Abstract
When assembling a nephron during development a multipotent stem cell pool becomes restricted as differentiation ensues. A faulty differentiation arrest in this process leads to transformation and initiation of a Wilms’ tumor. Mapping these transitions with respective surface markers affords accessibility to specific cell subpopulations. NCAM1 and CD133 have been previously suggested to mark human renal progenitor populations. Herein, using cell sorting, RNA sequencing, in vitro studies with serum-free media and in vivo xenotransplantation we demonstrate a sequential map that links human kidney development and tumorigenesis; In nephrogenesis, NCAM1+CD133− marks SIX2+ multipotent renal stem cells transiting to NCAM1+CD133+ differentiating segment-specific SIX2− epithelial progenitors and NCAM1−CD133+ differentiated nephron cells. In tumorigenesis, NCAM1+CD133− marks SIX2+ blastema that includes the ALDH1+ WT cancer stem/initiating cells, while NCAM1+CD133+ and NCAM1−CD133+ specifying early and late epithelial differentiation, are severely restricted in tumor initiation capacity and tumor self-renewal. Thus, negative selection for CD133 is required for defining NCAM1+ nephron stem cells in normal and malignant nephrogenesis.
Highlights
For SIX2-epressing CM cells, representing a mitotically active cell population harboring stem/progenitor traits, including enhanced clonogenic and renal differentiation capacity and therapeutic potential in a 5/6 nephrectomy kidney injury model
Associated cellular compartments in human fetal kidney (hFK) and Wilms’ tumor (WT), we initially carried out immunohistochemical staining (IHC) of hFK, primary WT and pure blastema WT-patient-derived xenografts (WT PDX) for the surface markers NCAM1, FZD7 and CD133 and the transcription factor SIX2 (Fig. 1A, Table 1 and Figure S1)
While NCAM1 localized mainly to the CM, blastema, early post-mesenchymal to epithelial (MET) structures (C/Sshaped bodies and immature tubules in hFK and primary Wilms’ tumor (pWT), respectively) and interstitium, CD133 was detected in mature epithelial structures and to a lesser extent in early post-MET structures, but was completely excluded from the CM and blastema
Summary
Simple Prospective Purification of received:24October2014 accepted: 08 March 2016. Naomi Pode-Shakked1,2,3,9,*, Oren Pleniceanu1,2,9,*, Rotem Gershon[1,2,9], Rachel Shukrun[1,2,9], Itamar Kanter[4], Efrat Bucris[4], Ben Pode-Shakked[3,5,9], Gal Tam[4], Hadar Tam[4], Revital Caspi[1,2,9], Sara Pri-Chen[1,6], Einav Vax[1,2,9], Guy Katz[1,2,3,7], Dorit Omer[1,2,9], Orit Harari-Steinberg[1,2], Tomer Kalisky4 & Benjamin Dekel[1,2,8,9]. We were interested in identifying a specific surface marker expression pattern of both nephron stem/progenitors in hFK and cancer stem cells in WT, which could allow prospective isolation of the former as well as further characterization of the latter, towards more efficient eradication of the tumor. To achieve this goal, we investigated the expression of NCAM1, FZD7 and CD133 in the various cellular compartments of human fetal kidney (hFK), primary Wilms’ tumor (pWT) and Wilms, tumor patient–derived xenografts (WT-PDX). These findings allow establishment of a more generalized scheme of the various cellular components of hFK and WT, and afford simple method to isolate human nephron stem cells and define CSCs in primary human WT
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