A subpopulation of tissue remodeling monocytes stimulates revascularization of the ischemic limb

Ashish S Patel; Francesca E Ludwinski; Alexander Kerr; Simon Farkas; Puja Kapoor; Laura Bertolaccini; Ramon Fernandes; Paul R Jones; Donal McLornan; Lefteris Livieratos; Prakash Saha; Alberto Smith; Bijan Modarai

doi:10.1126/scitranslmed.adf0555

A subpopulation of tissue remodeling monocytes stimulates revascularization of the ischemic limb

Ashish S Patel, Francesca E Ludwinski, Alexander Kerr, Simon Farkas, Puja Kapoor, Laura Bertolaccini, Ramon Fernandes, Paul R Jones, Donal McLornan, Lefteris Livieratos, Prakash Saha, Alberto Smith, Bijan Modarai

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

3 Citations (Scopus)

Abstract

Despite decades of effort aimed at developing clinically effective cell therapies, including mixed population mononuclear cells, to revascularize the ischemic limb, there remains a paucity of patient-based studies that inform the function and fate of candidate cell types. In this study, we showed that circulating proangiogenic/arteriogenic monocytes (PAMs) expressing the FcγIIIA receptor CD16 were elevated in patients with chronic limb-threatening ischemia (CLTI), and these amounts decreased after revascularization. Unlike CD16-negative monocytes, PAMs showed large vessel remodeling properties in vitro when cultured with endothelial cells and smooth muscle cells and promoted salvage of the ischemic limb in vivo in a mouse model of hindlimb ischemia. PAMs showed a propensity to migrate toward and bind to ischemic muscle and to secrete angiogenic/arteriogenic factors, vascular endothelial growth factor A (VEGF-A) and heparin-binding epidermal growth factor. We instigated a first-in-human single-arm cohort study in which autologous PAMs were injected into the ischemic limbs of five patients with CLTI. Greater than 25% of injected cells were retained in the leg for at least 72 hours, of which greater than 80% were viable, with evidence of enhanced large vessel remodeling in the injected muscle area. In summary, we identified up-regulation of a circulatory PAM subpopulation as an endogenous response to limb ischemia in CLTI and tested a potentially clinically relevant therapeutic strategy.

Original language	English
Article number	eadf0555
Journal	Science translational medicine
Volume	16
Issue number	752
DOIs	https://doi.org/10.1126/scitranslmed.adf0555
Publication status	Published - 19 Jun 2024

Keywords

Humans
Monocytes/metabolism
Animals
Ischemia/pathology
Neovascularization, Physiologic
Hindlimb/blood supply
Receptors, IgG/metabolism
Mice
Male
Vascular Endothelial Growth Factor A/metabolism
Female
Aged
Middle Aged
Cell Movement
Heparin-binding EGF-like Growth Factor/metabolism

UN SDGs

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

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10.1126/scitranslmed.adf0555

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Patel, A. S., Ludwinski, F. E., Kerr, A., Farkas, S., Kapoor, P., Bertolaccini, L., Fernandes, R., Jones, P. R., McLornan, D., Livieratos, L., Saha, P., Smith, A., & Modarai, B. (2024). A subpopulation of tissue remodeling monocytes stimulates revascularization of the ischemic limb. Science translational medicine, 16(752), Article eadf0555. https://doi.org/10.1126/scitranslmed.adf0555

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title = "A subpopulation of tissue remodeling monocytes stimulates revascularization of the ischemic limb",

abstract = "Despite decades of effort aimed at developing clinically effective cell therapies, including mixed population mononuclear cells, to revascularize the ischemic limb, there remains a paucity of patient-based studies that inform the function and fate of candidate cell types. In this study, we showed that circulating proangiogenic/arteriogenic monocytes (PAMs) expressing the FcγIIIA receptor CD16 were elevated in patients with chronic limb-threatening ischemia (CLTI), and these amounts decreased after revascularization. Unlike CD16-negative monocytes, PAMs showed large vessel remodeling properties in vitro when cultured with endothelial cells and smooth muscle cells and promoted salvage of the ischemic limb in vivo in a mouse model of hindlimb ischemia. PAMs showed a propensity to migrate toward and bind to ischemic muscle and to secrete angiogenic/arteriogenic factors, vascular endothelial growth factor A (VEGF-A) and heparin-binding epidermal growth factor. We instigated a first-in-human single-arm cohort study in which autologous PAMs were injected into the ischemic limbs of five patients with CLTI. Greater than 25% of injected cells were retained in the leg for at least 72 hours, of which greater than 80% were viable, with evidence of enhanced large vessel remodeling in the injected muscle area. In summary, we identified up-regulation of a circulatory PAM subpopulation as an endogenous response to limb ischemia in CLTI and tested a potentially clinically relevant therapeutic strategy.",

