Mesenchymal stromal cells genetically engineered to overexpress IGF-I enhance cell-based gene therapy of renal failure-induced anemia.
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.
Kucic
Terrence
T
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Copland
Ian B
IB
Cuerquis
Jessica
J
Coutu
Daniel L
DL
Chalifour
Lorraine E
LE
Gagnon
Raymonde F
RF
Galipeau
Jacques
J
D000740:Anemia / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D005818:Genetic Engineering / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D006400:Hematocrit; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D051437:Renal Insufficiency / Q000150:complications / Q000378:metabolism / Q000628:therapy*
D012333:RNA, Messenger; D004921:Erythropoietin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1