Mechanism of primitive duct formation in the pancreas and submandibular glands: a role for SDF-1
- Anne-Christine Hick†1,
- Jonathan M van Eyll†1,
- Sabine Cordi1,
- Céline Forez1,
- Lara Passante2,
- Hiroshi Kohara3,
- Takashi Nagasawa3,
- Pierre Vanderhaeghen2,
- Pierre J Courtoy1,
- Guy G Rousseau1,
- Frédéric P Lemaigre1 and
- Christophe E Pierreux1Email author
© Hick et al; licensee BioMed Central Ltd. 2009
Received: 29 April 2009
Accepted: 14 December 2009
Published: 14 December 2009
The exocrine pancreas is composed of a branched network of ducts connected to acini. They are lined by a monolayered epithelium that derives from the endoderm and is surrounded by mesoderm-derived mesenchyme. The morphogenic mechanisms by which the ductal network is established as well as the signaling pathways involved in this process are poorly understood.
By morphological analyzis of wild-type and mutant mouse embryos and using cultured embryonic explants we investigated how epithelial morphogenesis takes place and is regulated by chemokine signaling. Pancreas ontogenesis displayed a sequence of two opposite epithelial transitions. During the first transition, the monolayered and polarized endodermal cells give rise to tissue buds composed of a mass of non polarized epithelial cells. During the second transition the buds reorganize into branched and polarized epithelial monolayers that further differentiate into tubulo-acinar glands. We found that the second epithelial transition is controlled by the chemokine Stromal cell-Derived Factor (SDF)-1. The latter is expressed by the mesenchyme, whereas its receptor CXCR4 is expressed by the epithelium. Reorganization of cultured pancreatic buds into monolayered epithelia was blocked in the presence of AMD3100, a SDF-1 antagonist. Analyzis of sdf1 and cxcr4 knockout embryos at the stage of the second epithelial transition revealed transient defective morphogenesis of the ventral and dorsal pancreas. Reorganization of a globular mass of epithelial cells in polarized monolayers is also observed during submandibular glands development. We found that SDF-1 and CXCR4 are expressed in this organ and that AMD3100 treatment of submandibular gland explants blocks its branching morphogenesis.
In conclusion, our data show that the primitive pancreatic ductal network, which is lined by a monolayered and polarized epithelium, forms by remodeling of a globular mass of non polarized epithelial cells. Our data also suggest that SDF-1 controls the branching morphogenesis of several exocrine tissues.
Branching morphogenesis is a process that allows the formation of a branched network of tubes, as exemplified by the airways of the lung or the excretory ducts of the pancreas and salivary glands [1, 2]. During branching morphogenesis, the epithelial cells interact with the surrounding mesenchyme and organize into polarized monolayers with their apical pole facing the tube lumen [3, 4]. How this process takes place and is regulated in exocrine tissues such as the pancreas and salivary glands remains poorly understood.
In the mouse, the pancreas originates from a pre-patterned endodermal epithelium located in a caudal region of the foregut that is to become the duodenum. Between embryonic days (e) 8.5 and e9.5, two outgrowths develop from the dorsal and ventral sides of this endodermal region, and form epithelial buds surrounded by mesenchyme. From e9.5-e10.5 onwards, the pancreatic bud cells proliferate, differentiate and undergo extensive morphogenesis to generate ductal structures called primitive ducts. The latter then expand, and give rise to the endocrine islets of Langerhans and to a branched ductal network that drains the secretions of the exocrine acini [5–10]. The submandibular glands (SMG) also derive from the foregut endoderm. Their development starts around e11.5 by formation of two epithelial thickenings beneath the tongue. These thickenings protrude into the underlying mesenchyme. Around e13.5, small clefts appear at the periphery of the budding epithelial mass, and after continuous proliferation and repetitive clefting, a tree-like network of ducts whose branches end in acini is generated [11, 12].
Regulation of epithelial morphogenesis in the pancreas and SMG is controlled by the surrounding mesenchyme [13, 14]. Moreover, gene inactivation studies and ex vivo culture experiments have identified several signaling molecules that regulate SMG branching morphogenesis [15–19]. In the developing pancreas, gene inactivation studies inhibiting FGF10, EGF, or Rbpj expression revealed impaired branching morphogenesis. However, these studies focused on the role of the signaling molecules on pancreatic cell differentiation and not on the mechanisms of branching [20–23].
Stromal cell-Derived Factor-1 (SDF-1, also called CXCL12 or PBSF) is a secreted protein of the α-chemokine family, and a potent chemoattractant for many cell types [24–26]. Whereas SDF-1 is the sole ligand for the chemokine CXC-motif receptor 4 (CXCR4), CXCR7 can bind SDF-1 and CXCL11/I-TAC . Sdf1 and cxcr4 knockout mice die perinatally and display profound defects in the hematopoietic and nervous system [28–32], whereas cxcr7 knockout embryos die at birth due to defects in heart formation . No role has been ascribed to SDF-1/CXCR4 signaling in the SMG. In contrast, two functions for SDF-1 signaling in adult pancreas have been proposed. One day before birth, when pancreatic cells still differentiate and extensive islet neogenesis occurs, CXCR4 is expressed in endocrine cells and in some ductal cells, whereas SDF-1 is only found in endocrine cells . The same expression pattern persists in adult pancreas. Using a genetic model of endocrine pancreas regeneration (mice expressing IFN-γ under the control of the insulin gene promoter), it was proposed that SDF-1 is involved in endocrine cell renewal . More recently, it has been shown that SDF-1 promotes β-cell survival, via activation of Akt, in adult mouse islets . However, it is not known if SDF-1/CXCR4 signaling plays a role in early pancreas development.
