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Am J Physiol Renal Physiol 295: F488-F496, 2008. First published June 4, 2008; doi:10.1152/ajprenal.00044.2008
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Mesenchymal stromal cells genetically engineered to overexpress IGF-I enhance cell-based gene therapy of renal failure-induced anemia

Terrence Kucic,1 Ian B. Copland,1 Jessica Cuerquis,1 Daniel L. Coutu,1 Lorraine E. Chalifour,1 Raymonde F. Gagnon,2 and Jacques Galipeau1,3

1Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital; 2Division of Nephrology, McGill University Health Centre; and 3Division of Hematology/Oncology, Department of Medicine, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada

Submitted 25 January 2008 ; accepted in final form 28 May 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.

erythropoietin; chronic kidney disease; bone marrow-derived progenitor cells; coimplantation


Address for reprint requests and other correspondence: J. Galipeau, Sir Mortimer B. Davis Jewish General Hospital (McGill Univ.), 3755 Chemin de la Cote Ste-Catherine, Montreal, PQ, Canada H3T 1E2 (e-mail: jacques.galipeau{at}mcgill.ca)






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