Correspondence

Peritoneal Dialysis and Epithelial-to-Mesenchymal Transition

N Engl J Med 2003; 348:2037-2039May 15, 2003

Article

To the Editor:

The article by Yáñez-Mó et al. (Jan. 30 issue)1 is timely, since there have been many recent reports showing similar epithelial-to-mesenchymal transitions in inflammatory and malignant processes.2 We would, however, like to address several aspects of the article that might be challenged.

Many key experiments were performed with the use of omental rather than peritoneal mesothelial cells, but whether these cells are interchangeable is questionable. The authors, in fact, demonstrate in Figures 2 and 3 of their article that the two cell types have different levels of expression of E-cadherin, an important epithelial marker.

The contribution of snail to peritoneal fibrosis is not clearly established. Figure 4 fails to show a “progressive increase” in snail expression with transdifferentiation, and snail expression was inconsistent in duplicate experiments, as shown in the figure.

Jennifer A. Stein, Ph.D.
New York University School of Medicine, New York, NY 10016
steinj05@med.nyu.edu

2 References

1
Yanez-Mo M, Lara-Pezzi E, Selgas R, et al. Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 2003;348:403-413
Full Text | Web of Science | Medline

2
Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002;3:155-166
CrossRef | Web of Science | Medline

To the Editor:

The conclusions of Yáñez-Mó et al. may be interpreted differently. It is known that an up-regulation of matrix metalloproteinases triggers epithelial-to-mesenchymal transition, by liberating transforming growth factor β (TGF-β), cleaving E-cadherin, and promoting malignant changes in the cellular phenotype.1 Peritoneal mesothelial cells were shown to synthesize matrix metalloproteinases and their specific inhibitors constitutively2; the secretion of matrix metalloproteinases (up-regulated by interleukin-1 and TGF-β)2,3 and the down-regulation of tissue inhibitors of metalloproteinases4 represent an alternative mechanism that may influence peritoneal-tissue repair, extracellular matrix remodeling, and fibrinogenesis.2 This process modulates both the normal maintenance of peritoneal-membrane integrity and the related changes that occur during continuous ambulatory peritoneal dialysis.3 Peritoneal mesothelial cells play an active part in the structural and functional alteration of the peritoneum during dialysis, but the involvement of matrix metalloproteinases in the pathophysiology of peritoneal fibrosis and ultrafiltration failure during continuous ambulatory peritoneal dialysis cannot be ruled out.

Ferdinando Mannello, Ph.D.
Università Carlo Bo, 61029 Urbino, Italy
f.mannello@uniurb.it

4 References

1
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2:161-174
CrossRef | Web of Science | Medline

2
Martin J, Yung S, Robson RL, Steadman R, Davies M. Production and regulation of matrix metalloproteinases and their inhibitors by human peritoneal mesothelial cells. Perit Dial Int 2000;20:524-533
Web of Science | Medline

3
Ma C, Tarnuzzer RW, Chegini N. Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in mesothelial cells and their regulation by transforming growth factor-beta1. Wound Repair Regen 1999;7:477-485
CrossRef | Web of Science | Medline

4
Mannello F, Gazzanelli G. Tissue inhibitors of metalloproteinases and programmed cell death: conundrums, controversies and potential implications. Apoptosis 2001;6:479-482
CrossRef | Web of Science | Medline

To the Editor:

Yáñez-Mó et al. do not mention the possible causal role of hepatocyte growth factor (HGF). This factor is produced by cells of mesenchymal origin and by mononuclear cells in tissues that have been injured by toxic, inflammatory, or mechanical insults; it works as an effector of tissue repair. The pleiotropic effects of HGF include loss of cell adhesion, cell migration, and transformation to a fibroblast-like phenotype.1-3 We showed that during peritonitis, HGF is released into the serum and peritoneal fluid of patients undergoing peritoneal dialysis. In addition, in cultured mesothelial cells, HGF from the serum and peritoneal fluid of patients with peritonitis caused detachment, transformation from epithelial to fibroblast-like shape, loss of cytokeratin, overexpression of vimentin, and collagen synthesis.4 The phenotypic changes observed by Yáñez-Mó et al. were related to peritonitis and reproduce those caused by HGF. Therefore, we would propose HGF, rather than TGF-β or inflammatory cytokines, as a likely prime inducer of mesenchymal transformation in mesothelial cells in patients undergoing peritoneal dialysis.

