FIG 5.3 Cardiomyocyte and fibroblast architecture (A–B) Cardiomyocytes are shown in red (stained with troponin antibody) and fibroblasts in green (stained with periostin) Note the peripheral location of the much smaller fibroblasts to the cardiomyocytes Sections are derived from an adult mouse left ventricular wall (C) An electron micrograph showing the small size of the fibroblast (Fib) compared to a cardiomyocyte (CM), which is only partially shown (D) Activated myofibroblast surrounded by the collagen matrix Note the abnormal morphology of the surrounding cells Fibroblasts are highly motile, and the basal body and root of the fibroblast's flagella are shown FIG 5.4 Myofibroblast formation Both physical stressors and cytokine signaling can trigger the differentiation of fibroblasts into myofibroblasts that subsequently elaborate collagen and form additional extracellular matrix Although fibroblast to myofibroblast conversion plays a critical role in wound healing and tissue remodeling, aberrant or prolonged activity can lead to fibrosis and pathogenic scarring processes Defining characteristics of myofibroblasts include the formation of smooth muscle α-actin stress fibers that provide the structural network for generating sustained contractile force Myofibroblasts synthesize substantial amounts of extracellular matrix proteins including collagen The proto-myofibroblast state is somewhat ill-defined and may simply be a figment of semantics, but some investigators maintain that it is an intermediate stage of activation, characterized by increased synthesis of fibroblast-specific protein-1, Thy-1 (a glycosylphosphatidylinositol-anchored protein with a molecular weight of 25 to 37 kDa), periostin and fibroblast activating protein-α, all of which are synthesized at relatively high levels in the myofibroblasts TGF-β, Transforming growth factor-β (Modified from Matthijs Blankesteijn W Has the search for a marker of activated fibroblasts finally come to an end? J Mol Cell Cardiol 2015;88:120–123.) The diverse cellular origins ascribed to the fibroblast population underlies and reflects the difficulty in defining cell markers that are absolutely restricted to fibroblasts.35 It is now generally accepted that the majority of these cells arise from the proepicardial organ (see Fig 5.1), which subsequently serves as a source for the migratory cells that cover the developing heart and form the embryonic epicardial layer, and that contribute to the vascular endothelium.36–38 These epicardial cells support cardiomyocyte proliferation in the developing heart tube and provide the precursors for what will become fibroblasts and vascular smooth muscle cells Some of these cells undergo an epithelial-tomesenchymal transition, peel off from the epicardium and populate the atrial and ventricular walls, where, in the latter compartments, they are necessary for the formation of the compact myocardium.4 These cardiac fibroblasts continue to proliferate, essentially doubling in number during the postnatal period They form the underlying myocardial scaffold and actively signal to and with the other cellular populations, including the cardiomyocytes, to actively proliferate at the appropriate developmental times or in times of cardiac stress.39,40 Data defining the percentage of fibroblasts in the total cardiac cell population have varied widely with some investigators concluding that as many as 40% to 50% of the cells in the heart may be fibroblasts,2,35 although the majority of estimates place the percentages between 25% and 35%.2,19 Recent data from the mouse, using carefully defined, multiple markers and sophisticated lineage tracing techniques, have come up with surprisingly low percentages, with the fibroblasts comprising only approximately 20% of the nonmyocyte cells in the mouse heart or 12% to 15% of the total cells.20 These data have yet to be independently verified, but the investigators analyzed adult human cardiac tissue as well and those data mirrored the murine results Vascular Smooth Muscle Cells These cells make up the main supportive cells for the vessel walls and regulate overall vascular tone in the heart (and elsewhere) Smooth muscle cells derive from a number of different mesodermal derivatives and sources, including the splanchnic, lateral plate and the somatic or paraxial mesoderm.41 Because of the complicated origins of these cells, and their inherent plasticity, there are conflicting data as to whether there are unique subpopulations.42–45 Smooth muscle cells can differentiate and then dedifferentiate as the vascular wall forms and remodels under different conditions Embryonic smooth muscle proliferates rapidly and actively migrates as the nascent vasculature forms but cardiac vascularization is complex due to the multiple sources of the different cells that contribute to vascular development and the separate but related process of angiogenesis.5 Lineage tracing has shown that proepicardial cells (see Fig 5.1) give rise to the smooth muscle cells found in the coronary arteries and epicardium.46 A prenatal vascular plexus arises from the epicardium, which is composed of a continuous layer of epithelial cells, some of which undergo an ... Has the search for a marker of activated fibroblasts finally come to an end? J Mol Cell Cardiol 2015;88:120? ?123. ) The diverse cellular origins ascribed to the fibroblast population underlies and reflects the difficulty in defining cell markers that are absolutely restricted to