Macrophages control vascular stem/progenitor cell plasticity through tumor necrosis factor-α-mediated nuclear factor-κB activation.
OBJECTIVE
Vascular lineage differentiation of stem/progenitor cells can contribute to both tissue repair and exacerbation of vascular diseases such as in vein grafts. The role of macrophages in controlling vascular progenitor differentiation is largely unknown and may play an important role in graft development. This study aims to identify the role of macrophages in vascular stem/progenitor cell differentiation and thereafter elucidate the mechanisms that are involved in the macrophage- mediated process.


RESULTS
We provide in vitro evidence that macrophages can induce endothelial cell (EC) differentiation of the stem/progenitor cells while simultaneously inhibiting their smooth muscle cell differentiation. Mechanistically, both effects were mediated by macrophage-derived tumor necrosis factor-α (TNF-α) via TNF-α receptor 1 and canonical nuclear factor-κB activation. Although the overexpression of p65 enhanced EC (or attenuated smooth muscle cell) differentiation, p65 or TNF-α receptor 1 knockdown using lentiviral short hairpin RNA inhibited EC (or rescued smooth muscle cell) differentiation in response to TNF-α. Furthermore, TNF-α-mediated EC differentiation was driven by direct binding of nuclear factor-κB (p65) to specific VE-cadherin promoter sequences. Subsequent experiments using an ex vivo decellularized vessel scaffold confirmed an increase in the number of ECs and reduction in smooth muscle cell marker expression in the presence of TNF-α. The lack of TNF-α in a knockout mouse model of vein graft decreased endothelialization and significantly increased thrombosis formation.


CONCLUSIONS
Our study highlights the role of macrophages in directing vascular stem/progenitor cell lineage commitment through TNF-α-mediated TNF-α receptor 1 and nuclear factor-κB activation that is likely required for endothelial repair in vascular diseases such as vein graft.
From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (M.M.W., A.M., B.W., P.C., C.P., Y.H., Q.X.); and Department of Vascular Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China (Y.C.).
Mei Mei
MM
Wong
Yikuan
Y
Chen
Andriani
A
Margariti
Bernhard
B
Winkler
Paola
P
Campagnolo
Claire
C
Potter
Yanhua
Y
Hu
Qingbo
Q
Xu
D053687:Adult Stem Cells / Q000166:cytology* / Q000187:drug effects; D042501:Angiogenic Proteins / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D015850:Interleukin-6 / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism*; D058426:Neointima / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011828:Radiation Chimera; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D019851:Thrombophilia / Q000209:etiology / Q000503:physiopathology; D054457:Tissue Scaffolds; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D014680:Veins / Q000637:transplantation; D000099152:Cadherin 5
D042501:Angiogenic Proteins; D015703:Antigens, CD; D015820:Cadherins; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D016328:NF-kappa B; D052250:Nitric Oxide Synthase Type III; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099152:Cadherin 5; C498144:Rela protein, mouse; C506236:Tnfrsf1a protein, mouse; C496315:Nos3 protein, mouse
endothelial cells; macrophages; stem cells; tumor necrosis factor-alpha; vascular smooth muscle