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doi = "10.1126/scitranslmed.adf0555",

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T1 - A subpopulation of tissue remodeling monocytes stimulates revascularization of the ischemic limb

AU - Patel, Ashish S

AU - Ludwinski, Francesca E

AU - Kerr, Alexander

AU - Farkas, Simon

AU - Kapoor, Puja

AU - Bertolaccini, Laura

AU - Fernandes, Ramon

AU - Jones, Paul R

AU - McLornan, Donal

AU - Livieratos, Lefteris

AU - Saha, Prakash

AU - Smith, Alberto

AU - Modarai, Bijan

PY - 2024/6/19

Y1 - 2024/6/19

N2 - Despite decades of effort aimed at developing clinically effective cell therapies, including mixed population mononuclear cells, to revascularize the ischemic limb, there remains a paucity of patient-based studies that inform the function and fate of candidate cell types. In this study, we showed that circulating proangiogenic/arteriogenic monocytes (PAMs) expressing the FcγIIIA receptor CD16 were elevated in patients with chronic limb-threatening ischemia (CLTI), and these amounts decreased after revascularization. Unlike CD16-negative monocytes, PAMs showed large vessel remodeling properties in vitro when cultured with endothelial cells and smooth muscle cells and promoted salvage of the ischemic limb in vivo in a mouse model of hindlimb ischemia. PAMs showed a propensity to migrate toward and bind to ischemic muscle and to secrete angiogenic/arteriogenic factors, vascular endothelial growth factor A (VEGF-A) and heparin-binding epidermal growth factor. We instigated a first-in-human single-arm cohort study in which autologous PAMs were injected into the ischemic limbs of five patients with CLTI. Greater than 25% of injected cells were retained in the leg for at least 72 hours, of which greater than 80% were viable, with evidence of enhanced large vessel remodeling in the injected muscle area. In summary, we identified up-regulation of a circulatory PAM subpopulation as an endogenous response to limb ischemia in CLTI and tested a potentially clinically relevant therapeutic strategy.

AB - Despite decades of effort aimed at developing clinically effective cell therapies, including mixed population mononuclear cells, to revascularize the ischemic limb, there remains a paucity of patient-based studies that inform the function and fate of candidate cell types. In this study, we showed that circulating proangiogenic/arteriogenic monocytes (PAMs) expressing the FcγIIIA receptor CD16 were elevated in patients with chronic limb-threatening ischemia (CLTI), and these amounts decreased after revascularization. Unlike CD16-negative monocytes, PAMs showed large vessel remodeling properties in vitro when cultured with endothelial cells and smooth muscle cells and promoted salvage of the ischemic limb in vivo in a mouse model of hindlimb ischemia. PAMs showed a propensity to migrate toward and bind to ischemic muscle and to secrete angiogenic/arteriogenic factors, vascular endothelial growth factor A (VEGF-A) and heparin-binding epidermal growth factor. We instigated a first-in-human single-arm cohort study in which autologous PAMs were injected into the ischemic limbs of five patients with CLTI. Greater than 25% of injected cells were retained in the leg for at least 72 hours, of which greater than 80% were viable, with evidence of enhanced large vessel remodeling in the injected muscle area. In summary, we identified up-regulation of a circulatory PAM subpopulation as an endogenous response to limb ischemia in CLTI and tested a potentially clinically relevant therapeutic strategy.

KW - Humans

KW - Monocytes/metabolism

KW - Animals

KW - Ischemia/pathology

KW - Neovascularization, Physiologic

KW - Hindlimb/blood supply

KW - Receptors, IgG/metabolism

KW - Mice

KW - Male

KW - Vascular Endothelial Growth Factor A/metabolism

KW - Female

KW - Aged

KW - Middle Aged

KW - Cell Movement

KW - Heparin-binding EGF-like Growth Factor/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85196688591&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.adf0555

DO - 10.1126/scitranslmed.adf0555

M3 - Article

C2 - 38896604

SN - 1946-6234

VL - 16

JO - Science translational medicine

JF - Science translational medicine

IS - 752

M1 - eadf0555

ER -

A subpopulation of tissue remodeling monocytes stimulates revascularization of the ischemic limb

Abstract

Keywords

UN SDGs

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