Abstract 421: Activated Cardiac Myofibroblasts Can Revert Back to Become Resident Fibroblasts Upon Injury Cessation

• Published in: Circulation research 2016-07, Vol.119 (suppl_1)
• Main Authors: Kanisicak, Onur, Karch, Jason, Khalil, Hadi, Maliken, Bryan, Molkentin, Jeffery D
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.119.suppl_1.421

Abstract only Resident cardiac fibroblasts (CFs) are potential therapeutic targets in treating heart failure given the prominent role that fibrosis plays in this disorder. CFs directly convert to myofibroblasts (MFs) with injury where they mediate both adaptive wound healing after acute myocardial infarction as well as long-standing fibrosis during chronic disease states. However, the fate of activated MFs after injury recovery or when an infarction scar is stabilized remains poorly understood, in part because the field has lacked a definitive strategy for identifying and tracing MFs and CFs in vivo. To address this issue we recently generated a novel mouse model that permits lineage tracing of all MFs in the heart after injury or stress stimulation, which we used to address the fate of MFs after injury resolution. MFs were lineage traced with a tamoxifen inducible periostin allele knockin of the MerCreMer cDNA (PostnMCM), with a Rosa26-eGFP dependent reporter. PostnMCM x R26-eGFP mice were transiently injured with the combined infusion of angiotensin II and phenylephrine (Ang/PE) for 2 weeks, during which time tamoxifen was also given to trace all newly formed MFs. Mice were then allowed to “rest” for 2 weeks or longer with no Ang/PE as the fibrotic response regressed, and the fate of the eGFP + cells was assessed. The data show that immediately after 2 weeks of Ang/PE infusion nearly all the eGFP+ periostin lineage-traced myofibroblasts were αSMA positive and have an activated myofibroblast gene expression profile. However, when the fibrotic response regressed weeks later, a number of periostin-lineage traced eGFP+ cells were still present in the heart and these cells showed a phenotypic and molecular reversion back to CFs with a loss of myofibroblast marker genes. These results suggest that CFs are very unique cell types that can differentiate to MFs then back again to resident CFs.