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dc.contributor.authorMcDaniels, Jennifer
dc.contributor.authorShetty, Amol C.
dc.contributor.authorRousselle, Thomas
dc.contributor.authorBardhi, Elissa
dc.contributor.authorMaluf, Daniel
dc.contributor.authorMas, Valeria
dc.descriptionThe article processing charges (APC) for this open access article were partially funded by the Health Sciences and Human Services Library's Open Access Publishing Fund for Early-Career Researchers.en_US
dc.description.abstractDespite recent advances made in short-term outcomes; minimal improvements have been observed in long-term kidney transplantation outcomes. Due to an imbalance between organ transplant availability and patient waiting list, expanding kidney allograft longevity is a critical need in the field. Prior studies have either focused on early ischemic and immunological conditions a􀀀ecting kidney allografts (e.g., delayed graft function, acute rejection) or late stage chronic injury when interventions are no longer feasible. However, studies characterizing kidney allografts with normal function by its cellular distribution, cell-cell interactions, and associated molecular pathways are lacking. Herein, we used single nuclei RNA-sequencing to uncover the cellular landscape and transcriptome of the normal kidney allograft. We profiled 40,950 nuclei from seven human kidney biopsies (normal native, N = 3; normal allograft, N = 4); normal allograft protocol biopsies were collected 15-months post-transplant. A total of 17 distinct cell clusters were identified with proximal tubules (25.70 and 21.01%), distal tubules (15.22 and 18.20%), and endothelial cells (EC) (4.26 and 9.94%) constituting the major cell populations of normal native and normal allograft kidneys, respectively. A large proportion of cycling cells from normal native kidneys were in G1-phase (43.96%) whereas cells from normal allograft were predominantly in S-phase (32.69%). This result suggests that transcriptional di􀀀erences between normal native and normal allograft biopsies are dependent on the new host environment, immunosuppression, and injury-a iction. In the normal allograft, EC-specific genes upregulated metabolism, the immune response, and cellular growth, emphasizing their role in maintaining homeostasis during the ongoing alloreactive stress response. Immune cells, including B (2.81%), macrophages (24.96%), monocytes (15.29%), natural killer (NK) (12.83%), neutrophils (8.44%), and T cells (14.41%, were increased in normal allografts despite lack of histological or clinical evidence of acute rejection. Phenotypic characterization of immune cell markers supported lymphocyte activation and proinflammatory cytokines signaling pathways (i.e., IL-15, IL-32). The activation of B, NK, and T cells reveals potential immune cells underlying subclinical inflammation and repair. These single nuclei analyses provide novel insights into kidney and immune cell associated signaling pathways that portray kidney grafts with normal allograft function beyond 2-years post-transplant, revealing a novel perspective in understanding long-term allograft graft survival.en_US
dc.relation.ispartofFrontiers in Transplantationen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.subjectalloimmune responseen_US
dc.subject.meshKidney Transplantationen_US
dc.subject.meshBiopsy, Large-Core Needleen_US
dc.subject.meshSequence Analysis, RNAen_US
dc.titleThe cellular landscape of the normal kidney allograft: Main players balancing the alloimmune responseen_US

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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International