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First published online 25 June 2008
doi: 10.1242/dev.022145
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Research Report |
Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
Author for correspondence (e-mail:
jamie.davies{at}ed.ac.uk)
Accepted 6 June 2008
SUMMARY
Branching morphogenesis of epithelia is an important mechanism in animal development, being responsible for the characteristic architectures of glandular organs such as kidney, lung, prostate and salivary gland. In these systems, new branches usually arise at the tips of existing branches. Recent studies, particularly in kidney, have shown that tip cells express a set of genes distinct from those in the stalks. Tip cells also undergo most cell proliferation, daughter cells either remaining in the tip or being left behind as the tips advance, to differentiate and contribute to new stalk. Published time-lapse observations have suggested, though, that new branches may be able to arise from stalks. This happens so rarely, however, that it is not clear whether this reflects true plasticity and reversal of differentiation, or whether it is just an occasional instance of groups of tip cells being `left behind' by error in a mainly stalk zone. To determine whether cells that have differentiated into stalks really do retain the ability to make new tips, we have removed existing tips from stalks, verified that the stalks are free of tip cells, and assessed the ability of tip-free stalks to initiate new branches. We find stalks to be fully capable of regenerating tips that express typical tip markers, with these tips going on to form epithelial trees, at high frequency. The transition from tip to stalk is therefore reversible, at least for early stages of development. This observation has major implications for models of pattern formation in branching trees, and may also be important for tissue engineering and regenerative medicine.
Key words: Kidney, Regeneration, Stem cell, Ureteric bud, Branching
INTRODUCTION
Branching morphogenesis of epithelia is a common event in mammalian
organogenesis. The process forms the airways of the lung, the milk ducts of
the mammary glands, the exocrine ducts of the pancreas, the urine collecting
ducts of the kidney, the seminiferous ducts of the prostate, and the ducts of
salivary, lacrymal and uterine glands
(Davies, 2005
). Generally,
these systems develop by dipodial branching, in which the ends of existing
branches bifurcate and separate from one another as the tubule elongates.
Although branching morphogenesis has been studied intensively for several
years, significant gaps in our knowledge remain. One of the most important
unanswered questions is whether the ability to initiate new branches is
confined only to certain cells in a branching epithelium, for example those at
the tip of an existing branch, or whether all parts of the epithelium can do
it. The answer will have important implications for our basic understanding of
how branched systems organize themselves and may also have implications for
regenerative medicine. This report addresses this question in one of the
most-studied branching epithelia, the renal collecting duct system.
The renal urinary collecting duct system arises from an initially
unbranched epithelium, the ureteric bud, which invades the metanephric
mesenchyme half way through mouse gestation and branches within it to produce
approximately 1600 branches over approximately 10-11 rounds of bifurcation
(Cebrian et al., 2004).
Although much work has been done on this system, it is still not clear whether
the ability to branch is confined to just a subset of cells or whether it is
spread generally throughout the system: there is circumstantial evidence on
both sides of the argument.
The main arguments that the ability to produce new branches is restricted
to the tip concern the normal pattern of branching, the normal pattern of cell
differentiation, and a close correlation between the two. Detailed time-lapse
observations of renal branching morphogenesis have shown that most branching
events (94%) take place by bifurcation at the ends of existing branches
(Watanabe and Costantini,
2004). Cells in the terminal 70 µm of branches (`tips') are the
main zone of cell proliferation (Michael
and Davies, 2004) and show patterns of gene expression that differ
from those in the regions behind them (`stalks'). Tip-specific markers include
Wnt11 and Sox9, while stalk-specific markers include
collagen XVIII, Wnt9b and a glycoprotein that binds Dolichos
biflorus agglutinin (DBA) (Lin et
al., 2001; Michael et al.,
2007; Kent et al.,
1996; Carroll et al.,
2005; Kispert et al.,
1996). Careful measurements suggest that the zone of
proliferation, the zone of Wnt11 expression, and the zone of absence
of DBA and collagen XVIII seem to respect a common boundary
(Table 1). The fact that most
branching takes place in the tip zone, which shows different gene expression
to the stalks, suggests that there may be a tip state of differentiation that
makes cells capable of initiating branches.
