Tubular regeneration and the role of bone marrow cells: 'stem cell therapy'--a panacea?

The kidney possesses an impressive regeneration capacity and is the most performant among all tissues in the body. Yet ischaemic injury to the kidney produces acute tubular necrosis and apoptosis followed by tubular regeneration and recovery of renal function. Although mitotic cells are present in the tubules of postischaemic kidneys, the origins of the proliferating cells were considered until recently as the result of this regeneration capacity of the kidney, whereby the surviving remaining tubular cells start proliferating and migrating along the denuded basement membrane. In both humans and mice, the proof-of-principle clinical observation has been obtained in support of the ability of cells emanating from the bone marrow (BM) to become renal epithelial cells. Several groups have reported the presence of Y-chromosome-positive renal tubular cells in kidneys of male recipients who received a renal transplant from a female donor, which suggests that cells from outside the kidney can populate the renal tubule (0.6–6.8% of the tubular cells) [1–3]. The lineage-negative (primitive stem cells) fraction of bone marrow contains multiple cell types, including rare subpopulations of haematopoietic stem cells and marrow stromal cells, alternatively referred to as mesenchymal stem cells (MSCs). Protection of the kidney against ischaemia/ reperfusion injury after injection of in vitro expanded skeletal muscle-derived stem cells, differentiated along the endothelial lineage (not after injection of nondifferentiated stem cells) was reported. After intrarenal injection, engraftment of the differentiated cells into the renal microvasculature that accompanied protected renal function after ischaemia, was documented [4]. In a cisplatin model of acute renal failure, injection of MSCs of bone marrow origin, but not injection of haematopoietic cells, protected syngeneic female mice against severe tubular injury and renal functional impairment. MSCs markedly accelerated tubular proliferation and partial repopulation of the tubule by Y-chromosome-containing cells [5]. Lin et al. [6] showed that haematopoietic stem cells contributed to the regeneration of renal tubular epithelial cells. In the kidneys of non-transgenic female recipients that had been subjected to unilateral ischaemia, these authors showed that still after 4 weeks b-galactosidase-expressing Y-chromosome-positive cells from transgenic male donors were detected. It was suggested that these findings are accounted for by ‘transdifferentiation’, i.e. phenotypic conversion of pluripotent somatic stem cells of one tissue type to another tissue type [2,3]. One cannot, however, exclude cell hybridization, i.e. the possibility that bone-marrow-derived cells adapted the phenotype of other cell lineages by ‘fusion’ [7,8]. Oliver and colleagues [9] demonstrated that the adult kidney contained numerous (resident) stem cells in the renal papilla, which proliferate and disappear from the papilla during the repair phase of ischaemia. In other words, the adult kidney possesses a ‘reservoir of kidney stem cells’. Three recent papers published almost simultaneously by three research teams, independently came to the conclusion that the majority of the cells that were dividing to repair the injured tubules comes from an endogenous cell population rather than from bone marrow-derived cells [10–12]. They clearly demonstrate that the majority of tubule repair does not occur via proliferation of bone marrow-derived cells. They even suggested that in vivo differentiation of BMC cells into renal tubular cells may not occur at all, or is at most a minor component of the repair process after ischaemic injury. In contrast, it seems to be that the paracrine effects of the incoming or resident stem cells caused downregulation of pro-inflammatory and upregulation of anti-inflammatory cytokines contributing substantially to the repair process. In the study by Tögel et al. [10], MSCs were isolated from rat femurs, and well characterized by isolation as adherent cells, their specificity being validated by their ability to differentiate into osteocytes and adipocytes. Correspondence and offprint requests to: Marc E. De Broe, M.D., PhD, Department of Nephrology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk (Antwerpen), Belgium. Email: [email protected]