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

Sci Rep. 2016 Mar 29;6:23562. doi: 10.1038/srep23562.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen / genetics
  • AC133 Antigen / metabolism
  • Animals
  • Biomarkers / metabolism*
  • CD56 Antigen / genetics
  • CD56 Antigen / metabolism
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • Gene Expression Regulation
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunohistochemistry
  • Infant
  • Kidney / embryology
  • Kidney / metabolism*
  • Male
  • Mice, Inbred NOD
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Nephrons / cytology
  • Nephrons / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Organogenesis / genetics
  • Prospective Studies
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cells / metabolism*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • AC133 Antigen
  • Biomarkers
  • CD56 Antigen
  • Homeodomain Proteins
  • NCAM1 protein, human
  • Nerve Tissue Proteins
  • SIX2 protein, human