|
). The low frequency of these events makes their
interpretation difficult. It is known from careful analyses of mosaic organs,
a few cells of which express green fluorescent protein (GFP), that some cells
get `left behind' by the tips to contribute to the stalk
(Shakya et al., 2005). It is
therefore possible that the very infrequent lateral branches actually arise
from small groups of such tip cells that have not yet differentiated into
stalks. A second, circumstantial, argument, comes from the fact that cell
lines from renal collecting ducts can produce branching tubules in
three-dimensional culture systems without - as far as is known - requiring
branch-producing cells to be in a separate state of differentiation
(Santos and Nigam, 1993). A
third argument is that various physical models of branching morphogenesis,
such as viscous fingering, have no need for the ability to initiate branches
to be restricted to specific cells (Fleury
and Watanabe, 2002; Fleury et
al., 2004). A fourth possible argument is that the Wolffian duct,
from which the ureteric bud normally emerges as a single side branch, can be
induced to produce supernumerary side branches by the focal application of
ramogens, such as GDNF (Sainio et al.,
1997; Davies et al.,
1999). The problem with this argument is that the production of a
side branch is an essential property of the amniote Wolffian duct, so extra
side-branching from it does not necessarily imply that side-branching is a
normal ability of the ureteric bud itself. Establishing whether the ability to initiate branching is restricted or distributed within the ureteric bud/collecting duct system is important, because it carries major implications for understading patterning mechanisms and for creating strategies to promote regeneration. We have therefore directly tested the ability of stalk regions to generate new branching tips. Our results support a model in which the ability to initiate branches is distributed widely, and not restricted to cells that already express genetic markers characteristic of branch tips.
MATERIALS AND METHODS
Dissection and organ culture
Metanephric rudiments were dissected from E11.5-E17.5 CD1 mouse embryos,
the ureteric bud being cut close to its junction with the Wolffian
duct/bladder. Ureteric `stalks' were removed from tip regions by cutting just
below the `T' junction of E11.5 kidneys, and the remaining tip regions were
retained for staining for Wnt11 or with Dolichos biflorus agglutinin
(DBA). Deliberate injuries to ureteric bud stalks or mesenchyme, for the
experiments that needed them, were achieved by stabbing with 0.5x16-mm
needles. Where surrounding stroma had to be removed from ureters (see main
text), this was achieved by trypsinization in 2x trypsin-EDTA for two
minutes followed by manual separation of the stroma and stalk. Organs were
cultured on Isopore filters (Millipore) on Trowell-type grids in 35-mm petri
dishes in MEM (Sigma M5650), with 10% fetal calf serum and
penicillin-streptomycin solution in 5% CO2 at 37°C.
RT-PCR for Wnt 11
For determination of the maximum possible extent of contamination of stalk
numbers by tip cells, we used conventional end-point PCR to detect
Wnt11 in various dilutions of kidney cDNA that represented known
numbers of tip cells. In this way, we established that we could detect
Wnt11 cDNA derived from as few as 0.81±0.1 tip cells clearly
(and very faintly from reactions from smaller numbers of cells). At the same
time, we used the same PCR technique (described below) to attempt to detect
Wnt11 from stalk-derived cDNA without dilution, and showed the signal
in a reaction representing cDNA from 0.44 stalks (see below) to be barely
detectable. This was used to conclude that 0.44 stalks included fewer than
0.81 contaminating tip cells, or that a stalk contained fewer than two
contaminating tip cells.
