Detection of infiltrating fibroblasts by single-cell transcriptomics in human kidney allografts.

TitleDetection of infiltrating fibroblasts by single-cell transcriptomics in human kidney allografts.
Publication TypeJournal Article
Year of Publication2022
AuthorsSuryawanshi H, Yang H, Lubetzky M, Morozov P, Lagman M, Thareja G, Alonso A, Li C, Snopkowski C, Belkadi A, Mueller FB, Lee JR, Dadhania DM, Salvatore SP, Seshan SV, Sharma VK, Suhre K, Suthanthiran M, Tuschl T, Muthukumar T
JournalPLoS One
Date Published2022
KeywordsAllografts, Fibroblasts, Fibrosis, Graft Rejection, Humans, Kidney, Kidney Diseases, Kidney Transplantation, Living Donors, Transcriptome

We tested the hypothesis that single-cell RNA-sequencing (scRNA-seq) analysis of human kidney allograft biopsies will reveal distinct cell types and states and yield insights to decipher the complex heterogeneity of alloimmune injury. We selected 3 biopsies of kidney cortex from 3 individuals for scRNA-seq and processed them fresh using an identical protocol on the 10x Chromium platform; (i) HK: native kidney biopsy from a living donor, (ii) AK1: allograft kidney with transplant glomerulopathy, tubulointerstitial fibrosis, and worsening graft function, and (iii) AK2: allograft kidney after successful treatment of active antibody-mediated rejection. We did not study T-cell-mediated rejections. We generated 7217 high-quality single cell transcriptomes. Taking advantage of the recipient-donor sex mismatches revealed by X and Y chromosome autosomal gene expression, we determined that in AK1 with fibrosis, 42 months after transplantation, more than half of the kidney allograft fibroblasts were recipient-derived and therefore likely migratory and graft infiltrative, whereas in AK2 without fibrosis, 84 months after transplantation, most fibroblasts were donor-organ-derived. Furthermore, AK1 was enriched for tubular progenitor cells overexpressing profibrotic extracellular matrix genes. AK2, eight months after successful treatment of rejection, contained plasmablast cells with high expression of immunoglobulins, endothelial cell elaboration of T cell chemoattractant cytokines, and persistent presence of cytotoxic T cells. In addition to these key findings, our analysis revealed unique cell types and states in the kidney. Altogether, single-cell transcriptomics yielded novel mechanistic insights, which could pave the way for individualizing the care of transplant recipients.

Alternate JournalPLoS One
PubMed ID35657798
PubMed Central IDPMC9165878
Grant ListR37 AI051652 / AI / NIAID NIH HHS / United States
K08 DK087824 / DK / NIDDK NIH HHS / United States
R03 DK105270 / DK / NIDDK NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
Related Faculty: 
Surya V. Seshan, M.D. Steven P. Salvatore, M.D.

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