Transdifferentiation, a Potential Mechanism for Covering Vascular Grafts Grown Within Recipient’s Peritoneal Cavity With Endothelial-Like Cells
To the Editor:
We found the study by Campbell et al1 to be very interesting, and we believe that it deserves the full attention of the tissue engineering and vascular biology scientific communities. This study offers a promising way of growing self-compatible vascular replacements, at a time when the need for transplantable vessels increases constantly.
This approach was recently criticized in a Letter to the Editor published in Circulation Research, on the grounds that the cells covering the graft are not “true” endothelial cells. However, what Cebotari et al2 documented was “a typical inflammatory reaction to the foreign body, and the cells present on the silastic tube surface are in fact inflammatory cells and do not carry a typical endothelial function.” While replicating the major finding reported by Campbell et al,1 ie, the repopulation of implanted graft scaffolds in the given time period, Cebotari et al found that the supposed endothelial cells stained positively for CD31 and CD18, two “specific markers for leukocytes.” However, Cebotari et al also found that <5% of these cells were able to take up acetylated LDL.
In fact, Campbell et al1 did not claim that the intimal cells in their construct were “endothelial” but rather “mesothelial.” Nevertheless, these cells stained positively for von Willebrand factor and, as shown by Cebotari et al,2 for CD31 (PECAM-1) as well. It can therefore be argued that the cells stained positively for two typical markers of endothelial cells. The other marker, CD18, suggests that these intimal cells may indeed be derived from leukocytes, either as a direct result of blood perfusion or as part of the foreign body reaction, as suggested by both the Campbell and Cebotari groups.3 In any case, this mixed phenotype is indicative of a transdifferentiation process, which may be further stimulated4,5⇓ and exploited.
On the basis of our previously published work,4,6⇓ we find these data quite expected and not so damaging for the proposed application of the peritoneal-derived autografts, as the critics may believe. Significant evidence accumulated in recent years (see reviews7,8⇓) has argued that peripheral blood mononuclear cells might contribute to angiogenesis in adult animals. In addition, these cells may become endothelial-like by transdifferentiation. Actually, the very notion of an “endothelial” phenotype tends to become more comprehensive under the pressure of many documented examples of vascular mimicry.8,9⇓
Even if the intimal cells in the Campbell et al1 model were to never become fully endothelial, the vascular graft maintains its patency. This offers a very promising advantage for vascular surgery. Instead of dismissing this opportunity on a theoretical basis, we would rather encourage the intensification of research in this field toward two practical goals: (1) accelerate the acquisition of more endothelial traits by preexposing the grafts to appropriate angiogenic factors; (2) find the reason for, and then take control of, the reported collagen denaturation and calcification of these composite grafts.
- ↵Campbell JH, Efendy JL, Campbell GR. Novel vascular graft grown within recipient’s own peritoneal cavity. Circ Res. 1999; 85: 1173–1178.
- ↵Schmeisser A, Garlichs CD, Zhang H, Eskafi S, Graffy C, Ludwig J, Strasser RH, Daniel WG. Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovasc Res. 2001; 49: 671–680.
- ↵Moldovan NI, Goldschmidt-Clermont PJ, Parker-Thornburg J, Shapiro SD, Kolattukudy PE. Contribution of monocytes/macrophages to compensatory neovascularization: the drilling of metalloelastase-positive tunnels in ischemic myocardium. Circ Res. 2000; 87: 378–384.
- ↵Graf T. Differentiation plasticity of hematopoietic cells. Blood. 2002; 99: 3089–3101.