Induction of erythropoiesis using human vascular networks genetically engineered for controlled erythropoietin release

For decades, autologous ex vivo gene therapy has been postulated as a potential alternative to parenteral administration of recombinant proteins. However, achieving effective cellular engraftment of previously retrieved patient cells is challenging. Recently, our ability to engineer vasculature in v...

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Bibliographic Details
Published in:Blood 2011-11, Vol.118 (20), p.5420-5428
Main Authors: Lin, Ruei-Zeng, Dreyzin, Alexandra, Aamodt, Kristie, Li, Dan, Jaminet, Shou-Ching S., Dudley, Andrew C., Melero-Martin, Juan M.
Format: Article
Language:English
Subjects:
Anemia - etiology
Anemia - genetics
Anemia - therapy
Animals
Biological and medical sciences
Blood Vessels - physiology
Cells, Cultured
Disease Models, Animal
Erythropoiesis - physiology
Erythropoietin - genetics
Erythropoietin - metabolism
Feasibility Studies
Gene Expression Regulation - physiology
Gene Therapy
Genetic Engineering - methods
Genetic Therapy - methods
Hematologic and hematopoietic diseases
Humans
Medical sciences
Mesenchymal Stem Cell Transplantation
Mice
Mice, Nude
Radiation Injuries - complications
Red Cells, Iron, and Erythropoiesis
Renal Insufficiency - complications
Subcutaneous Tissue - blood supply
Transfection - methods
Transplantation, Autologous
Transplantation, Heterologous
Vascular Biology
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Summary:For decades, autologous ex vivo gene therapy has been postulated as a potential alternative to parenteral administration of recombinant proteins. However, achieving effective cellular engraftment of previously retrieved patient cells is challenging. Recently, our ability to engineer vasculature in vivo has allowed for the introduction of instructions into tissues by genetically modifying the vascular cells that build these blood vessels. In the present study, we genetically engineered human blood–derived endothelial colony-forming cells (ECFCs) to express erythropoietin (EPO) under the control of a tetracycline-regulated system, and generated subcutaneous vascular networks capable of systemic EPO release in immunodeficient mice. These ECFC-lined vascular networks formed functional anastomoses with the mouse vasculature, allowing direct delivery of recombinant human EPO into the bloodstream. After activation of EPO expression, erythropoiesis was induced in both normal and anemic mice, a process that was completely reversible. This approach could relieve patients from frequent EPO injections, reducing the medical costs associated with the management of anemia. We propose this ECFC-based gene-delivery strategy as a viable alternative technology when routine administration of recombinant proteins is needed.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2011-08-372946