Cell therapy for renal regeneration--time for some joined-up thinking?

How the kidney copes with the task of regenerating its parenchymal cells in baseline conditions, or after damage, is relatively poorly understood—particularly in comparison with the gastrointestinal tract, skin, hair follicle and cornea. There are, however, recent reports that the ‘rescue’ of tubular epithelium in models of hereditary tyrosinaemia 1 [1] and of podocytes in mice that model Alport syndrome [2,3] utilizes cells derived from experimentally grafted bone marrow. As this procedure is relatively simple, it may be that some will consider trying it in humans, but the mechanisms responsible are complex and poorly understood, and there are precious few reproducible results in rodents. It may be that cell therapies can eventually be developed, but our thinking about these approaches needs to be joined up, especially if the rescue relies upon cells joining together imperfectly. Understanding the basics of stem cell biology may provide the key to new treatments for renal damage— as it has for the cornea and for the skin. For example, effective new treatments are possible for individuals with chemical burns to the cornea by isolating from the limbus of the contralateral eye a small number of stem or ‘master’ cells, from which the differentiated cells of the cornea derive, followed by propagation in vitro and then re-seeding [4]. There are strategies also for reducing the severity of forms of epidermolysis bullosa by targeting skin stem cells to achieve long-term expression of therapeutic gene constructs [5]. So what about renal stem cells? Most researchers agree that the kidney should likely possess stem cells responsible for the generation of many of the great variety of differentiated cells that are present in the adult kidney [6], but evidence for functional renal stem cells within adult mammals remains elusive, and their regenerative ability is incomplete, restricted mostly to replenishing some tubular epithelium. In contrast, fish such as the skate [7] and even the common goldfish [8] can generate entire new nephrons in response to damage. The search for renal stem cells has led some to identify them tentatively as cells within the renal papilla that can retain a DNA label for several months, but these cells are likely to be not all stem cells, because many divided and lost their label when challenged by ischaemic injury [9]. Epithelial progenitors that exhibit some properties of stem cells have been cultured in vitro from tubules of rabbit [10] and those from rat contribute to tubular regeneration after ischaemia/reperfusion injury [11]; such cells from human kidney have been trialled in a type of renal-assist device [12]. A non-haematopoietic population of CD133þ cells has been isolated from human kidney, cloned in vitro and found able to contribute to tubular regeneration in severe combined immune deficiency (SCID) mice [13]. In addition, cells with attributes of mesenchymal stem cells (including differentiation into fat and bone) have been cultured from glomeruli and whole kidneys of mice [14] although their ability to generate epithelial cell types was not explored. A possible explanation for adult mammalian kidneys being unable to generate new nephrons is that the necessary stem cell population migrates away to the bone marrow (BM) along with haematopoiesis, whereas species that can make new nephrons host haematopoietic stem cells in their renal interstitium [15]. This hypothesis is supported in part by the presence in tubules of appropriately differentiated epithelial cells that are of extra-renal origin, e.g. the epithelial nucleus bears an unexpected Y-chromosome in either a male recipient of a female renal allograft, or in a female recipient of a male bone marrow graft [16]. Laser capture microdissection and analysis of a neutral genetic marker indicated that renal epithelium can be derived from extra-renal precursors in 88% of graft recipients [17]. So, perhaps, these studies allow us to detect a natural process that regenerates tubules (imperfectly) that is invisible unless a graft-derived marker is available. Correspondence and offprint requests to: Prof. Richard Poulsom, DSc, FRCPath, Histopathology Unit, Cancer Research UK – London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK. Email: richard.poulsom@cancer.org.uk Nephrol Dial Transplant (2006) 21: 3349–3353