Human kidney clonal proliferation disclose lineage-restricted precursor characteristics

Cohen Zontag Osnat, Gershon Rotem, Harari Steinberg Orit, Kanter Itamar, Omer Dorit, Pleniceanu Oren, Tam Gal, Oriel Sarit, Ben Hur Herzel, Katz Guy, Zohar Dotan, Kalisky Tomer, Dekel Benjamin*, Pode Shakked Naomi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

In-vivo single cell clonal analysis in the adult mouse kidney has previously shown lineage-restricted clonal proliferation within varying nephron segments as a mechanism responsible for cell replacement and local regeneration. To analyze ex-vivo clonal growth, we now preformed limiting dilution to generate genuine clonal cultures from one single human renal epithelial cell, which can give rise to up to 3.4 * 106 cells, and analyzed their characteristics using transcriptomics. A comparison between clonal cultures revealed restriction to either proximal or distal kidney sub-lineages with distinct cellular and molecular characteristics; rapidly amplifying de-differentiated clones and a stably proliferating cuboidal epithelial-appearing clones, respectively. Furthermore, each showed distinct molecular features including cell-cycle, epithelial-mesenchymal transition, oxidative phosphorylation, BMP signaling pathway and cell surface markers. In addition, analysis of clonal versus bulk cultures show early clones to be more quiescent, with elevated expression of renal developmental genes and overall reduction in renal identity markers, but with an overlapping expression of nephron segment identifiers and multiple identity. Thus, ex-vivo clonal growth mimics the in-vivo situation displaying lineage-restricted precursor characteristics of mature renal cells. These data suggest that for reconstruction of varying renal lineages with human adult kidney based organoid technology and kidney regeneration ex-vivo, use of multiple heterogeneous precursors is warranted.

Original languageEnglish
Article number22097
JournalScientific Reports
Volume10
Issue number1
DOIs
StatePublished - Dec 2020

Funding

FundersFunder number
Bretler Foundation
Euro-Asian Jewish Congress foundation
Sackler School of Medicine
EU-FP7
Israel Science Foundation910/20111, 2071/2017
Israel Cancer Association20150911
Lisa and David Pulver Family Foundation2017/13, 1634/13, 1902/12
Ministry of Health, State of Israel3-10146
Seventh Framework Programme618592

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