Origin, development, and differentiation of cardiac fibroblasts

Abstract

Cardiac fibroblasts are the most abundant cell in the mammalian heart. While they have been historically underappreciated in terms of their functional contributions to cardiac development and physiology, they and their activated form, myofibroblasts, are now known to play key roles in both development and disease through structural, paracrine, and electrical interactions with cardiomyocytes. The lack of specific markers for fibroblasts currently convolutes the study of this dynamic cell lineage, but advances in marker analysis and lineage mapping technologies are continuously being made. Understanding how to best utilize these tools, both individually and in combination, will help to elucidate the functional significance of fibroblast-cardiomyocyte interactions in vivo. Here we review what is currently known about the diverse roles played by cardiac fibroblasts and myofibroblasts throughout development and periods of injury with the intent of emphasizing the duality of their nature.

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

“…10 Importantly, it has been suggested that persistent myofibroblast presence in the injured heart, particularly in the remote non-infarcted myocardium, may be detrimental as it may lead to excessive fibrosis and contribute to heart failure. 1,24 It is therefore important to also evaluate changes in the remote myocardium. MMP-9 was decreased while TIMP-1 and collagen-3 were increased in the remote myocardium after MI, which is suggestive of increased interstitial fibrosis, 1,13 but UM206 treatment did not modulate this expression.…”

“…Almost all Fzd members have been identified in the healthy heart tissue but signaling in the adults is silent. 20,24 The Wnt/Fzd signaling pathway is activated in wound healing after MI. 21,27 In the present study, Wnt3a as well as Fzd receptor expression patterns were indeed different in remote vs infarcted myocardium.…”

Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction

“…Furthermore, since fibroblasts are heterogeneous cell populations, the characteristics and definition of fibroblast are complex (20), leading to difficulty in interpreting the results of previous studies that investigated the role of fibroblasts in cardiac remodeling. To circumvent this problem, we generated a mouse model in which ROCK2 was conditionally deleted in activated fibroblasts (ROCK2 Postn-/-), using the promoter of a matricellular protein, periostin, as a Cre-recombinase driver.…”

“…ROCK1 expression in activated fibroblasts, however, was comparable among all groups ( Figure 1C). The α-smooth muscle actin (α-SMA or Acta2) is known to be expressed in myofibroblasts, an activated form of fibroblasts (20). Interestingly, the increase in α-SMA expression following Ang II infusion was also suppressed in fibroblasts from ROCK2…”

Sca-1+Cardiac Progenitor Cells and Heart-Making: A Critical Synopsis

“…Fibroblasts are recognized mediators of the heart repair response to MI and to other pathological conditions. Several other functions have also been attributed to cardiac fibroblasts, including (i) production of mitogenic stimuli during heart development, (ii) secretion of growth factors, ECM and ECM-remodeling proteins throughout life, and (iii) electrical coupling with CMs [106]. Despite all this, it is still difficult to define a ''fibroblast'' mainly because the designation is given to a heterogeneous population [107] with a largely undefined molecular signature.…”