Can we create new organs from our own tissues?
The many new technologies of the past few years have set the stage for novel human therapeutic methods. Identification of pluripotent stem cells as being capable of generating various cell types in the body, together with advanced genetic and cell engineering techniques, may enable the design of custom tissues and organs and thus solve the problem of donor organ scarcity and the need for immune compatibility and immunosuppression to avoid graft rejection. One of the most prevalent metabolic disorders that will benefit from such technologies is insulin-dependent diabetes mellitus. The purpose of our study is to review potential future methods of curing metabolic disorders such as diabetes, and analyze the capacity to genetically manipulate the developmental fate of a tissue in vivo using "master regulator" genes. We systemically delivered the homeobox gene Pancreatic and Duodenal Homeobox gene-1 to liver of mice, by recombinant adenovirus technology, and analyzed whether it induces a developmental shift toward a beta cell phenotype. We demonstrated that PDX-1 is sufficient to activate the endogenous, otherwise silent, mouse insulin 1 and 2 and pro-insulin convertase gene expression in liver. PDX-1 expression in liver resulted in a 25-fold increase in hepatic immunoreactive insulin content and a threefold increase in plasma immunoreactive insulin levels, as compared to control adenovirus-treated mice. Hepatic immunoreactive insulin, induced by PDX-1, was processed to mature mI-1 and mI-2 and was biologically active; it ameliorated hyperglycemia in streptozotocin-treated diabetic mice. PDX-1 has the capacity to reprogram extra-pancreatic tissue toward a beta cell phenotype. The data provide a valuable approach to generate "self" surrogate beta cells that are suitable for replacing impaired islet cell function in diabetics.
Ferber
S
S
Endocrine Institute, Sheba Medical Center, Tel-Hashomer, Israel. sferber@netvision.net.il
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy; D005801:Genes, Homeobox / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics; D005818:Genetic Engineering; D005821:Genetic Techniques; D006648:Histocompatibility; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007165:Immunosuppression Therapy; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000502:physiology; D013677:Medical Laboratory Science; D008659:Metabolic Diseases / Q000628:therapy; D051379:Mice; D016377:Organ Transplantation; D013234:Stem Cells / Q000502:physiology; D014019:Tissue Donors; D015534:Trans-Activators / Q000235:genetics
D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein