Effect of Foetal and Adult Stem Cells in Acute and Chronic Kidney Diseases

Rota, Cinzia (2013). Effect of Foetal and Adult Stem Cells in Acute and Chronic Kidney Diseases. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f0b8

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) are serious illnesses associated to high mortality and unsatisfactory therapeutic treatments. In search for new therapies, it has become evident that stem cells could be a possible option for patients with AKI and CKD.

The evidence of the renoprotective effect of bone marrow-mesenchymal stem cells (BM-MSCs) in experimental model of AKI, prompted us to study the effect of stem cells isolated from sources that are more accessible as cord blood (CB) and amniotic fluid. Infusion of hCB-MSCs in immunodeficient mice with AKI ameliorated renal function and tubular structure, prolonging survival. Moreover, transplanted hCB-MSCs localized in peritubular areas, limiting oxidative stress and apoptosis. By virtue of stem cell capacity to produce growth factors, hCB-MSCs were able to induce the pro-survival factor Akt in tubular cells and subsequently their proliferation.

Using the well-established model of AKI in immunodeficient mice, we studied the pro-regenerative effect of amniotic fluid stem (hAFS) cells. Infusion of hAFS cells in cisplatin-mice improved renal function and limited tubular damage, although not to control level, and prolonged animal survival. These cells engrafted injured kidney predominantly in peritubular region and through a paracrine mechanism are able to exert an anti-apoptotic effect, to activate Akt and stimulate proliferation of tubular cells. We enhanced the therapeutic potential of hAFS cells by cell pre-treatment with GDNF, which markedly ameliorated renal function and tubular injury by increasing stem cell homing to the tubulointerstitial compartment.

In AKI models, the renoprotective effect of BM-MSCs is well established, however the role of these stem cells in model of CKD is controversial and not demonstrated so far. Therefore, we tested the effect of BM-MSCs in a model of adriamycin-induced nephropathy. Repeated infusions of BM-MSCs limited podocyte loss, and normalized distribution of parietal epithelial cells along the Bowman's capsule, reducing glomerulosclerosis. Moreover, through the local release of growth factors as VEGF, BM-MSCs were able to provide a local prosurvival environment that limited glomerular inflammation and microvascular rarefaction.