Epithelial-mesenchymal transition and its implications for fibrosis.
Journal: 2004/January - Journal of Clinical Investigation
ISSN: 0021-9738
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.
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J Clin Invest 112(12): 1776-1784

Epithelial-mesenchymal transition and its implications for fibrosis

Center for Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA Departments of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Address correspondence to: Raghu Kalluri, Center for Matrix Biology, Beth Israel Deaconess Medical Center, 330 Brookline Ave. (DANA 514), Boston, Massachusetts 02215, USA. Phone: (617) 667-0455; Fax: (617) 975-5663; E-mail: ude.dravraH.CMDIB@irullaKr.
Address correspondence to: Raghu Kalluri, Center for Matrix Biology, Beth Israel Deaconess Medical Center, 330 Brookline Ave. (DANA 514), Boston, Massachusetts 02215, USA. Phone: (617) 667-0455; Fax: (617) 975-5663; E-mail: ude.dravraH.CMDIB@irullaKr.

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.

Abstract

For one hundred and forty-five years, biologists have known that cells come from cells (1). This concept is so fundamental today that we accept it implicitly; cells either divide asymmetrically to preserve stem cell progenitors, partition into sister cells, differentiate along fate pathways, or undergo oncogenesis following the formation of normal tissues. Specification and diversification of cell lineages are initiated by genetic programs under the control of morphogenic cues (24). These lineages evolve in a hierarchical manner conforming to developmental boundaries and oscillating biological clocks until reaching terminal differentiation (5). Epithelia from metazoans are emblematic of this process, and at maturity cover outer surfaces (6, 7) or line hollow cavities formed by tubular structures in complex tissues (810). Since epithelia typically serve specialized functions (1113), it is assumed that a state of terminal differentiation is necessary and protected once development is complete.

In recent years, however, this formidable notion has been challenged by observations that mature epithelia change their phenotype following morphogenic pressure from injured tissue. Since the phenomenon of epithelial plasticity was described before it had a firm biochemical basis (14, 15), one is confronted with a plethora of seemingly interchangeable vocabulary. Today, the terms “epithelial-mesenchymal transformation, interactions, or transition” are comingled inappropriately with the term “epithelial-mesenchymal transdifferentiation.” “Transformation” classically describes the oncogenic conversion of epithelia. Likewise, the induction of bone marrow stem cells to form somatic cells probably should be considered differentiation rather than transdifferentiation (16). Epithelial-mesenchymal interaction refers to proximate paracrine cross-talk between tissue epithelia and stromal fibroblasts and is completely different from the concept of epithelial-mesenchymal transition (EMT). EMT is a variant of transdifferentiation and a well-recognized mechanism for dispersing cells in vertebrate embryos (17), forming fibroblasts in injured tissues (18, 19), or initiating metastases in epithelial cancer (2023). We prefer the term “transition” to describe this conversion instead of “epithelial-mesenchymal transdifferentiation” because “transdifferentiation” classically refers to differentiated cells changing into other differentiated cells (24). Transdifferentiation has been observed in retinal pigmented cells that become lens epithelia (25, 26), in the conversion from white to brown adipocytes (27), endothelial cells that become vascular smooth muscle cells (28), lactotrophs that interconvert to somatotrophs in the pituitary (29), pancreatic acinar cells that become ductal epithelium (30, 31) or hepatocytes (32, 33), and hepatocytes that morph into pancreatic ductal cells (34). Although many investigators fail to make the distinction between transdifferentiation and transition, it may be time to do so. It is not yet clear whether the fibroblast transition of EMT is an expected middle phase of transdifferentiating epithelium or whether EMT producing fibroblasts is an arrested form of transdifferentiation (24). EMT of terminally differentiated epithelium, in its purest sense, produces a tissue fibroblast (19).

Developmental biologists have also known for decades that epiblasts undergo EMT to form primary mesenchyme in the creation of tripoblastic germ layers (17, 3537; Figure Figure1).1). In the mesoderm this is followed by mesenchymal-epithelial transitions to create secondary epithelium as part of somitogenesis (38, 39) and the further commitment and diversification of cells forming mesoendodermal structures (4042). Secondary epithelium in mature or adult tissues can also undergo EMT following epithelial stress, such as inflammation (18, 19) or wounding (17, 43) that leads to fibroblast production and fibrogenesis. Epithelia forming tumors also use EMT when carcinomas become metastatic (23, 44, 45).

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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.

We review here recent observations regarding the mechanism of EMT in culture and during fibrogenesis, especially associated with kidney disease. The problem of tissue fibrosis is that epithelial units are overtaken by scarification and lose their morphogenic cues, leaving involved organs to fail. While traditional studies of fibrosis have focused on the production of extracellular matrix, recent information now suggests that epithelia contribute to the problem by creating new fibroblasts. Experiments demonstrating the reversibility of organ fibrosis also highlight the need to consider cellular mechanisms of fibrogenesis and the basic biology that will, one hopes, contribute new molecules as useful therapeutics.

Acknowledgments

This work was supported by grants NIH/DK55001, and NIH/DK62987, The Espinosa Liver Fibrosis Fund, and research support from the Center for Matrix Biology at Beth Israel Deaconess Medical Center, all to R. Kalluri. E. Neilson is supported by NIH/DK46282 and Yamanouchi USA Foundation.

Acknowledgments

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Nonstandard abbreviations used: epithelial-mesenchymal transition (EMT); bone morphogenic protein 7 (BMP-7); integrin-linked kinase (ILK); lymphoid enhancer factor (LEF); glycogen synthase kinase (GSK); fibroblast-specific protein-1 (FSP1); α-smooth muscle actin (αSMA); tubular basement membrane (TBM); tissue plasminogen activator (tPA).

Footnotes

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