Dissecting Stages of Human Kidney Development and Tumorigenesis with Surface Markers Affords Simple Prospective Purification of Nephron Stem Cells

Naomi Pode-Shakked, Oren Pleniceanu, Rotem Gershon, Rachel Shukrun, Itamar Kanter, Efrat Bucris, Ben Pode-Shakked, Gal Tam, Hadar Tam, Revital Caspi, Sara Pri-Chen, Einav Vax, Guy Katz, Dorit Omer, Orit Harari-Steinberg, Tomer Kalisky, Benjamin Dekel

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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.

Original languageEnglish
Article number23562
JournalScientific Reports
StatePublished - 29 Mar 2016

Bibliographical note

Funding Information:
This work was supported by the ICRF (Grant no. 15731 and 15450), the Israel Cancer Association (Grant no. 20150916) and The Ziering Foundation (Grant no. 45124) (B. D). T.K., I.K., T.G., T.H. and E.B. was supported by the Israel Science Foundation (ICORE no. 1902/12 and Grants no.1634/13 and 2017/13), the Israel Cancer Association (Grant no. 20150911), the Israel Ministry of Health (Grant no. 3-10146), and the EU-FP7 (Marie Curie International Reintegration Grant no. 618592). We thank the Israel National Center for Personalized Medicine (INCMP) for their assistance in DNA sequencing and analysis.


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