Insulin-like growth factor-1 sustains stem cell mediated renal repair.
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.
Imberti
Barbara
B
Mario Negri Institute for Pharmacological Research, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy.
Morigi
Marina
M
Tomasoni
Susanna
S
Rota
Cinzia
C
Corna
Daniela
D
Longaretti
Lorena
L
Rottoli
Daniela
D
Valsecchi
Federica
F
Benigni
Ariela
A
Wang
Jun
J
Abbate
Mauro
M
Zoja
Carla
C
Remuzzi
Giuseppe
G
D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002945:Cisplatin; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D007674:Kidney Diseases / Q000628:therapy*; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
D007334:Insulin-Like Growth Factor I; D002945:Cisplatin