In this paper we show that pancreatic epithelial morphogenesis occurs according to a sequence of two opposite epithelial transitions. During the first transition the monolayer of endodermal cells lining the primitive gut gives rise to two pancreatic buds, each composed of a mass of non polarized epithelial cells. During the second transition, this mass reorganizes into branched polarized epithelial monolayers that further differentiate into ducts and acini. Similar sequential transitions were described earlier in the SMG [12, 14]. In the pancreas and SMG, sdf1 was expressed by the mesenchyme and cxcr4 by the epithelial cells. Using embryonic explants of pancreas and SMG, and mice deficient in SDF-1 signaling, we uncovered a new role for SDF-1 in branching morphogenesis.
Primitive duct morphogenesis and cell polarization during pancreas development
A similar epithelial transition, from a mass to monolayers, also occurs during submandibular gland (SMG) morphogenesis [12, 13]. As shown in Figure 3B, ZO-1 staining was not visible in the early stage of SMG morphogenesis and only became visible after remodeling of the epithelial mass into monolayers lining a lumen (Figure 3B). High magnification pictures of epithelial cell monolayers clearly demonstrated that ZO-1 separates the apical domain (now devoid of E-cadherin staining) from the lateral domain (insets in Figure 3A and 3B).
SDF-1 and its receptor CXCR4 are expressed in developing pancreas and SMG
In the developing SMG, the expression of Sdf1 and Cxcr4 was comparable to that in the pancreas (Figure 4E to 4H). From e12.5 to e14.5: sdf1 was expressed in the mesenchyme and cxcr4 in the epithelium. Moreover, CXCR7, the second receptor for SDF-1, was observed by immunolocalization in endothelial structures of the SMG (Additional file 3), but not of the pancreas (not shown). From this set of expression data, we concluded that the spatial and temporal expression pattern of SDF-1 and CXCR4 in the pancreas and SMG suggests a potential role for SDF-1 signaling in their development.
SDF-1 signaling controls pancreatic branching morphogenesis
To investigate if SDF-1 controls epithelial morphogenesis in developing pancreas, we performed gain- and loss-of-function experiments by treating cultured explants with exogenous recombinant SDF-1 and with a specific pharmacological inhibitor of CXCR4 (AMD3100) . Pancreatic explants cultured for 7 days were analyzed by immunofluorescence with antibodies against E-cadherin and mucin-1. No effect of exogenous SDF-1 on epithelial organization was observed as compared to control explants (Figure 5B). The absence of effect of exogenous SDF-1 is likely to result from the presence of endogenous SDF-1, whose activity cannot be amplified. In contrast, we found that upon AMD3100 treatment, morphogenesis was impaired (Figure 5B). Epithelial monolayers were not formed and the epithelial cells remained clustered. The mesenchyme was not imbricated with the epithelium and remained at the periphery of the explants. The lumina, as revealed by mucin-1 staining, were smaller and often surrounded by multiple layers of epithelial cells. Identical results were obtained with explants from e11.5 embryos (data not shown), and the effect of AMD3100 was dose-dependent, since milder anomalies were observed at 10 μM than at 20 μM. Thus, at the end of the culture, the AMD3100-treated explants resembled the e12.5 pancreas before the onset of remodeling into a monolayered epithelium (compare AMD3100 panels of Figure 5B with Day 0 panels of Figure 5A). AMD3100 treatment did not change the proliferation or the apoptosis index (Additional file 4A, B) and this was supported by the normal size of these explants. Immunostaining with antibodies against insulin, glucagon or carboxypeptidase-A revealed normal differentiation in the explants treated with AMD3100 (Additional file 4C). From these experiments we concluded that SDF-1/CXCR4 signaling is potentially required for the remodeling of the epithelial cell mass into primitive pancreatic ducts lined by a monolayered epithelium.
