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Insulin-Like Growth Factor-1 Sustains Stem Cell–Mediated Renal Repair

Barbara Imberti^*, Marina Morigi^*, Susanna Tomasoni^*, Cinzia Rota^*, Daniela Corna^*, Lorena Longaretti^*, Daniela Rottoli^*, Federica Valsecchi^*, Ariela Benigni^*, Jun Wang^*, Mauro Abbate^*, Carla Zoja^* and Giuseppe Remuzzi^*,

^* "Mario Negri" Institute for Pharmacological Research; and Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy

Correspondence: Dr. Marina Morigi, "Mario Negri" Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. Phone: +39-035-319-888; Fax: +39-035-319-331; E-mail: morigi{at}marionegri.it

Received for publication December 5, 2006. Accepted for publication June 19, 2007.

In mice with cisplatin-induced acute kidney injury, administration of bone marrow-derived mesenchymal stem cells (MSC) restores renal tubular structure and improves renal function, but the underlying mechanism is unclear. Here, we examined the process of kidney cell repair in co-culture experiments with MSC and cisplatin-injured proximal tubular epithelial cells (PTEC). Exposure of PTEC to cisplatin markedly reduced cell viability at 4 days, but co-culture with MSC provided a protective effect by promoting tubular cell proliferation. This effect was mediated by insulin-like growth factor-1 (IGF-1), highly expressed by MSC as mRNA and protein, since blocking the growth factor's function with a specific antibody attenuated cell proliferation of PTEC. Confirming this, knocking down IGF-1 expression in MSC by small interfering-RNA also resulted in a significant decrease in PTEC proliferation and increased apoptosis. Furthermore, in the murine model of cisplatin-induced kidney injury, administering IGF-1 gene-silenced MSC limited their protective effect on renal function and tubular structure. These findings indicate that MSC exert beneficial effects on tubular cell repair in acute kidney injury by producing the mitogenic and pro-survival factor IGF-1.

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