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

TY - JOUR

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

N1 - Publisher Copyright: © 2024 The authors,

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 - https://www.scopus.com/pages/publications/85196688591

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 -