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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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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 language	English
Pages (from-to)	1669-1684
Number of pages	16
Journal	Molecular Therapy
Volume	26
Issue number	7
Early online date	28 Mar 2018
DOIs	https://doi.org/10.1016/j.ymthe.2018.03.017
Publication status	Published - 5 Jul 2018

Keywords

cell therapy
critical limb ischemia
GMP

UN SDGs

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

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10.1016/j.ymthe.2018.03.017

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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. 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.",

keywords = "cell therapy, critical limb ischemia, GMP",

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.}",

year = "2018",

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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. 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.

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. 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.

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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

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Keywords

UN SDGs

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Resubmmission of MicroRNAs in ischaemic heart disease and diabetes mellitus: from cardiac surgery to basic science - and back

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

Abstract

Keywords

UN SDGs

Access to Document

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Other files and links

Embargoed Document

Embargoed Document

Fingerprint

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Resubmmission of MicroRNAs in ischaemic heart disease and diabetes mellitus: from cardiac surgery to basic science - and back

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