Epithelial organs such as the intestine and skin have a relatively high rate of cell loss and thus require a reservoir of stem cells capable of both replacing the lost epithelia and maintaining the reservoir. Whether the kidney has such a stem cell niche has been a subject of great interest; the majority of data suggest that replacement of renal epithelial cells occurs via dedifferentiation and proliferation of existing tubular cells, while some studies demonstrate the presence of potential tubular stem cells in the renal interstitium. However, recent reports have suggested that the bone marrow may also be a source of stem cells for tubule turnover and/or repair. In this issue of the JCI, 2 groups explore the role of endogenous cells versus bone marrow–derived cells in mediating tubule repair. Duffield and colleagues demonstrate that bone marrow does contain cells capable of protecting the kidney from ischemic injury, but found that these cells do not act by direct incorporation into the repaired tubular segments. In contrast, Lin and coworkers found that some bone marrow–derived cells do appear to incorporate into the injured tubule as epithelial cells (see the related article beginning on page 1756). Importantly, both groups conclude that the majority of tubule repair occurs via proliferation of endogenous renal cells rather than incorporation of bone marrow–derived cells.
Diane Krause, Lloyd G. Cantley
Submitter: Michael Mengel | email@example.com
Institute for Pathology, Medizinische Hochschule Hannover-Germany
Published July 18, 2005
In a recent editorial Diane Krause and Lloyd Cantley (1) commented on two studies (2, 3) published in JCI. In these papers two groups showed elegantly in mouse models that bone marrow derived progenitor cell contribute only in a minor fashion, if at all, to tubular epithelial cell regeneration after ischemic renal failure. These findings could have been expected from what has been already demonstrated in human kidney transplants (4). More than 80% of all investigated renal allografts exhibited chimeric, recipient derived cells in their tubuli. By combining laser-microdissection with DNA fingerprinting tubular epithelial chimerism could be demonstrated as soon as 8 days after transplantation and persisted in biopsies taken up to 8 years after transplantation. In the investigated biopsies (n=72) a maximum of 6.6% of tubular cells were replaced by recipient derived cells (average 4.2%). All transplants suffered from acute ischemic tubular damage which was at least partly caused by the cold ischemia period between harvest and revascularisation of the organ (shorter in living-related donation, longer in cadaver allografts). In addition during the early phase after transplantation immunological (rejection) and non-immunological (drug toxicity) pathomechanisms additionally damaged the tubular epithelial cells. With regard to the functional outcome of the allograft no positive or protective effect was associated with the presence or quantity of chimerism independently of the initial cause of tubular injury. Because several groups including the one of Krause et al. (5, 6) were able to show that the most probable source of the recipient derived chimerism in the setting of organ transplantation is the bone marrow, we concluded from the published data that recipient- derived, i.e. bone marrow-derived progenitor cells contribute only in low percentages to tubular regeneration of renal allografts and that tubular epithelial cell renewal is accomplished predominantly by local allograft derived cells. Accordingly, all epithelial tumours originating in renal allografts studied so far were donor- and not recipient-derived (7).
Michael Mengel, MD
Danny Jonigk, MD
Hans Kreipe, MD
Institute for Pathology
Medizinische Hochschule Hannover, Germany
References 1.Krause, D., and Cantley, L.G. 2005. Bone marrow plasticity revisited: protection or differentiation in the kidney tubule? J. Clin. Invest. 115:1705-1708.
2.Lin, F., Moran, A., and Igarashi, P. 2005. Intrarenal cells, not bone marrow-derived cells, are the major source for regeneration in postischemic kidney. J. Clin. Invest. 115:1756-1764.
3.Duffield, J.S., Park, K.M., Hsiao, L.-L., Kelley, V.R., Scadden, D.T., Ichimura, T., and Bonventre, J.V. 2005. Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J. Clin. Invest. 115:1743-1755.
4.Mengel, M., Jonigk, D., Marwedel, M., Kleeberger, W., Bredt, M., Bock, O., Lehmann, U., Gwinner, W., Haller, H., and Kreipe, H. 2004. Tubular chimerism occurs regularly in renal allografts and is not correlated to outcome. J Am Soc Nephrol 15:978-986.
5.Krause, D.S., Theise, N.D., Collector, M.I., Henegariu, O., Hwang, S., Gardner, R., Neutzel, S., and Sharkis, S.J. 2001. Multi-organ, multi- lineage engraftment by a single bone marrow-derived stem cell. Cell 105:369-377.
6.Poulsom, R., Forbes, S.J., Hodivala-Dilke, K., Ryan, E., Wyles, S., Navaratnarasah, S., Jeffery, R., Hunt, T., Alison, M., Cook, T., et al. 2001. Bone marrow contributes to renal parenchymal turnover and regeneration. J Pathol 195:229-235.
7.Mengel, M., Jonigk, D., Wilkens, L., Radermacher, J., von Wasielewski, R., Lehmann, U., Haller, H., Mihatsch, M., and Kreipe, H. 2004. Chimerism of Metanephric Adenoma but Not of Carcinoma in Kidney Transplants. Am J Pathol 165:2079-2085.