Urinary single-cell sequencing captures intrarenal injury and repair processes in human acute kidney injury
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ABSTRACT:
PROVIDER: PRJNA819390 | ENA |
REPOSITORIES: ENA
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Project description:Acute kidney injury (AKI) is a major health issue, the outcome of which depends primarily on damage and reparative processes of tubular epithelial cells (TEC). Mechanisms underlying AKI remain incompletely understood, specific therapies are lacking and monitoring the course of AKI in clinical routine is confined to measuring urine output and plasma levels of filtration markers. Here we demonstrate feasibility and potential of a novel approach to assess the cellular and molecular dynamics of AKI by establishing a robust urine-to-single cell RNA sequencing (scRNAseq) pipeline for excreted kidney cells via flow cytometry sorting. We analyzed 42,608 single cell transcriptomes of 40 urine samples from 32 AKI patients and compared our data with reference material from human AKI post-mortem biopsies and published mouse data. We demonstrate that TEC transcriptomes mirror intrarenal pathology and reflect distinct injury and repair processes, including oxidative stress, inflammation, and tissue rearrangement. In conclusion, single cell transcriptomics of kidney cells excreted in urine provides non-invasive, unprecedented insight into cellular processes underlying AKI, thereby opening novel opportunities for target identification, AKI sub-categorization and monitoring of natural disease course and interventions.
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Project description:Periurethral human mesenchymal stem cell (hMSC) injections are associated with functional improvement in animal models of post-partum stress urinary incontinence (SUI). However, limited data exists on the role of hMSCs in modulating gene expression in tissue repair after urethral injury. We quantified temporal gene expression modulation in hMSCs, and injured rat urethral tissue, using RNA seq in an animal model of SUI, over a 3-day time period following urethral injury, and local hMSC therapy. We injected PKH fluorescent-labeled human hMSC into the periurethral space of rats, following a 4h vaginal distention (3 rats per time point). Control rats underwent vaginal distention injury only, and were sacrificed at 12h, 24h, 36h, 72h post injury. Rat urethral and vaginal tissues were frozen and sectioned. Fluorescent labeled hMSCs were distinguished from adjacent, unlabeled rat urethral tissue. RNA was prepared from urethral tissue obtained by laser dissection of frozen tissue sections and sequenced on an Illumina HiSeq 2500. Differentially expressed genes (DEGs) over 72h were evaluated using a 2-group t-test (p<0.05). Our transcriptional analyses identified candidate genes involved in tissue injury, that were broadly sorted by injury and exposure to hMSC, throughout the first 72h of acute phase of injury. DEGs in treated urethra, compared with untreated urethra, were functionally associated with tissue repair, angiogenesis, neurogenesis, and oxidative stress suppression. DEGs included a variety of cytokines, extracellular matrix stabilization and regeneration genes, cytokine signaling modification, cell cycle regulation, muscle differentiation and stabilization. Moreover, our results revealed DEGs changes in the hMSCs (PKH-labelled), which were harvested from injured urethra. The expressions are related to DNA damage repair, transcription activation, stem cell regulation, cell survival, apoptosis, self-renewal, cell proliferation, migration and injury response.
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Project description:The anterior cruciate ligament (ACL) is an essential stabilizer of the tibiofemoral articulation. ACL tears often lead to functional instability and are associated with an increased risk for osteoarthritis. The healing potential of the injured ACL is poorly understood and is considered to be limited. Transcriptome-wide expression profiles of 24 human ACL remnants recovered at the time of surgical reconstruction were analyzed utilizing the Agilent human 8x60K microarray platform. Gene ontology was performed on differentially expressed transcripts based on time-from-injury (acute, <3 months; intermediate, 3-12 months; chronic, >12 months). A subset of transcripts was validated via microfluidic digital polymerase-chain-reaction. Expression of periostin, a highly differentially expressed transcript, was tested by immunohistochemistry. Numerous transcripts covering important functional classifications were differentially expressed by time-from-injury. In acute tears, processes representing angiogenesis were repressed while those representing stem-cell differentiation were elevated. In intermediate tears, processes representing stem-cell proliferation concomitant with cellular component organization/cellular localization were elevated. In chronic tears, processes denoting myosin filament organization were elevated while those representing cellular component organization/cell localization and extracellular matrix organization were repressed. Expression levels of periostin were down-regulated in chronic tears compared to acute (42-fold) and intermediate (29-fold) tears. Immunohistochemistry confirmed a decline in periostin expression in tissues from chronic tears. These findings suggest an initial attempt of the injured ACL to repair, which declines with time-from-injury. These findings have implications for efforts to repair the ACL and may be relevant for reconstruction of the ACL. The functional role of periostin in ACL injuries, and the potential implication for surgical treatment, warrants further investigation. Total RNA obtained frominjured anterior cruciate ligament (ACL) tissues from pateints undergoing ACL surgery.
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