Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Ruei-Zeng Lin1,2,
  2. Alexandra Dreyzin1,
  3. Kristie Aamodt1,
  4. Dan Li3,
  5. Shou-Ching S. Jaminet3,
  6. Andrew C. Dudley4, and
  7. Juan M. Melero-Martin1,2
  1. 1Department of Cardiac Surgery, Children's Hospital Boston, Boston, MA;
  2. 2Department of Surgery, Harvard Medical School, Boston, MA;
  3. 3Center for Vascular Biology, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; and
  4. 4Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC

Abstract

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.

  • Submitted August 9, 2011.
  • Accepted September 10, 2011.
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