In detail, total RNA was isolated from 28 whole kidneys, or from 35 stalks-plus-surrounding mesenchyme, using the SV total RNA isolation kit (Promega), and 200 ng of each type of RNA was used to make cDNA using the MLV-RT kit (Promega). One twentieth of the cDNA was then used for each normal PCR reaction. The actual volumes and dilutions of each stage were recorded accurately for subsequent calculations of the number of tip cells and stalks represented in PCR reactions (these calculations also used the fact that each tip consists of 117±18 cells, the measurement of which is described in the immunofluorescence section below). Tracking the dilutions of the samples as they were processed indicated that each PCR reaction from stalk cDNA represented the RNA of about 0.44 stalks and that each normal PCR reaction from kidney included RNA from a mean of 81±12 tip cells (together with many non-tip cells). Primers for β-actin were used in the normal PCR reactions to provide a further check that the dilutions used to create the normal stalk and kidney PCRs were correct and represented the same total number of cells. In addition to standard PCR reactions, reactions were also performed in which the kidney cDNA from the reverse transcription (RT) step was diluted 1/10, 1/100, 1/500, 1/1000 and 1/5000: these therefore represented RNA from 8.1, 0.81, 0.16, 0.081 and 0.016 tip cells. This dilution series was run in lanes adjacent to the normal PCRs from kidney and stalk to establish a threshold of clear detection.
For detection of Wnt11 expression in tips growing from ureteric bud stalks, total RNA was isolated from four stalks that had been allowed to generate new tips by surrounding them with fresh E11.5 mesenchyme, and cDNA was synthesized using the same techniques and concentrations as are described above.
Fixation and immuno/lectin-fluorescence
Kidneys/recombinants intended for immuno- or lectin-fluorescence were fixed
in methanol, washed in PBS with 4% milk powder and incubated in 1/100 mouse
anti-calbindin-D28k (Abcam) and/or 1/200 rabbit anti-laminin
(Sigma) in PBS overnight at 4°C. They were then washed in PBS, and
transferred to donkey anti-mouse IgG-Texas Red (Abcam) diluted 1:100 and
lectin from Dolichos biflorus (horse gram)-FITC (Sigma) diluted 10
ng/ml (1:100 of 1 mg/ml PBS stock) or 1/100 FITC anti-rabbit (Sigma) in 4%
milk powder in PBS overnight at 4°C. A final wash for 30 minutes was
carried out in PBS at room temperature while agitating gently. For
determination of the mean number of cells in a tip, staining with Dolichos
biflorus lectin was used to define (negatively) the tip, as described by
Michael et al. (Michael et al.,
2007), and confocal microscopy was used to measure the mean volume
of the cellular part of a tip
(4.8x104±6x103 µm3) and
the mean volume of tip cells (413±37 µm3). The ratio was
used to determine the mean number of cells per tip (117±18).
Culture of stalks in Matrigel
Culture in Matrigel was performed according to the methods of Sakurai et
al. and Qiao et al. (Sakurai et al.,
2001; Qiao et al.,
1999). Briefly, stalks were isolated and cultured in a 1:1 mix of
Growth Factor Reduced Matrigel (BD Biosciences) and kidney culture medium with
125 ng/ml recombinant human GDNF (Promega), 250 ng/ml recombinant human FGF1
(R&D Systems) and 625 ng/ml recombinant human pleiotrophin (R&D
Systems). The stalks were cultured for 144 hours, fixed for two hours in 4%
paraformaldehyde in PBS (pH 7.0), washed in 1% Triton X-100 in PBS for 30
minutes, stained overnight in FITC-phalloidin (Sigma P5282) at 4°C and
washed in PBS for 1 hour at room temperature.
