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1.
Am J Physiol Renal Physiol ; 295(2): F488-96, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18524862

ABSTRACT

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.


Subject(s)
Anemia/therapy , Genetic Engineering/methods , Genetic Therapy/methods , Insulin-Like Growth Factor I/metabolism , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , Renal Insufficiency/therapy , Anemia/etiology , Anemia/metabolism , Animals , Apoptosis , Cells, Cultured , Disease Models, Animal , Erythropoietin/metabolism , Female , Hematocrit , Insulin-Like Growth Factor I/genetics , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred C57BL , RNA, Messenger/metabolism , Receptor, IGF Type 1/metabolism , Renal Insufficiency/complications , Renal Insufficiency/metabolism
2.
J Obstet Gynaecol Can ; 29(10): 843-8, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17915069

ABSTRACT

This article is a consensus statement by an international interdisciplinary group of academic experts and Canadian policy-makers on emerging ethical, legal and social issues in human embryonic stem cells (hESC) research in Canada. The process of researching consensus included consultations with key stakeholders in hESC research (regulations, stem cell researchers, and research ethics experts), preparation and distribution of background papers, and an international workshop held in Montreal in February 2007 to discuss the papers and debate recommendations. The recommendations provided in the consensus statement focus on issues of immediate relevance to Canadian policy-makers, including informed consent to hESC research, the use of fresh embryos in research, management of conflicts of interest, and the relevance of public opinion research to policy-making.


Subject(s)
Embryonic Stem Cells , Ethics, Research , Health Planning Guidelines , Stem Cell Transplantation/ethics , Stem Cell Transplantation/legislation & jurisprudence , Conflict of Interest , Humans
3.
Hum Mutat ; 27(1): 31-43, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16281286

ABSTRACT

Cobalamin nonresponsive methylmalonic acidemia (MMA, mut complementation class) results from mutations in the nuclear gene MUT, which codes for the mitochondrial enzyme methylmalonyl CoA mutase (MCM). To better elucidate the spectrum of mutations that cause MMA, the MUT gene was sequenced in 160 patients with mut MMA. Sequence analysis identified mutations in 96% of disease alleles. Mutations were found in all coding exons, but predominantly in exons 2, 3, 6, and 11. A total of 116 different mutations, 68 of which were novel, were identified. Of the 116 different mutations, 53% were missense mutations, 22% were deletions, duplications or insertions, 16% were nonsense mutations, and 9% were splice-site mutations. Sixty-one of the mutations have only been identified in one family. A novel mutation in exon 2, c.322C>T (p.R108C), was identified in 16 of 27 Hispanic patients. SNP genotyping data demonstrated that Hispanic patients with this mutation share a common haplotype. Three other mutations were seen exclusively in Hispanic patients: c.280G>A (p.G94R), c.1022dupA, and c.970G>A (p.A324T). Seven mutations were seen almost exclusively in black patients, including the previously reported c.2150G>T (p.G717V) mutation, which was identified in 12 of 29 black patients. Two mutations were seen only in Asian patients. Some frequently identified mutations were not population-specific and were identified in patients of various ethnic backgrounds. Some of these mutations were found in mutation clusters in exons 2, 3, 6, and 11, suggesting a recurrent mutation.


Subject(s)
Amino Acid Metabolism, Inborn Errors/ethnology , Amino Acid Metabolism, Inborn Errors/genetics , Haplotypes , Hispanic or Latino/genetics , Methylmalonyl-CoA Mutase/genetics , Mutation/genetics , Alleles , Cell Line , Child, Preschool , DNA Mutational Analysis , Exons/genetics , Genetic Complementation Test , Homozygote , Humans , Infant , Infant, Newborn , Phenotype , Polymorphism, Genetic
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