Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product

Mark G MacAskill, Jaimy Saif, Alison Condie, Maurits A Jansen, Thomas J MacGillivray, Adriana A S Tavares, Lucija Fleisinger, Helen L Spencer, Marie Besnier, Ernesto Martin, Giovanni Biglino, David E Newby, Patrick W F Hadoke, Joanne C Mountford, Costanza Emanueli, Andrew H Baker

Research output: Contribution to journalArticle

Abstract

Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC-ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31+/CD144+), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy.

Original languageEnglish
Pages (from-to)1669-1684
Number of pages16
JournalMolecular Therapy
Volume26
Issue number7
DOIs
Publication statusPublished - 5 Jul 2018

Bibliographical note

© 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Keywords

  • Animals
  • Biomarkers/metabolism
  • Cell Differentiation/physiology
  • Cell Line
  • Embryonic Stem Cells/cytology
  • Endothelial Cells/cytology
  • Hindlimb/cytology
  • Humans
  • Ischemia/metabolism
  • Mesenchymal Stem Cells/cytology
  • Mice
  • Neovascularization, Physiologic/physiology
  • Pericytes/cytology
  • Pluripotent Stem Cells/cytology
  • Stem Cell Transplantation/methods

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