In situ hybridization
The plasmid used to generate Wnt11 probes for in situ
hybridization has been used elsewhere
(Kispert et al., 1996) and was
kindly donated by S. Vainio. It consisted of a 2.1 kb cDNA of Wnt11
in pSKII. Antisense DIG-labelled probes were generated by cutting the plasmid
with XhoI and using T3 RNA polymerase; sense `probes' were generated
by cutting the plasmid with XbaI and using T7 polymerase. Cultures
were first fixed in cold methanol to enhance their adhesion to their filters,
then fixed overnight in 4% paraformaldehyde in PBS, incubated in 0.1% Tween 20
in PBS (`PBT') for 10 minutes, treated with 10 µg/ml proteinase K in PBT
for 15 minutes at room temperature, washed for 3x5 minutes in PBT and
post-fixed for 40 minutes in 4% formaldehyde in PBT. They were then incubated
for 2-4 hours at 65°C in 50% deionized formamide, 25% 20xSSC, 2%
Roche blocking powder, 0.1% Tween 20, 0.5% CHAPS, 1 mg/ml yeast tRNA, 0.5 M
EDTA and 0.05% heparin. Probe, pre-heated to 80°C for 3 minutes, was added
at 250 ng/ml and left overnight at 60°C. Samples were then washed in
post-hybridization solution (50% formamide, 25% 20xSSC, 0.1% Tween 20,
0.5% CHAPS) for 2x10 minutes, then in 75% post-hybridization solution
(2xSSC), then in 50%, then in 25%, each for 10 minutes. They were then
washed in 2xSSC, 0.1% CHAPS for 2x30 minutes, and 0.2xSSC,
0.1% CHAPS for the same amount of time. They were then blocked in TBST with
10% sheep serum, incubated overnight in 1:200 alkaline phosphatase-conjugated
anti-DIG (Roche) and developed the next day with NBT/BCIP solution. All buffer
solutions used for in situ hybridization were treated with diethyl
pyrocarbonate, and ProtectRNA (Sigma) was used in all solutions after
proteinse K digestion. Sense controls were performed to support antisense
experiments, and were negative.
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De-tipped ureteric bud stalks regenerate tips and undergo branching
In principle, ureteric bud stalks may refrain from producing new tips
because they are intrinsically incapable of doing so, because they are
inhibited by existing tips, or because the mesenchyme surrounding them has
been rendered unsupportive of branching by the previous passage of the tip. To
test the intrinsic ability of stalks to produce new tips, we removed them from
the influence of existing tips, by amputating those tips, and we provided
fresh mesenchyme (Fig. 1A). To
confirm that the entire tip region had been removed, each amputated tip region
was stained either for Wnt11 mRNA or with fluorescent DBA, to ensure
that it contained the tip-stalk boundary
(Fig. 1B-D). These are the same
markers that we have previously used to study stalk/tip boundaries
(Michael et al., 2007), and
they define the tip with much more precision than other alleged tip markers,
such as Ret and Ros, as explained by Michael et al.
(Michael et al., 2007). In any
(rare) case that complete removal of the tip could not be confirmed, the
corresponding stalk was discarded. To ensure that the fresh mesenchymes did
not contain ureteric tips, they were used only if a complete ureteric bud
could be recovered from the donor kidney. As an additional check on the
efficiency of dissection, samples of mesenchyme were also stained with
anti-calbindin-D28K, a marker for ureteric buds
(Davies, 1994); they were
negative, as expected.
As an additional check that stalks meeting the above criteria for purity really were free of contaminating cells, a dilution-series RT-PCR was performed to set an upper limit on the possible number of tip cells that could be present in an allegedly pure stalk sample. The details of the RT-PCR and the calculations made from it are explained in the Materials and methods. It showed that Wnt11 in as few as 0.81±0.12 tip cells, represented by the 1/100 dilution of kidney cDNA in Fig. 1E, could be detected clearly. The Wnt11 in a PCR reaction representing the undiluted cDNA from 0.44 stalks shows a barely detectable band (Fig. 1E). Therefore, each stalk was contaminated by fewer than 0.81/0.44=1.8 tip cells. This is far fewer than those needed to make even one tip (117±18 cells), even after a few cell cycles. These PCR data therefore support the in situ hybridization and immunostaining data in the paragraph above, and suggest that the stalks are not significantly contaminated by tip cells.
|
), and it is not reasonable to assume that these could have
arisen from `lost' clusters of tip cells left behind: if there were that many
`lost' tip cells, we and others would have seen them in Wnt11 in situ
stains.
Branching and tip formation can be induced even from the wrong end of the ureteric bud
To determine whether the ability to initiate branches was still present
even in the most distal regions of the ureteric bud stalk, we left the
existing tips of ureteric buds alone and instead packed fresh mesenchyme
around the distal end of the ureter that was severed when the kidney was
isolated from the embryo (Fig.
