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Transplantation of Human Embryonic Stem Cell–Derived Pericyte-Like Cells Transduced with Basic Fibroblast Growth Factor Promotes Angiogenic Recovery in Mice with Severe Chronic Hindlimb Ischemia

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Abstract

Critical limb ischemia (CLI) is a state of severe peripheral artery disease, with no effective treatment. Cell therapy has been investigated as a therapeutic tool for CLI, and pericytes are promising therapeutic candidates based on their angiogenic properties. We firstly generated highly proliferative and immunosuppressive pericyte-like cells from embryonic stem (ES) cells. In order to enhance the angiogenic potential, we transduced the basic fibroblast growth factor (bFGF) gene into the pericyte-like cells and found a significant enhancement of angiogenesis in a Matrigel plug assay. Furthermore, we evaluated the bFGF-expressing pericyte-like cells in the previously established chronic hindlimb ischemia model in which bone marrow–derived MSCs were not effective. As a result, bFGF-expressing pericyte-like cells significantly improved blood flow in both laser Doppler perfusion imaging (LDPI) and dynamic contrast-enhanced MRI (DCE-MRI). These findings suggest that bFGF-expressing pericyte-like cells differentiated from ES cells may be a therapeutic candidate for CLI.

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Abbreviations

CLI:

Critical limb ischemia

ES cells:

Embryonic stem cells

hES cells:

Human embryonic stem cells

bFGF:

Basic fibroblast growth factor

MSC’s:

Mesenchymal stem cells

LDPI:

Laser Doppler perfusion imaging

DCE-MRI:

Dynamic contrast-enhanced magnetic resonance imaging

PAD:

Peripheral artery disease

HLI:

Hindlimb ischemia

Ang-1:

Angiopoietin-1

SDF-1:

Stromal cell–derived factor-1

PDGF-BB:

Platelet-derived growth factor isoform BB

IL-8:

Interleukin-8

HUVECs:

Human umbilical vein endothelial cells

BMMSCs:

Bone marrow mesenchymal stem cells

IHC:

Immunohistochemistry

H&E:

Hematoxylin-eosin

MAB:

Mesoangioblast

FGF2:

Basic fibroblast growth factor

ES-PLCs:

ES-derived pericyte-like cells

VEGF:

Vascular endothelial growth factor

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Funding

This work was supported by Astellas Pharma Inc.

Author information

Author notes

  1. Kenichiro Shimatani and Hiromu Sato have contributed equally to this work.

Authors and Affiliations

  1. Institute for Regenerative Medicine Applied Cell Therapy Research, Astellas Pharma Incorporated, 21 Miyukigaoka, Tsukuba-Shi, Ibaraki, 305-8585, Japan

    Kenichiro Shimatani, Hiromu Sato, Kazuhiko Mizukami & Masazumi Kamohara

  2. Joint Research Chair On Design for Advanced Medical System, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Atsuhiro Saito

  3. Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Masao Sasai & Shigeru Miyagawa

  4. Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Jun-Ichiro Enmi & Yoshichika Yoshioka

  5. Center for Information and Neural Networks (CiNet), National Institute of Information and Communications Technology (NICT) and Osaka University, 1-4 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Jun-Ichiro Enmi & Yoshichika Yoshioka

  6. Department of Cardiovascular Surgery, Hyogo Medical University Hospital, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    Kenichi Watanabe

  7. Department of Future Medicine Division of Health Science, Osaka University Graduate School of Medicine, 1-3 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Yoshiki Sawa

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  1. Kenichiro Shimatani
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Correspondence to Kenichiro Shimatani.

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All procedures performed in this study involving animals were approved by the Institutional Animal Care and Use Committee of Osaka University. No human studies were carried out by the authors for this article.

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K.S., H.S., K.M., and M.K. are employed by Astellas Pharma Inc.

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Shimatani, K., Sato, H., Mizukami, K. et al. Transplantation of Human Embryonic Stem Cell–Derived Pericyte-Like Cells Transduced with Basic Fibroblast Growth Factor Promotes Angiogenic Recovery in Mice with Severe Chronic Hindlimb Ischemia. J. of Cardiovasc. Trans. Res. (2024). https://doi.org/10.1007/s12265-024-10496-9

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