Shah R Ali1, Sara Ranjbarvaziri1, Mahmood Talkhabi1, Peng Zhao1, Ali Subat1, Armin Hojjat1, Paniz Kamran1, Antonia M S Müller1, Katharina S Volz1, Zhaoyi Tang1, Kristy Red-Horse1, Reza Ardehali2. 1. From the Departments of Pathology and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (S.R.A.); Department of Internal Medicine, Division of Cardiology, and Broad Stem Cell Research Center, University of California Los Angeles School of Medicine (S.R., M.T., P.Z., A.S., A.H., P.K., Z.T., R.A.); and Division of Blood and Marrow Transplantation, Department of Medicine (A.M. S.M.) and Department of Biology (K.S.V., K.R.-H.), Stanford University, CA. 2. From the Departments of Pathology and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (S.R.A.); Department of Internal Medicine, Division of Cardiology, and Broad Stem Cell Research Center, University of California Los Angeles School of Medicine (S.R., M.T., P.Z., A.S., A.H., P.K., Z.T., R.A.); and Division of Blood and Marrow Transplantation, Department of Medicine (A.M. S.M.) and Department of Biology (K.S.V., K.R.-H.), Stanford University, CA. RArdehali@mednet.ucla.edu.
Abstract
RATIONALE: Fibrosis is mediated partly by extracellular matrix-depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. OBJECTIVE: We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. METHODS AND RESULTS: We showed that Thy1(+)CD45(-)CD31(-)CD11b(-)Ter119(-) cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar gene expression profiles. CONCLUSIONS: The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts on pressure overload could suggest that common signaling mechanisms stimulate their pathological response.
RATIONALE: Fibrosis is mediated partly by extracellular matrix-depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. OBJECTIVE: We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. METHODS AND RESULTS: We showed that Thy1(+)CD45(-)CD31(-)CD11b(-)Ter119(-) cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar gene expression profiles. CONCLUSIONS: The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts on pressure overload could suggest that common signaling mechanisms stimulate their pathological response.
Authors: Shuin Park; Sara Ranjbarvaziri; Fides D Lay; Peng Zhao; Mark J Miller; Jasmeet S Dhaliwal; Adriana Huertas-Vazquez; Xiuju Wu; Rong Qiao; Justin M Soffer; Christoph Rau; Yibin Wang; Hanna K A Mikkola; Aldons J Lusis; Reza Ardehali Journal: Circulation Date: 2018-09-18 Impact factor: 29.690
Authors: C M Kofron; T Y Kim; M E King; A Xie; F Feng; E Park; Z Qu; B-R Choi; U Mende Journal: Am J Physiol Heart Circ Physiol Date: 2017-07-14 Impact factor: 4.733