1A). Forty percent of the E11.5 kidneys so treated showed prolific
branching from the severed ureter to produce `double-ended' trees
(Fig. 2D). These tips lost
DBA-binding activity (Fig.
2E,F) and also induced the formation of nephrons in the
surrounding mesenchyme (Fig.
3C,D). This ability is retained by ureters from both E11.5 and
E12.5 kidneys (Fig. 3A).
These results demonstrate that the ability of the ureteric bud to initiate
new branch tips is not restricted to existing tips but is instead distributed
widely, at least for the first few days of the bud's existence. This
possibility has been suspected recently from time-lapse studies of ureteric
branching (Shakya et al.,
2005; Watanabe and Costantini,
2004), but, as pointed out in the recent review of Costantini and
Shakya, it has not been directly examined before
(Costantini and Shakya, 2006).
The finding also implies that the specialized state of gene expression at the
tips (Wnt11-positive, DBA-negative, etc) might be required for the proper
organization of branching morphogenesis, but it cannot be needed for cells to
make their first response to ramogenic signals. If it were, the
Wnt11-, DBA+ stalks could not have responded. Expression
of molecules such as Wnt11 must therefore be secondary to the events that
first induce new branches to form.
Although the distal ends of ureters of E11.5 and E12.5 kidneys could
produce new branches when provided with fresh mesenchyme, those of E13.5,
E14.5 and E15.5 kidneys failed to do so. These epithelia are surrounded by a
sleeve of stroma that might, conceivably, inhibit tip formation. To address
this possibility, we removed the stroma enzymatically before applying fresh
E11.5 mesenchyme to the ureter epithelium. It was possible to remove 100% of
stromal cells from ureters up to and including E13.5, but from E14.5 only
about 90% of the cells could be removed (leaving significant uncovered areas
of epithelium); further extending the enzymatic incubations resulted in the
tissue losing structure completely. The E13.5 ureters freed completely from
stroma were able to produce new tips when provided with fresh E11.5
mesenchyme, and these tips went on to induce nephrons in that mesenchyme,
suggesting that the failure of E13.5 ureters surrounded by stroma to produce
new tips was due to an inhibitory influence of the stroma. Later ureters that
could be freed substantially but not completely from stroma still failed to
form tips. A simple mechanical influence of stroma, for example that it forms
a diffusion barrier to molecules such as GDNF from the fresh mesenchyme
outside it, is unlikely to explain this effect, as even the older
enzyme-treated ureters had lost enough stroma to make the epithelium
accessible. Bmps such as Bmp4 and Bmp5 are expressed strongly in this stroma
(Dudley and Robertson, 1997),
and are known to be inhibitors of branching
(Hartwig et al., 2008;
Gupta et al., 1999;
Miyazaki et al., 2000;
Michos et al., 2007). Gremlin
1 is a powerful antagonist of Bmps, particularly Bmp2 and Bmp4, and treatment
of cultured kidney rudiments with exogenous gremlin 1 is sufficient to
antagonize Bmp activity and alter ureteric branching in intact kidneys
(Michos et al., 2007). To test
whether the secretion of Bmps by the remaining peri-ureteric stroma might
account for the repression of tip formation in our system, we applied the Bmp
antagonist gremlin 1 at 5 µg/ml to the cultures. This concentration was the
same as that used by Michos et al., and, in our hands, it had a modest effect
on increasing the amount of branching in E11.5 kidneys, by 14%
(P=0.073), suggesting that the molecule was active. It failed,
however, to induce tip formation from the enzyme-treated E14.5 ureter/fresh
mesenchyme combinations. This suggests that the stroma secretes an inhibitor
other than Bmps, or that the ability to produce new tips is lost as the
epithelium itself matures.
