina.
authors.forename: Carmelo A
authors.initials: CA
authors.lastname: Milano
authors.affiliation: Department of Surgery, Duke University Medical Center , Durham, North Carolina.
authors.forename: Smita K
authors.initials: SK
authors.lastname: Nair
mesh_terms: D000185:Actinin / Q000235:genetics / Q000378:metabolism; D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D002460:Cell Line; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020107:Troponin T / Q000235:genetics / Q000378:metabolism
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C095552:NKX2-5 protein, human; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D014157:Transcription Factors; D020107:Troponin T; C063843:insulin gene enhancer binding protein Isl-1; D000185:Actinin; D019009:Proto-Oncogene Proteins c-kit; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases