Mesenchymal stromal cells genetically engineered to overexpress IGF-I enhance cell-based gene therapy of renal failure-induced anemia

• Published in: American journal of physiology. Renal physiology 2008-08, Vol.295 (2), p.F488-F496
• Main Authors: Kucic, Terrence, Copland, Ian B, Cuerquis, Jessica, Coutu, Daniel L, Chalifour, Lorraine E, Gagnon, Raymonde F, Galipeau, Jacques
• Format: Article
• Language: English
• Subjects: Anemia; Anemia - etiology; Anemia - metabolism; Anemia - therapy; Animals; Apoptosis; Cells; Cells, Cultured; Disease Models, Animal; Erythropoietin - metabolism; Female; Gene expression; Gene therapy; Genetic engineering; Genetic Engineering - methods; Genetic Therapy - methods; Hematocrit; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Kidney diseases; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Mice; Mice, Inbred C57BL; Proteins; Receptor, IGF Type 1 - metabolism; Renal Insufficiency - complications; Renal Insufficiency - metabolism; Renal Insufficiency - therapy; RNA, Messenger - metabolism; Rodents
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00044.2008

We previously demonstrated that erythropoietin (EPO)-secreting mesenchymal stromal cells (MSC) can be used for the long-term correction of renal failure-induced anemia. The present study provides evidence that coimplantation of insulin-like growth factor I (IGF-I)-overexpressing MSC (MSC-IGF) improves MSC-based gene therapy of anemia by providing paracrine support to EPO-secreting MSC (MSC-EPO) within a subcutaneous implant. IGF-I receptor RNA expression in murine MSC was demonstrated by RT-PCR. Functional protein expression was confirmed by immunoblots and MSC responsiveness to IGF-I stimulation in vitro. IGF-I was also shown to improve MSC survival following staurosporin-induced apoptosis in vitro. A cohort of C57Bl/6 mice was rendered anemic by right kidney electrocoagulation and left nephrectomy. MSC-EPO were subsequently admixed in a bovine collagen matrix and implanted, in combination with MSC-IGF or MSC null, by subcutaneous injection in renal failure mice. In mice receiving MSC-EPO coimplanted with MSC-IGF, hematocrit elevation was greater and enhanced compared with control mice; heart function was also improved. MSC-IGF coimplantation, therefore, represents a promising new strategy for enhancing MSC survival within implanted matrices and for improving cell-based gene therapy of renal anemia.