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De-tipped stalks branch when placed in a three-dimensional matrix
Intact ureteric buds will grow and branch when placed in a
three-dimensional gel matrix, consisting of Matrigel supplemented with GDNF,
FGF1 and pleiotrophin (Sakurai et al.,
2001). Isolated, de-tipped stalks transferred to this culture
system, grow and branch in a manner similar to that of intact ureteric buds
(Fig. 3B). This demonstrates
that ramogenic factors already characterized in normal mesenchyme (GDNF, FGF1
and pleiotrophin) are sufficient to promote the regeneration of tips. It is
notable that the density of tips is much higher in this system than in normal
kidneys.
Ureteric stalks, then, are capable of forming new tips if provided with
fresh mesenchyme or with a Matrigel artificially loaded with ramogens, such as
GDNF and FGF1, known to be manufactured by fresh mesenchyme
(Sainio et al., 1997;
Sakurai et al., 2001). It is
known that GDNF is not expressed by mesenchyme cells after they have been
induced, by contact with the ureteric bud, to form neprhons and stroma
(Sainio et al., 1997). FGF1
persists a little longer, but is still lost as nephrons mature beyond the
`S'-shaped stage (Cancilla et al.,
1999). Indeed, not only do maturing nephrons and stroma cease to
produce ramogens, they also begin to secrete anti-ramogenic factors, such as
Bmp2 and Tgfβ (Lyons et al.,
1995; Ritvos et al.,
1995; Davies and Fisher,
2002; Dudley and Robertson,
1997; Bush et al.,
2004; Gupta et al.,
1999; Piscione et al.,
1997). This suggests a model in which stalks are normally
prevented from branching because the mesenchyme that surrrounds them has
already ceased to express ramogens. The likely importance of the mesenchyme in
modulating the production of tips by the stalks is supported by the behaviour
of stalks in ramogen-enriched Matrigel. The density of tips formed by the
stalk is much higher than that seen in normal kidney development, suggesting
that in the normal organ the mesenchyme surrounding the stalk must be
non-permissive for tip formation. Indeed, it is the source of factors, such as
heregulin 
(neuregulin 1 - Mouse Genome Informatics), that support
growth and maturation of the bud without inducing branching
(Sakurai et al., 2005).
This system described above would, under normal circumstances, tend to
restrict branching to the existing tips because these are the only cells that
meet uninduced mesenchyme. Only if mesenchymal cell mixing, and/or inefficient
branching of the bud throughout the mesenchyme, brought a population of
uninduced mesenchyme cells near to a stalk would production of a new tip by
the stalk occur. A system organized according to these principles would be
robust against errors, because any zones of the kidney `missed out' by the
branching of the tree would be able to induce secondary branches from stalks
until they were adequately served. This presumably accounts for the very low,
but non-zero (6%), frequency with which lateral branches have been observed to
occur in culture (Watanabe and Costantini,
2004).
Understanding that the whole of the ureteric bud is capable of producing a
branching tree, at least until it has matured too far, may have implications
beyond the need to revise models for the control of pattern formation in this
system. There is increasing interest in using the techniques of stem cell
biology and tissue engineering to repair kidneys made defective by congenital
disease or infection (Hayashi,
2006; Rookmaaker et al.,
2004). Most current effort is aimed at using transplanted
progenitor cells to create areas of kidney in which new nephrons, free of
genetic defects, develop. The absence, in a fully formed kidney, of active
ureteric bud tips to provide these areas with a collecting duct system has
been seen as a potential problem of the technique. If, however, the stalks of
the cortical bud/collecting duct system can generate new tips anyway, either
at once or as a result of minor treatment, the entire enterprise becomes much
more hopeful. For this reason, our observation that stalks can regenerate tips
may have implications for regenerative medicine, as well as for basic
developmental biology.
ACKNOWLEDGMENTS
We thank Seppo Vainio for the Wnt11 probe; Linda Wilson and Trudi Gillespie for help with confocal microscopy; and Darren Logan, Jane Armstrong, Jane Brennan and Markus Winter for helpful discussions and advice. The work described in this paper was funded by grants from the BBSRC and the Leverhulme Trust. D.S. was funded by a PhD studentship from the Anatomical Society of Great Britain and Ireland. N.L. is funded by the EuReGene EU Framework VI programme.
Footnotes
* These authors contributed equally to this work 
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