Teresa Rampino, M.D.
Istituto di Ricovero e Cura a Carattere, Scientifico Policlinico San Matteo, 27100 Pavia, Italy
t.rampino@smatteo.pv.it

Antonio Dal Canton, M.D.
University of Pavia, 27100 Pavia, Italy

4 References

1
Boros P, Miller CM. Hepatocyte growth factor: a multifunctional cytokine. Lancet 1995;345:293-295
CrossRef | Web of Science | Medline

2
Furlong RA, Takehara T, Taylor WG, Nakamura T, Rubin JS. Comparison of biological and immunochemical properties indicates that scatter factor and hepatocyte growth factor are indistinguishable. J Cell Sci 1991;100:173-177
Web of Science | Medline

3
Rampino T, Libetta C, De Simone W, et al. Hemodialysis stimulates hepatocyte growth factor release. Kidney Int 1998;53:1382-1388
CrossRef | Web of Science | Medline

4
Rampino T, Cancarini G, Gregorini M, et al. Hepatocyte growth factor/scatter factor released during peritonitis is active on mesothelial cells. Am J Pathol 2001;159:1275-1285
CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Stein raises the question of whether omental and peritoneal mesothelial cells are interchangeable. We have observed that, in terms of transdifferentiation, they behave in a similar manner. It is important to note that in Figures 2 and 3 of our article we compared the level of expression of E-cadherin in injured (effluent-derived) mesothelial cells with that in healthy (omentum-derived) mesothelial cells — not the level of expression in healthy mesothelial cells derived from omentum with that in healthy mesothelial cells derived from peritoneum.

We agree with Dr. Stein that the contribution of snail to peritoneal fibrosis has not yet been definitely established. However, we do think that there is a correlation between snail expression and mesothelial-cell transdifferentiation. In Figure 4A of our article, we show that omentum-derived mesothelial cells are negative for snail expression, whereas fibroblast-like cells, which represent the last stage of mesothelial transdifferentiation, are positive. The expression of snail is more variable in effluent-derived cobblestone-like or transitional mesothelial cells, but we have observed a clear increase in the percentage of samples that are positive for snail as the alterations in the mesothelium proceed. Whereas only a few samples of cobblestone-like preparations are positive for snail, more than 50 percent of the transitional cells are positive for this transcription factor. Because of space limitations, this issue was not clearly addressed in our article. It should be noted that the expression of snail is an early and transitory event in the transdifferentiation process (as shown in Fig. 4B and 4C of our article) and becomes constitutive only once the mesenchymal phenotype has been established.

We agree with Dr. Mannello and Drs. Rampino and Dal Canton that matrix metalloproteinases and HGF may have a role in the regulation of mesothelial-cell transdifferentiation and, ultimately, in peritoneal fibrosis and ultrafiltration failure. The epithelial-to-mesenchymal transition is a complex process that can be induced by various stimuli and is regulated by a wide variety of molecules.1,2 In our study, we used TGF-β plus interleukin-1 and wound healing to trigger mesothelial cell transdifferentiation in vitro, but we think that other stimuli might also be operative in vivo.

María Yáñez-Mó, Ph.D.
Enrique Lara-Pezzi, Ph.D.
Manuel López-Cabrera, Ph.D.
Hospital Universitario de la Princesa, 28006 Madrid, Spain
mlopez.hlpr@salud.madrid.org

2 References