Submitted on January 25, 2008
Accepted on May 28, 2008
Mesenchymal stromal cells genetically engineered to overexpress IGF-I enhance cell-based gene therapy of renal failure-induced anemia
Terrence Kucic1, Ian B Copland2, Jessica Cuerquis2, Daniel L Coutu2, Lorraine E. Chalifour3, Raymonde F. Gagnon4, and Jacques Galipeau5*
1 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Canada
2 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada
3 Cardiology, Lady Davis Institute for Medical Research, Montreal, Canada
4 Division of Nephrology, McGill University Health Centre, Montreal, Canada
5 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada; Division of Hematology/Oncology, Department of Medicine, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada
* To whom correspondence should be addressed. E-mail: jacques.galipeau{at}mcgill.ca.
We have previously demonstrated that erythropoietin (EPO)-secreting mesenchymal stromal cells (MSC) can be used for the long-term correction of renal failure-induced anemia. The current study provides evidence that co-implantation 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 by subcutaneous injection in renal failure mice, in combination with either MSC-IGF or null MSC. Mice receiving MSC-EPO co-implanted with MSC-IGF experienced a greater and enhanced hematocrit elevation compared to control mice; heart function was also improved. MSC-IGF co-implantation therefore represents a promising new strategy for enhancing MSC survival within implanted matrices, and for improving cell-based gene therapy of renal anemia.
