from Leadership Medica n. 277/2009

Chronic Kidney Disease (CKD) is estimated to affect about 10% of the adult population in Western countries (1). It can progress towards End Stage Renal Disease (ESRD), which requires dialysis or transplantation.
The high morbidity and mortality of CKD has prompted research towards the possible use of stem cells to achieve tissue regeneration of injured kidney tissue. Stem cells are indeed able to self renew and to intervene in building/maintaining the structural and functional integrity of tissues, and might be used to set up strategies of regenerative medicine for CKD. The use of stem cells to set up cell-therapies of renal tissue regeneration has been impaired by our poor knowledge of the mechanisms of kidney repair (2).

A better knowledge of the regenerative properties of the kidney might indeed profoundly and positively affect our possibility of treatment of CKD. One of the main problems is the repair of glomerular injury. Indeed, most renal pathologies that ultimately lead to chronic renal failure originate within the glomerulus and it has now been established that a depletion of podocytes, the visceral epithelium of the capillary tuft, is central in initiation of glomerulosclerosis, which is the common final pathway of all glomerular diseases leading to ESRD (3). Indeed, the podocyte is a terminally differentiated cell, that cannot undergo proliferation and replace adjacent injured podocytes. However, glomerular disorders can undergo spontaneous regression and remission, suggesting the possible existence of a stem cell compartment in adult kidneys (4). Recently, we provided evidence for the existence of a population of renal progenitor cells characterized by the expression of the stem cell markers CD133 and CD24 in normal adult human kidney (2,5,6). These cells are localized at the urinary pole of the Bowman's capsule. The injection of CD133+CD24+ renal stem cells but not of CD133-CD24- renal cells into SCID mice that had acute renal failure resulted in the regeneration of tubular structures of different portions of the nephron (2,5). More importantly, treatment of acute renal failure with CD133+CD24+ renal stem cells significantly ameliorated the morphologic and functional kidney damage (5,6). More recently we demonstrated that CD133+CD24+ cells consist of a hierarchical population of progenitors that are arranged in a precise sequence within Bowman's capsule and exhibit heterogeneous potential for differentiation and regeneration (7). In this study, we provided the first evidence that CD133+CD24+ renal stem cells can regenerate podocytes and lay the foundations that podocyte injuries can be repaired in principle by a resident stem cell compartment (7). These findings in humans were also confirmed in a parallel study performed in rodents by Appel et al., who unequivocally demonstrated using an elegant model of genetic tagging of parietal epithelial cells in a triple-transgenic doxycycline-inducible mouse line, that podocytes are recruited from parietal epithelial cells, which proliferate and differentiate from the urinary to the vascular stalk generating novel podocytes (8). In addition, assessment of the regenerative properties of CD133+CD24+ renal stem cells in different in vivo models of CKD, has demonstrated that these cells can perspectively be used to repair glomerular damage (7).

Thus, several lines of evidence suggest that the kidney contains a "renopoietic system" (Figure below), and the urinary pole of the Bowman's capsule represents a stem cell niche, which is a specific site in adult tissues where stem cells reside (9).

In many cases, the excitement for the promising results of cell therapy of organ failure, has led to clinical trials before an adequate knowledge of stem cell biology could be achieved. Knowledge of the properties of CD133+CD24+ renal stem cells might help to set up cell therapies of CKD which should be effective and safe (2).

More importantly, understanding of how self-renewal and fate decision of CD133+CD24+ renal stem cells may be perturbed in pathological conditions will be of crucial importance for the explanation of the impaired regenerative capacity of the kidney in several renal disorders, and might help to unlock latent regenerative pathways in human kidney which would change medical practice in clinical nephrology.

Prof. Paola Romagnani
Associate Professor of Nephrology
Coordinator of the Specialization School in Nephrology
Member of the Scientific Board of the Centre of Excellence for Research, Transfer and High Education DENOTHE (De Novo Therapies), University of Florence, Italy

Bibliografia

1. Szczech LA, Lazar IL. Projecting the United States ESRD population: Issues regarding treatment of patients with ESRD. Kidney Int Suppl 2004; 90(suppl):S3-S7.
2. Wiggins RC. The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int. 2007 Jun;71(12):1205-14.
3. Remuzzi G, Benigni A, Remuzzi A: Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest. 2006, 116:288-96.
4. Sagrinati C, Ronconi E, Lazzeri E, Lasagni L, Romagnani P. Stem-cell approaches for kidney repair: choosing the right cells. Trends Mol Med. 2008 Jul;14(7):277-85.
5. Sagrinati C, Netti GS, Mazzinghi B, Lazzeri E, Liotta F, Frosali F, Ronconi E, Meini C, Gacci M, Squecco R, Carini M, Gesualdo L, Francini F, Maggi E, Annunziato F, Lasagni L, Serio M, Romagnani S, Romagnani P: Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys. J Am Soc Nephrol 2006, 17:2443-2456.
6. Mazzinghi B, Ronconi E, Lazzeri E, Sagrinati C, Ballerini L, Angelotti ML, Parente E, Mancina R, Netti GS, Becherucci F, Gacci M, Carini M, Gesualdo L, Rotondi M, Maggi E, Lasagni L, Serio M, Romagnani S, Romagnani P: Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med 2008, 205: 479-490.
7. Ronconi E, Sagrinati C, Angelotti ML, Lazzeri E, Mazzinghi B, Ballerini L, Parente E, Becherucci F, Gacci M, Carini M, Maggi E, Serio M, Vannelli GB, Lasagni L, Romagnani S, Romagnani P: Regeneration of Glomerular Podocytes by Human Renal Progenitors. J Am Soc Nephrol. 2009;20:322-32.
8. Appel D, Kershaw DB, Smeets B, Yuan G, Fuss A, Frye B, Elger M, Kriz W, Floege J, Moeller MJ. Recruitment of Podocytes from Glomerular Parietal Epithelial Cells. J Am Soc Nephrol. 2009;20:333-43.
9. Romagnani P. Towards the identification of a "renopoietic system"? Stem Cells, in press