Abstract: SA-OR66
Cell Subtypes and Cell-Specific Pathways Associated with Acute-to-Chronic Injury Transition in Posttransplant AKI
Session Information
- Kidney Transplantation: New Translational Insights
November 04, 2023 | Location: Room 115, Pennsylvania Convention Center
Abstract Time: 05:42 PM - 05:51 PM
Category: Transplantation
- 2102 Transplantation: Clinical
Authors
- Akalin, Enver, Montefiore Medical Center, New York, New York, United States
- Azim, Shafquat, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Shetty, Amol C., University of Maryland School of Medicine, Baltimore, Maryland, United States
- Rousselle, Thomas, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Zubair, Haseeb, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Mas, Valeria R., University of Maryland School of Medicine, Baltimore, Maryland, United States
Background
Kidney transplants (KT) offer a unique opportunity to evaluate molecular pathways involved in development and response to acute kidney injury (AKI). This study of transplanted kidneys with AKI aims to identify cells involved in injury or impaired reparation.
Methods
A total of 14 kidney samples (normal donor kidneys, n=5, normal allografts, n=4, and samples from patients with post-KT AKI, n=4 (<6weeks post-KT)) were evaluated using single nuclei (sn) RNA-seq.
Results
The analyses of 49,787 combined nuclei showed increased fibroblasts in post-KT AKI samples. Fibroblasts in post-KT AKI compared to normal allografts showed increased expression of genes enriched in extracellular matrix (ECM) organization, proteoglycans, ecollagen formation, and response to wounding. The analyses of these fibroblasts in 3 sex-mismatched cases using an XY-gene expression signature showed both donor- and recipient-derived fibroblasts (Fig 1A) not observed in normal allografts. Up-regulated genes in recipient fibroblasts were enriched in laminin interactions, ECM organization, and cellular response to TGF-β stimulus. Increased macrophages (MΦ) proportions in AKI samples, and 3 MΦ subsets were identified, including: MΦ1 (MRC1, LGMN, STAB1) and MΦ3 (FCN1, LYN1, KYNU1, RTN11), and the MΦ2 (CSF3R, LUCAT1, NCF1, LIMK2) (Fig 1B-C) characterized by markers of myofibroblasts/fibroblast-like (COL18A1, COL4A3, COL4A4, VCAN, AB3BP, FGL2, GAS6, THSD4). Resident and infiltrating MΦ present a pro-inflammatory profile and enriched in immunoregulatory response signaling pathways.
Conclusion
These novel data emphasize the critical role of resident MΦ in responding to injury transform into MΦ with fibroblast-like markers and a transcriptomic phenotype leading to impaired repair.
Funding
- Other NIH Support