TY - JOUR
T1 - Transition of Macrophages to Fibroblast-Like Cells in Healing Myocardial Infarction
AU - Haider, Nezam
AU - Boscá, Lisardo
AU - Zandbergen, H. Reinier
AU - Kovacic, Jason C.
AU - Narula, Navneet
AU - González-Ramos, Silvia
AU - Fernandez-Velasco, María
AU - Agrawal, Sudhanshu
AU - Paz-García, Marta
AU - Gupta, Sudhir
AU - DeLeon-Pennell, Kristine
AU - Fuster, Valentin
AU - Ibañez, Borja
AU - Narula, Jagat
PY - 2019/12/24
Y1 - 2019/12/24
N2 - Background: Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content. Objectives: This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis. Methods: Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre/+);ROSA26(EYFP/+) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI. Results: Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3+Col1A1+ cells in the heart after MI. Conclusions: The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.
AB - Background: Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content. Objectives: This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis. Methods: Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre/+);ROSA26(EYFP/+) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI. Results: Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3+Col1A1+ cells in the heart after MI. Conclusions: The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.
KW - cardiac fibroblast
KW - fibroblast markers
KW - infiltration
KW - macrophage/fibroblast-like transition
KW - myeloid tracers
KW - myocardial infarction
UR - http://www.scopus.com/inward/record.url?scp=85076060607&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85076060607&origin=inward
U2 - https://doi.org/10.1016/j.jacc.2019.10.036
DO - https://doi.org/10.1016/j.jacc.2019.10.036
M3 - Article
C2 - 31856969
SN - 0735-1097
VL - 74
SP - 3124
EP - 3135
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 25
ER -