Ontogeny of CD24 in the human kidney
Larissa Ivanova1, Michael J. Hiatt1, Mervin C. Yoder2,3, Alice F. Tarantal3,4,5,6and Douglas G. Matsell1,3
1Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada;
2Department of Pediatrics, Indiana University, Indianapolis, Indiana, USA;3Center of Excellence in Translational Human Stem Cell
Research, Davis, California, USA;4California National Primate Research Center, University of California, Davis, Davis, California, USA;
5Department of Pediatrics, University of California, Davis, Davis, California, USA and6Department of Cell Biology and Human Anatomy,
University of California, Davis, Davis, California, USA
The heat-stable antigen, CD24, is a cell-surface
sialoglycoprotein expressed on immature cells that
disappears after they have reached their final stage of
differentiation. In mice, CD24 expression is preferentially
upregulated in the developing mouse metanephros as
compared with the surrounding intermediate mesoderm, but
its role and expression in the developing human kidney has
not been well described. Here we found in normal human
fetal kidneys (8 to 38 weeks of gestation) that CD24
expression was upregulated and restricted to the early
epithelial aggregates of the metanephric blastema and to the
committed proliferating tubular epithelia of the S-shape
bodies. Individual cells expressing CD24 were identified in
the interstitium of later gestation and postnatal kidneys. In
freshly isolated cells, FACS analysis identified distinct CD24þ
and CD24þ133þcell populations constituting up to 16 and
14 percent, respectively, of the total cells analyzed. Early fetal
urinary tract obstruction resulted in upregulation of CD24
expression both in developing epithelial structures of early
stages and in the cells of the injured tubular epithelium of
the later gestation kidneys. Our results highlight the cell-
specific expression of CD24 in the developing human kidney
and its dysregulation during fetal urinary tract obstruction.
Kidney International (2010) 77, 1123–1131; doi:10.1038/ki.2010.39;
published online 24 March 2010
KEYWORDS: kidney development; obstructive uropathy; renal epithelial cell;
renal stem cell
Novel approaches for regenerative medicine include the use
of stem and progenitor cell therapy, which may be useful for
repair of kidneys damaged by disease.1Uninduced meta-
nephric mesenchymal cells isolated from embryonic kidneys
have been shown to form renal epithelial structures, and also
integrate into the developing renal collecting system of the
embryo.2,3Using early fetal mouse metanephric tissue and a
subtractive gene array strategy, Challen et al.4defined a
number of genes that were preferentially upregulated in the
developing mouse metanephros when compared with the
surrounding intermediate mesoderm. Among these, CD24
and cadherin-11, both cell-surface proteins, were significantly
upregulated. Recent studies have also identified a population
of parietal epithelial cells, isolated from the Bowman’s capsule
of human adult kidneys, which are CD24þCD133þ, and
which show properties of self-renewal, pluripotency, and the
ability to engraft in injured mouse kidneys.5,6This same
group characterized a CD24þCD133þrenal progenitor cell
population in human embryonic kidneys with a similar
ability of self-renewal, pluripotency, and engraftment in
In this study, we have shown the temporal and spatial
expression of CD24 during normal human fetal kidney
development and in kidneys affected by fetal urinary tract
Ontogeny of CD24 expression
CD24 protein expression was analyzed by immunohistochem-
istry. Expression was noted as early as 8 weeks gestation and
was localized specifically and abundantly in early induced
epithelial cells in the nephrogenic zone of the developing
metanephros (Figure 1). Under high-power magnification,
there was abundant expression in the early-induced epithelial
aggregates, derived from the metanephric blastema cells, most
pronounced in the vesicle and comma-shaped stage of
epithelial differentiation, persisting into the S-shape nephron
(Figure 1, insets; Figures 2a–c). These features were most
apparent in the earlier gestation kidneys (Figure 2).
