Single nuclei transcriptomics delineates complex immune and kidney cell interactions contributing to kidney allograft fibrosis.

Autor:	McDaniels JM; Division of Surgical Sciences, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA., Shetty AC; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA., Kuscu C; Transplant Research Institute, James D. Eason Transplant Institute, University of Tennessee Health Science Center, Memphis, Tennessee, USA; Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA., Kuscu C; Transplant Research Institute, James D. Eason Transplant Institute, University of Tennessee Health Science Center, Memphis, Tennessee, USA; Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA., Bardhi E; Division of Surgical Sciences, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA., Rousselle T; Division of Surgical Sciences, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA., Drachenberg C; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA., Talwar M; Transplant Research Institute, James D. Eason Transplant Institute, University of Tennessee Health Science Center, Memphis, Tennessee, USA., Eason JD; Transplant Research Institute, James D. Eason Transplant Institute, University of Tennessee Health Science Center, Memphis, Tennessee, USA., Muthukumar T; Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA., Maluf DG; Division of Surgical Sciences, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA; Program in Transplantation, University of Maryland School of Medicine, Baltimore, Maryland, USA., Mas VR; Division of Surgical Sciences, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA. Electronic address: vmas@som.umaryland.edu.
Jazyk:	angličtina
Zdroj:	Kidney international [Kidney Int] 2023 Jun; Vol. 103 (6), pp. 1077-1092. Date of Electronic Publication: 2023 Feb 28.
DOI:	10.1016/j.kint.2023.02.018
Abstrakt:	Chronic allograft dysfunction (CAD), characterized histologically by interstitial fibrosis and tubular atrophy, is the major cause of kidney allograft loss. Here, using single nuclei RNA sequencing and transcriptome analysis, we identified the origin, functional heterogeneity, and regulation of fibrosis-forming cells in kidney allografts with CAD. A robust technique was used to isolate individual nuclei from kidney allograft biopsies and successfully profiled 23,980 nuclei from five kidney transplant recipients with CAD and 17,913 nuclei from three patients with normal allograft function. Our analysis revealed two distinct states of fibrosis in CAD; low and high extracellular matrix (ECM) with distinct kidney cell subclusters, immune cell types, and transcriptional profiles. Imaging mass cytometry analysis confirmed increased ECM deposition at the protein level. Proximal tubular cells transitioned to an injured mixed tubular (MT1) phenotype comprised of activated fibroblasts and myofibroblast markers, generated provisional ECM which recruited inflammatory cells, and served as the main driver of fibrosis. MT1 cells in the high ECM state achieved replicative repair evidenced by dedifferentiation and nephrogenic transcriptional signatures. MT1 in the low ECM state showed decreased apoptosis, decreased cycling tubular cells, and severe metabolic dysfunction, limiting the potential for repair. Activated B, T and plasma cells were increased in the high ECM state, while macrophage subtypes were increased in the low ECM state. Intercellular communication between kidney parenchymal cells and donor-derived macrophages, detected several years post-transplantation, played a key role in injury propagation. Thus, our study identified novel molecular targets for interventions aimed to ameliorate or prevent allograft fibrogenesis in kidney transplant recipients. (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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