. 2019 Jun 24;4(3):449–467. doi: 10.1016/j.jacbts.2019.02.006

Table 2.

Cellular Origin of Fibroblasts in Myocardial Infarction

Reference #	Main Conclusions of the Study	Strategies Used to Study the Cellular Origin of Infarct Fibroblasts	Markers Used for Fibroblast Identification
(41)	Activated fibroblasts in infarcted and remodeling hearts are derived from Tcf21⁺ tissue-resident fibroblasts. Endothelial cells, myeloid cells, and smooth muscle cells do not significantly contribute to the activated fibroblast population.	Lineage-tracing analysis using Cre drivers to study the fate of resident cardiac fibroblasts (Tcf21^MCM), activated myofibroblasts (Postn^MCM), myeloid cells (LysM^Cre), endothelial cells (Cdh5^Cre), and vascular smooth muscle cells (Myh11^CreERT2).	Vimentin, PDGFRα, α-SMA, FSP1
(137)	Resident Tcf21⁺ cardiac fibroblasts become activated and proliferative within 2–4 days after nonreperfused infarction, then undergo myofibroblast conversion, secreting large amounts of ECM proteins. Finally in mature scars, fibroblasts show reduced expression of α-SMA and express tendon genes.	The fate of fibroblasts was studied using 3 different lineage-tracing models: Tcf21^MCM/+ (resident cardiac fibroblasts), Postn-^MCM (activated fibroblasts), and Acta2-^CreERT2 (activated myofibroblasts).	Vimentin, α-SMA
(206)	Epicardial-derived resident mesenchymal cells, not bone marrow cells, are the main source of fibroblasts in the infarcted heart.	WT1Cre mice were used for permanent genetic tracing of epicardium-derived cells. Mice reconstituted with RFP⁺ bone marrow cells were used to study bone marrow origin.	Collagen I, FSP1, DDR2, CD90, α-SMA
(207)	Following nonreperfused infarction, subsets of epicardium-derived cells differentiate into fibroblasts and smooth muscle cells.	Lineage tracing of epicardium derived cells by using inducible WT1^CreERT2 mice.	FSP1, procollagen I, collagen III, fibronectin, α-SMA
(42)	The vast majority of activated collagen-producing fibroblasts (∼96%) in nonreperfused infarcts are derived from epicardial cells. Hematopoietic, bone marrow lineages, and endothelial cells do not significantly contribute to the fibroblast population.	Lineage-tracing models to label epicardial cells (Wt1-Cre), endothelial cells (Tie2-Cre), hematopoietic cells (Vav-Cre). Transplantation with RFP⁺ bone marrow to study bone marrow origin.	Breeding with collagen 1α1-GFP reporter mice, α-SMA
(39)	Post-infarction, 35%–40% of α-SMA⁺ mesenchymal cells are derived from endothelial cells, possibly through endothelial-to-mesenchymal transition.	The endothelial cell-specific endothelial-SCL^CreERT mouse line was used to trace endothelial cells.	α-SMA expression, Snail, FSP1, vimentin and collagen I mRNA expression
(208)	24% of myofibroblasts in nonreperfused myocardial infarcts originate from bone marrow cells.	Transplantation with EGFP-tagged bone marrow, or bone marrow from proCol1α2 gene-driven luciferase or β-Gal reporter mice.	αSMA staining, β galactosidase activity in pro-Col1α2-driven chimeric mice
(40)	25% of vimentin⁺ fibroblasts and 57% of α-SMA⁺ myofibroblasts in nonreperfused infarcts are derived from bone marrow cells.	Transplantation with bone marrow from EGFP reporter mice to document bone marrow origin.	α-SMA, vimentin
(209)	Blood-derived cells contributed to the myofibroblast population. Treatment with G-CSF enhances recruitment of bone marrow–derived myofibroblasts.	Transplantation of GFP⁺ bone marrow.	Vimentin, α-SMA
(210)	Gli-1⁺ perivascular cells contribute to the myofibroblast population in the infarcted myocardium (approximately 60% of activated myofibroblasts are derived from Gli1⁺ cells).	Lineage tracing using Gli1^CreERT2 mice.	Collagen I, PDGFRα, α-SMA

ECM = extracellular matrix; EGFP = enhanced green fluorescent protein; G-CSF = granulocyte-colony stimulating factor; mRNA = messenger ribonucleic acid; other abbreviations as in Table 1.