The subcellular distribution of CD24 changed with
increasing gestational age. In fetal kidneys at 8 and 11 weeks
gestation, CD24 immunoreactivity localized to the apical and
& 2010 International Society of Nephrology
Received 15 June 2009; revised 4 December 2009; accepted 5 January
2010; published online 24 March 2010
Correspondence: Douglas G. Matsell, Department of Pediatrics, University
of British Columbia, BC Children’s Hospital, 4480 Oak Street, Room K4-150,
Vancouver, British Columbia, Canada V6H 3V4. E-mail: email@example.com
Kidney International (2010) 77, 1123–1131
basolateral membranes (Figure 1, insets; Figure 2a), at 17
weeks gestation was localized more diffusely to the cytoplasm
(Figure 2b), and by 27 weeks was in the cytoplasm of the
epithelia of the developing S-shape nephrons and in scattered
interstitial cells (Figure 2c). Very weak CD24 immunoreac-
tivity was detected in the occasional comma and S-shape
bodies in the nephrogenic zone of 36-week gestation kidneys
(Figure 2d). After nephrogenesis was complete, CD24
expression was absent in most epithelia of the nephron
(Figure 2e) but again was found in scattered interstitial cells
(Figure 2f). In the postnatal kidneys CD24 showed punctate
expression in the cells of the macula densa, adjacent to the
juxtaglomerular cells of the glomerular vasculature (Figures
2g and h).
Ontogeny of CD133 expression
In the 11-week gestation kidneys, CD133 immunoreactivity
colocalized with CD24 in the epithelia of the developing
ureteric bud, renal vesicles, and S-shape bodies (Figure 2a).
However, in contrast to CD24 expression, CD133 localized to
the apical membrane throughout the developing ureteric bud
epithelium (Figure 2a), and was observed in the cells of the
uninduced metanephric mesenchyme. At this stage cells
showed uniform surface membrane expression of the CD133
protein. The later gestation 17- to 27-week kidneys showed
similar CD133 expression; however uninduced metanephric
mesenchyme contained significantly less cells expressing
CD133 (Figures 2b and c). After completion of nephrogen-
esis, and with development of vascularized glomeruli, CD133
Figure 1|Fetal kidney CD24 expression. Eight week gestation
human fetal kidney with CD24 immunoreactivity (IR) (red)
localized to early-induced epithelial cells in the nephrogenic zone
(arrows). Bar¼100mm. There was abundant expression in the
early-induced epithelial aggregates (insets). Bars¼10mm.
Figure 2|Ontogeny of CD24 and CD133 expression. (a–c)
Eleven, 17, and 27 week gestation kidneys respectively, showing
CD24-IR in the early epithelial aggregate (a), vesicle (v), and
comma-shaped (c) stage of epithelial differentiation, persisting
into the S-shape nephron (s) (arrows). CD133-IR (green) was
colocalized to epithelial precursors of the developing tubular
epithelium and to the apical membrane throughout the
developing ureteric bud epithelium in early gestation
(arrowheads). u¼ureteric bud. (d) CD24-IR was localized to
interstitial cells in the 36 week gestation fetal kidney (arrow),
whereas CD133 was localized predominantly to the developing
parietal and visceral epithelia of the glomerulus (arrowheads).
(e, f) In the postnatal kidneys CD24-IR was absent in the epithelia
of the nephron, but occasional CD24þcells were again identified
in the interstitium (arrows). CD133-IR was localized to the visceral
and parietal epithelium of the developed glomerulus (g) and to
the proximal tubule (arrowheads). (g) CD24-IR was observed in
cells of the macula densa of the early distal tubule (arrow). (h)
Colocalization of CD24 and CD133-IR in the cells of macula densa
(arrow) and expression of CD133 in the visceral and parietal cells
of glomeruli (arrowheads). Bars: (a–g)¼25mm; (h)¼10mm.
Kidney International (2010) 77, 1123–1131
L Ivanova et al.: Kidney CD24
Statistical analysis for gene microarray data was conducted using
the LMGene software for data transformation and identification of
differentially expressed genes in gene expression arrays, and data
were normalized using Affy/RMA. The new version 2.6.0 of R was
used for the analysis. To identify differentially expressed genes,
posterior-FDR P-value was computed for each probe set. P-values
less than 0.05 were considered significant.
All the authors declared no competing interests.
This work was supported by NIH grants HL085036 and RR00169.
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L Ivanova et al.: Kidney CD24