title: CD16⁺ monocytes with smooth muscle cell characteristics are reduced in human renal chronic transplant dysfunction.
abstract: In chronic transplant dysfunction (CTD), persistent (allo)immune-mediated inflammation eventually leads to tissue remodeling including neointima formation in intragraft arteries. We previously showed that recipient-derived neointimal α-SMA(+) smooth muscle-like cells are present in human renal allografts with CTD. Human PBMC contain myeloid cells capable of differentiating into α-SMA(+) cells in vitro; the phenotype of the ancestral subset is as yet unknown. This study aimed to investigate whether monocyte subsets contain cells with smooth muscle-like cell differentiation capacity and whether CTD in renal transplant recipients is associated with a shift in these monocyte subsets. To accomplish this goal, monocyte subsets from healthy controls were sorted based on CD14 and CD16 expression to investigate gene expression levels of mesenchymal markers α-SMA and SM22α. CD14(+)/CD16(++) monocytes displayed increased α-SMA and SM22α mRNA expression compared with CD14(++)/CD16(-) monocytes, suggesting increased differentiation potential toward smooth muscle-like cells. Flow cytometry revealed that in non-CTD transplant recipients the percentage of CD14(+)/CD16(++) monocytes was reduced, with an even further reduction in patients with CTD. To determine a potential correlation between CD14(+)/CD16(++) monocytes and α-SMA(+) cell outgrowth potential in vitro, PBMC of healthy controls and transplant recipients with and without CTD were cultured under fibrotic culture conditions, and indeed a significant correlation (p=0.0002, r=0.62) was observed. Finally, double staining for α-SMA and CD16 revealed presence of α-SMA(+)CD16(+) cells in kidney explants from CTD patients, albeit at very low numbers. Our data represent evidence that, compared to CD14(++)CD16(-) monocytes, CD14(+)CD16(++) monocytes have an increased expression of smooth muscle cell-associated genes. This monocyte subpopulation is reduced in renal transplant patients with CTD, possibly due to selective migration into the allograft.
authors.affiliation: Department of Pathology & Medical Biology, Division of Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: m.boersema@umcg.nl.
authors.forename: M
authors.initials: M
authors.lastname: Boersema
authors.affiliation: Department of Pathology & Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: van den Born
authors.affiliation: Department of Pathology & Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van Ark
authors.affiliation: Department of Pathology & Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Harms
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Seelen
authors.affiliation: Department of Pathology, Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: M C R F
authors.initials: MC
authors.lastname: van Dijk
authors.affiliation: Department of Pathology & Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Goor
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Navis
authors.affiliation: Department of Pathology & Medical Biology, Division of Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: E R
authors.initials: ER
authors.lastname: Popa
authors.affiliation: Department of Pathology & Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: J L
authors.initials: JL
authors.lastname: Hillebrands
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D064591:Allografts / Q000098:blood supply / Q000276:immunology*; D002454:Cell Differentiation; D002908:Chronic Disease; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology*; D006801:Humans; D016030:Kidney Transplantation; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D015166:Monitoring, Immunologic / Q000379:methods; D009000:Monocytes / Q000276:immunology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000276:immunology*; D058426:Neointima / Q000209:etiology / Q000276:immunology*; D011183:Postoperative Complications / Q000276:immunology*; D017452:Receptors, IgG / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D018950:Lipopolysaccharide Receptors; D008840:Microfilament Proteins; D009124:Muscle Proteins; D017452:Receptors, IgG; C051615:transgelin
keywords: Chronic transplant dysfunction; Kidney; Monocyte heterogeneity; Monocytes; Smooth-muscle-like cells; Transplantation