Genetic lineage tracing defines myofibroblast origin and function in the injured heart

Onur Kanisicak, Hadi Khalil, Malina J. Ivey, Jason Karch, Bryan D. Maliken, Robert N. Correll, Matthew J. Brody, Suh-Chin J. Lin, Bruce J. Aronow, Michelle D. Tallquist and Jeffery D. Molkentin ()
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Onur Kanisicak: Cincinnati Children's Hospital Medical Center
Hadi Khalil: Cincinnati Children's Hospital Medical Center
Malina J. Ivey: Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii
Jason Karch: Cincinnati Children's Hospital Medical Center
Bryan D. Maliken: Cincinnati Children's Hospital Medical Center
Robert N. Correll: Cincinnati Children's Hospital Medical Center
Matthew J. Brody: Cincinnati Children's Hospital Medical Center
Suh-Chin J. Lin: Cincinnati Children's Hospital Medical Center
Bruce J. Aronow: Cincinnati Children's Hospital Medical Center
Michelle D. Tallquist: Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii
Jeffery D. Molkentin: Cincinnati Children's Hospital Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction (MI) and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell type in terms of their origins and functional effects in vivo. Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen-inducible Cre for cellular lineage-tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Lineage tracing with four additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after MI. Periostin-traced myofibroblasts also revert back to a less-activated state upon injury resolution. Our results define the myofibroblast as a periostin-expressing cell type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts.

Date: 2016
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DOI: 10.1038/ncomms12260

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