The study of human nephrogenesis and Wilms` tumor (WT) carcinogenesis would benefit from a cell lineage map similar to that of the hematopoietic lineages. Here we sought to define cell lineage relationships based on the expression of NCAM1, CD133 and FZD7 in primary human WT (pWT), WT xenografts (WT-Xn) and human fetal kidney (hFK). Renal developmental cell lineages fractionated according to these surface markers were assayed for clonogenic potential, gene expression, tumor initiation and cell differentiation. CD133 was surprisingly established as an epithelial differentiation marker in all tissues analyzed. Up-regulation of CD133 was accompanied by reduced renal progenitor gene expression and clonal capacity, and restriction of WT initiation. Accordingly, NCAM1+CD133- identified WT blastema, harboring the ALDH1+ WT cancer stem cells, and hFK cap mesenchyme (CM). In contrast, NCAM1+CD133+ and NCAM1-CD133+ represent early tubular differentiation stages and mature renal epithelia, respectively, in both normal and malignant tissues. FZD7 expressed in all nephron compartments but not in WT stroma or hFK interstitium which harbor non-nephron lineage NCAM1+CD133- cells. Thus FZD7 can facilitate the specific isolation of CM (NCAM1+FZD7+CD133-). In conclusion, these markers identify specific stages of renal lineage commitment and WT differentiation, providing a framework for therapeutic applications.
