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*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

11 Citations (Scopus)
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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. To translate hESC-ECP into the clinic for CLI treatment, MacAskill et al. developed a robust, GMP-compatible method for hESC-ECP generation. hESC-ECP remained within ischemic limbs for ∼7 days and significantly improved foot perfusion and capillary density in murine models of limb ischemia with/without an intact immune system or diabetes mellitus.

Original languageEnglish
Pages (from-to)1669-1684
Number of pages16
JournalMolecular Therapy
Volume26
Issue number7
Early online date28 Mar 2018
DOIs
Publication statusPublished - 5 Jul 2018

Keywords

  • cell therapy
  • critical limb ischemia
  • GMP

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    MacAskill, M. G., Saif, J., Condie, A., Jansen, M. A., MacGillivray, T. J., Tavares, A. A. S., Fleisinger, L., Spencer, H. L., Besnier, M., Martin, E., Biglino, G., Newby, D. E., Hadoke, P. W. F., Mountford, J. C., Emanueli, C., & Baker, A. H. (2018). Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product. Molecular Therapy, 26(7), 1669-1684. https://doi.org/10.1016/j.ymthe.2018.03.017