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

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

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

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

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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

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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}",

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month = jul,

day = "5",

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

UR - https://www.sciencedirect.com/science/article/pii/S1525001618301448?via%3Dihub

U2 - 10.1016/j.ymthe.2018.03.017

DO - 10.1016/j.ymthe.2018.03.017

M3 - Article

C2 - 29703701

SN - 1525-0016

VL - 26

SP - 1669

EP - 1684

JO - Molecular Therapy

JF - Molecular Therapy

IS - 7

ER -

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

Abstract

Bibliographical note

Keywords

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