Reactivation of NCAM1 defines a subpopulation of human adult kidney epithelial cells with clonogenic and stem/progenitor properties.
The nephron is composed of a monolayer of epithelial cells that make up its various compartments. In development, these cells begin as mesenchyme. NCAM1, abundant in the mesenchyme and early nephron lineage, ceases to express in mature kidney epithelia. We show that, once placed in culture and released from quiescence, adult human kidney epithelial cells (hKEpCs), uniformly positive for CD24/CD133, re-express NCAM1 in a specific cell subset that attains a stem/progenitor state. Immunosorted NCAM1(+) cells overexpressed early nephron progenitor markers (PAX2, SALL1, SIX2, WT1) and acquired a mesenchymal fate, indicated by high vimentim and reduced E-cadherin levels. Gene expression and microarray analysis disclosed both a proximal tubular origin of these cells and molecules regulating epithelial-mesenchymal transition. NCAM1(+) cells generated clonal progeny when cultured in the presence of fetal kidney conditioned medium, differentiated along mesenchymal lineages but retained the unique propensity to generate epithelial kidney spheres and produce epithelial renal tissue on single-cell grafting in chick CAM and mouse. Depletion of NCAM1(+) cells from hKEpCs abrogated stemness traits in vitro. Eliminating these cells during the regenerative response that follows glycerol-induced acute tubular necrosis worsened peak renal injury in vivo. Thus, higher clone-forming and developmental capacities characterize a distinct subset of adult kidney-derived cells. The ability to influence an endogenous regenerative response via NCAM1 targeting may lead to novel therapeutics for renal diseases.
Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel; Sheba Center for Regenerative Medicine, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel.
Ella
E
Buzhor
Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel; Sheba Center for Regenerative Medicine, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel.
Dorit
D
Omer
Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel; Sheba Center for Regenerative Medicine, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel.
Orit
O
Harari-Steinberg
Department of Urology, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel.
Zohar
Z
Dotan
Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel; Sheba Center for Regenerative Medicine, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel.
Einav
E
Vax
Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel; Maurice and Gabriela Goldschleger Eye Research Institute, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel.
Sara
S
Pri-Chen
Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel; Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Sally
S
Metsuyanim
Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel; Sheba Center for Regenerative Medicine, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel.
Oren
O
Pleniceanu
Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Ronald S
RS
Goldstein
Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel; Sheba Center for Regenerative Medicine, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel; Division of Pediatric Nephrology, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel. Electronic address: benjamin.dekel@gmail.com.
Benjamin
B
Dekel
D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001806:Blood Urea Nitrogen; D019002:CD56 Antigen / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002645:Chickens; D002999:Clone Cells; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D063990:Gene Ontology; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D058977:Molecular Sequence Annotation; D009399:Nephrons / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D000906:Antibodies; D015415:Biomarkers; D019002:CD56 Antigen; C522918:NCAM1 protein, human