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

doi:10.1016/j.ymthe.2018.03.017

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

Aston Medical School

University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK; Edinburgh Imaging, University of Edinburgh, Edinburgh, UK.
Scottish National Blood Transfusion Service, Edinburgh, UK.
Edinburgh Imaging, University of Edinburgh, Edinburgh, UK.
University of Edinburgh
Experimental Cardiovascular Medicine Division, Bristol Heart Institute, University of Bristol, Bristol, UK.
Scottish National Blood Transfusion Service, Edinburgh, UK; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Experimental Cardiovascular Medicine Division, Bristol Heart Institute, University of Bristol, Bristol, UK; National Heart and Lung Institute, Imperial College London, London, UK.
University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. Electronic address: [email protected].

Research output: Contribution to journal › Article › peer-review

55 Citations (Scopus)

86 Downloads (Pure)

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 language	English
Pages (from-to)	1669-1684
Number of pages	16
Journal	Molecular Therapy
Volume	26
Issue number	7
DOIs	https://doi.org/10.1016/j.ymthe.2018.03.017
Publication status	Published - 5 Jul 2018

Bibliographical note

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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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10.1016/j.ymthe.2018.03.017Licence: CC BY 3.0

Robust Revascularization in Models of Limb IschemiaFinal published version, 3.34 MBLicence: CC BY 3.0

Cite this

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

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

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.",

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",

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

note = "{\textcopyright} 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).",

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month = jul,

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doi = "10.1016/j.ymthe.2018.03.017",

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MacAskill, MG, Saif, J, Condie, A, Jansen, MA, MacGillivray, TJ, Tavares, AAS, Fleisinger, L, Spencer, HL, Besnier, M, Martin, E, Biglino, G, Newby, DE, Hadoke, PWF, Mountford, JC, Emanueli, C & Baker, AH 2018, 'Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product', Molecular Therapy, vol. 26, no. 7, pp. 1669-1684. https://doi.org/10.1016/j.ymthe.2018.03.017

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T1 - Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product

AU - MacAskill, Mark G

AU - Saif, Jaimy

AU - Condie, Alison

AU - Jansen, Maurits A

AU - MacGillivray, Thomas J

AU - Tavares, Adriana A S

AU - Fleisinger, Lucija

AU - Spencer, Helen L

AU - Besnier, Marie

AU - Martin, Ernesto

AU - Biglino, Giovanni

AU - Newby, David E

AU - Hadoke, Patrick W F

AU - Mountford, Joanne C

AU - Emanueli, Costanza

AU - Baker, Andrew H

PY - 2018/7/5

Y1 - 2018/7/5

N2 - 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.

AB - 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.

KW - Animals

KW - Biomarkers/metabolism

KW - Cell Differentiation/physiology

KW - Cell Line

KW - Embryonic Stem Cells/cytology

KW - Endothelial Cells/cytology

KW - Hindlimb/cytology

KW - Humans

KW - Ischemia/metabolism

KW - Mesenchymal Stem Cells/cytology

KW - Mice

KW - Neovascularization, Physiologic/physiology

KW - Pericytes/cytology

KW - Pluripotent Stem Cells/cytology

KW - Stem Cell Transplantation/methods

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SN - 1525-0016

VL - 26

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EP - 1684

JO - Molecular Therapy

JF - Molecular Therapy

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ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

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