Abstract
Aging has been associated with adverse fibrosis. Here we formulate a new hypothesis and present new evidence that unresponsiveness of mesenchymal stem cells (MSC) and fibroblasts to transforming growth factor beta (TGF-β), due to reduced expression of TGF-β receptor I (TβRI), provides a foundation for cardiac fibrosis in the aging heart via two mechanisms. 1) TGF-β promotes expression of Nanog, a transcription factor that retains MSC in a primitive state. In MSC derived from the aging heart, Nanog expression is reduced and therefore MSC gradually differentiate and the number of mesenchymal fibroblasts expressing collagen increases. 2) As TGF-β signaling pathway components negatively regulate transcription of monocyte chemoattractant protein-1 (MCP-1), a reduced expression of TβRI prevents aging mesenchymal cells from shutting down their own MCP-1 expression. Elevated MCP-1 levels that originated from MSC attract transendothelial migration of mononuclear leukocytes from blood to the tissue. MCP-1 expressed by mesenchymal fibroblasts promotes further migration of monocytes and T lymphocytes away from the endothelial barrier and supports the monocyte transition into macrophages and finally into myeloid fibroblasts. Both myeloid and mesenchymal fibroblasts contribute to fibrosis in the aging heart via collagen synthesis. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium ".
Highlights
Secretion of extracellular matrix (ECM) proteins can be both adaptive and deleterious
Our studies demonstrated a major role for the age dependent increase in myeloid fibroblasts in cardiac fibrosis of the aging mouse, which was likewise accompanied by increases in MCP-1 as well as myeloid fibroblasts [5]
We present here a new concept of biological cross-talk between fibroblasts of myeloid and mesenchymal origin that supports the development of chronic fibrosis in the aging uninjured heart
Summary
Secretion of extracellular matrix (ECM) proteins can be both adaptive and deleterious. Fibroblasts of myeloid origin are spindle-shaped and smaller than structural (mesenchymal) fibroblasts; they express collagen type I and alpha-smooth muscle actin (α-SMA), and are highly proliferative [7] The presence of these cells in the heart relies on expression of MCP-1 since genetic deletion of MCP-1 [17, 18] or its receptor [19] prevents development of cardiac fibrosis. We have examined the mechanism by which resistance to TGF-β might influence the aberrant function of MSC in the aging heart Multipotency of these stem cells is maintained mostly by Nanog [40], a transcription factor that is associated with various proteins in repression complexes, which controls other genes’ transcription and prevents differentiation [41].
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