Potential of mesenchymal stem cells in the repair of tubular injury

Abstract

Current interventions for the treatment of acute kidney injury (AKI) are not satisfactory, and it is time to approach new strategies in order to definitely take a step forward. At its beginning, cell therapy was innovative and promising. We have shown that mesenchymal stem cells (MSCs), isolated from human and murine bone marrow (BM), behave as an efficacious tool for the treatment of cisplatin-induced AKI in mice in terms of amelioration of renal function and structure, and animal survival. Although the mechanism has not been completely elucidated, we have provided data showing that BM-MSC-mediated renal recovery involves the release at the site of injury of the growth factor, insulin-like growth factor-1. Several biological effects have been observed in renal tissues of mice treated with BM-MSCs, including increased cell proliferation, hemodynamic changes, and cell apoptosis reduction. In the same experimental model, we have tested the effect of MSCs isolated from cord blood (CB-MSCs), which, similar to BM-MSCs, not only ameliorated renal function but also protected animals from death to a remarkably higher extent. Animals receiving CB-MSCs showed reduction of oxidative stress and activation of AKT prosurvival pathway in tubular cells. These results hold great promise for future studies in patients with AKI.

Keywords: acute renal failure; kidney regeneration; mesenchymal stem cells.

Figure 1

Bone marrow-mesenchymal stem cells (BM-MSCs) stimulated proximal tubular cell (PTEC) proliferation and inhibited cisplatin-induced apoptosis via insulin-like growth factor-1 (IGF-1). (a) Proliferation of PTECs treated with cisplatin (2.5 μM, 6 h), alone or in coculture for 4 days with BM-MSCs transfected with irrelevant (irrel) or IGF-1 small interfering (si) RNAs. Blocking of IGF-1 by RNA silencing (si-IGF-1) led to a strong reduction in the proliferation of cisplatin-treated PTECs as compared with BM-MSCs transfected with si-irrel. °P<0.01 versus PTECs; ^*P<0.01 versus PTECs+cisplatin; ^#P<0.05 versus si-irrel BM-MSCs. Data are means±s.e.m. (b) Cisplatin-induced apoptosis on PTECs is reduced by BM-MSCs treatment via IGF-1. Untreated PTECs and cisplatin-treated PTECs, alone or in coculture for 4 days with si-irrel BM-MSCs or si-IGF-1 BM-MSCs, were analyzed by fluorescence-activated cell sorter to determine late apoptosis (expression of caspase 3 and 7, propidium iodide). °P<0.01 versus PTECs; ^*P<0.01 versus PTECs+cisplatin; ^#P<0.05 versus si-irrel BM-MSCs and PTECs+cisplatin. Data are means±s.e.m.

Figure 2

Effect of human bone marrow-mesenchymal stem cells (hBM-MSCs) on peritubular capillaries in immunodeficient mice with cisplatin-induced acute kidney injury. Representative micrografts of kidney tissues of control mouse and cisplatin-treated mice that were administered saline or hBM-MSCs at 4 days after cisplatin. The peritubular capillary endothelium was labeled with MECA-32 (red), whereas renal structures were stained with fluorescein isothiocyanate-labeled lectin wheat germ agglutinin (green). Volume density of endothelial cells and capillary lumen was markedly reduced in cisplatin-treated mice that were administered saline as compared with control mice, as well as their capillary diameter. Treatment with hBM-MSCs normalized all these parameters. Original magnification, × 630.

Figure 3

Suggested mechanism for mesenchymal stem cell (MSC)-mediated tubular repair after acute injury. Administered MSCs are attracted to the site of injury following cytokine and chemokine release from damaged tubular cells. Recruited MSCs release growth factors such as insulin-like growth factor-1 (IGF-1), which may affect tubular functional and structural repair by induction of cell proliferation and inhibition of apoptosis. MAP-kinase, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase.