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Review
. 2003 Dec;112(12):1776-84.
doi: 10.1172/JCI20530.

V体育官网 - Epithelial-mesenchymal transition and its implications for fibrosis

Raghu Kalluri  1 , Eric G Neilson
Affiliations
Review

"V体育安卓版" Epithelial-mesenchymal transition and its implications for fibrosis

Raghu Kalluri et al. J Clin Invest. 2003 Dec.

"V体育官网" Abstract

Epithelial to mesenchymal transition (EMT) is a central mechanism for diversifying the cells found in complex tissues. This dynamic process helps organize the formation of the body plan, and while EMT is well studied in the context of embryonic development, it also plays a role in the genesis of fibroblasts during organ fibrosis in adult tissues. Emerging evidence from studies of renal fibrosis suggests that more than a third of all disease-related fibroblasts originate from tubular epithelia at the site of injury. This review highlights recent advances in the process of EMT signaling in health and disease and how it may be attenuated or reversed by selective cytokines and growth factors VSports手机版. .

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Figures

Figure 1
Figure 1
Primitive epithelia (epiblasts) form tropoblastic germ layers through EMT. The primary mesenchyme that migrates after EMT is reinduced to secondary epithelium by mesenchymal-epithelial transition. Secondary epithelia differentiate to form new epithelial tissues and undergo a second round of EMT to form the cells of connective tissue, including astrocytes, adipocytes chondrocytes, osteoblasts, muscle cells, and fibroblasts. Mature secondary epithelia that form epithelial organs can also transform into primary tumors that later undergo EMT to metastasize. These processes are regulated by morphogenic cues and a variety of transcription factors, and are potentially plastic in their adaptation to new biologic circumstances.
Figure 2
Figure 2
Epithelial plasticity can lead to classical EMT (loss of cell-cell and cell-substratum attachments, new actin rearrangements, and gain of mobility) or reversible scatter, which looks like EMT but is not enduring and can revert. These events are regulated by ligand-inducible intrinsic kinase receptors on the cell surface, which modulate small GTPases, Smads, PI3Ks, MAP kinases, and the availability of β-catenin to coactivate LEF in the nucleus. Free levels of b-catenin are regulated by E-cadherin or APC/β-catenin/Axin complexes, the latter of which shuttle b-catenin between ubiquination or utilization in adherens junctions. Activation of nuclear transcription provides new transcriptional regulators (Snail, SIP1, Ets, and FTS-BP/CarG box binding factor) of the EMT proteome. The EMT proteome comprises proteins listed in Table 1. The variability of receptors, kinases, and the emergence of combined preferences for signaling pathways determine the plasticity unique to each epithelium.
Figure 3
Figure 3
Origin of fibroblasts during kidney fibrosis. (a) Fibrotic kidney which displays accumulation of numerous fibroblasts (blue arrow), damaged kidney tubules (yellow arrow), and blood vessels (green arrow). (b) Normal kidney with proper tubular structures and very few fibroblasts. (c) Schematic illustration of three possible mechanisms via which fibroblasts can originate during kidney injury. Recent experiments suggest that approximately 14–15% of fibroblasts are from bone marrow, 36% can arise via local EMT involving tubular epithelial cells under inflammatory stress, and the rest are likely contributed by proliferation of fibroblasts from all sources. (d) Systemic treatment of mice with renal fibrosis using recombinant human BMP-7 results in reversal of renal disease due to severe decrease in EMT-derived fibroblasts and potentially bone marrow–derived fibroblasts. Such events likely have a cascade of beneficial effects that decreasing the overall number of fibroblasts in the kidney, and attenuating fibrosis.
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