SDF-1 signaling controls SMG branching morphogenesis
Genetic deficiency of CXCR4 or SDF-1 transiently affects epithelial morphogenesis
Since the consequences of Sdf1 ablation in vivo were rather modest as compared to the effects of Sdf1 inhibition in vitro, we looked at cxcr4-/- pancreas. At e12.5 and e15.5, the dorsal and ventral pancreata were not significantly different in cxcr4-/- embryos and in wild-type animals (not shown). However, when cultured on filters cxcr4-/- pancreatic explants showed a strong morphogenic deficiency, similar to that seen when wild-type explants were cultured in the presence of AMD3100, a SDF-1 antagonist (compare Figure 8B with Figure 5B). This similarity proves that AMD3100 specifically targets and inhibits SDF-1 signaling via the CXCR4 receptor. Taken together, these data indicated that SDF-1 controls pancreas morphogenesis in vivo, but also suggest that compensatory effects operating in vivo mask part of the role of SDF-1. We also analyzed the development of SMG in cxcr4-/- and sdf1-/- embryos, but the SMG phenotypes appeared normal, both in vitro and in vivo. We concluded that no genetic evidence for a role of SDF-1 signaling in SMG branching could be collected. However, the existence of compensatory mechanisms for genetic deficiencies in the pancreas suggests that compensation may also occur in the SMG.
In this paper we show that the primitive pancreatic ductal network, which is lined by a monolayered and polarized epithelium, forms by remodeling of a globular mass of non polarized epithelial cells. SDF-1 is expressed in the mesenchyme surrounding the epithelium and its receptor CXCR4 is found in the epithelial cells of the pancreas. SDF-1 signaling promotes branching morphogenesis of the pancreas in vitro and in vivo. We also provide in vitro evidence that SMG morphogenesis is controlled by SDF-1.
The time-course and 3-D analysis of embryonic pancreas development indicated that an initial phase of polarization occurs in cells of the outermost layer of the pancreatic bud at e11.5. This precedes remodeling of the bud, suggesting that, at the onset of pancreas development, remodeling may be triggered by the acquisition of polarity and not the reverse. Beyond this stage, acquisition of apico-basal polarity and primitive duct formation cannot be dissociated morphologically but must be orchestrated by several regulators acting on distinct aspects. Indeed, in our culture explants, blocking SDF-1 signaling did not prevent epithelial cells in the mass to acquire apical characteristics such as assembly of tight junction complexes and primary cilia (Additional file 4 and data not shown). Nevertheless, this polarization program could not go to completion, as the cells remained clustered and most of them did not acquire a basal domain.
During the remodeling of the pancreatic globular mass, the epithelium is in contact with the mesenchyme. The latter tissue has been proposed to provide signals that control epithelial proliferation, differentiation and morphogenesis. We have identified here SDF-1/CXCR4 signaling as a potential regulator of branching morphogenesis. Indeed, SDF-1 and its receptor, CXCR4, are expressed in embryonic pancreas in a complementary fashion. When epithelial cells are still organized as a non polarized mass, SDF-1 is expressed in the mesenchyme whereas CXCR4 is localized in the epithelium. Moreover, when SDF-1 signaling is inhibited by pharmacological means or by CXCR4 genetic deficiency, pancreas morphogenesis is perturbed. These data are consistent with a model in which the mesenchymally-produced SDF-1 promotes epithelial remodeling and thus primitive duct morphogenesis. While this work was under review, Ueland and collaborators demonstrated that SDF-1 controls epithelial kidney morphogenesis in vitro . Our data in the pancreas and SMG, together with those of Ueland et al. demonstrate the role of SDF-1 in epithelial branching morphogenesis. The molecular nature of the branching defects does not involve a change in the proliferation or apoptosis indexes (this study), but may be explained by a change in the migration potential of epithelial cells .
There is no perfect overlap between the results obtained with the pharmacological inhibition and with genetic inactivation of SDF-1 signaling in the pancreas. Pharmacological inhibition of SDF-1 signaling in vitro severely repressed branching morphogenesis, but genetic deficiency in Sdf1-/- pancreas showed more modest effects in vivo. Also, the effect of cxcr4 gene ablation only led to abnormal pancreas morphogenesis when the organ was cultured in vitro. We suggest that compensatory pathways may be active in vivo but not in vitro. In our culture system, endothelial cells are present and organized around the epithelium like in vivo, the main difference being that there is no blood circulation in the endothelial network in vitro. We suggest that signal(s) coming directly or indirectly from the circulation could participate in the control of epithelial branching morphogenesis of the pancreas and SMG. Such a model would further extend the role of the vasculature in pancreas development, since others previously showed that blood flow through the aorta is required for dorsal pancreas budding from the endoderm [48, 49].
In developing SMG, CXCR4 is expressed in the epithelium and SDF-1 in the mesenchyme, like in the pancreas. This suggests that SDF-1 controls branching morphogenesis by a direct mechanism on the epithelium. Importantly, CXCR7 is detected in endothelial cells of the SMG, but not in the pancreas. In SMG explants, we observed a branching defect when SDF-1 binding to CXCR7 was inhibited by CCX733. This suggests that SDF-1 can also indirectly control epithelial branching morphogenesis, via the endothelium. Activation of CXCR7 in the endothelium may induce the production of an unidentified factor which in turn would signal to the epithelium and act in parallel to or amplify the direct SDF-1 effects on epithelial morphogenesis. In the SMG we also noticed a difference between the effects of pharmacological inhibition of SDF-1 and genetic deficiencies induced by inactivation of the sdf1 or cxcr4 genes. In vitro and in vivo development of cultured cxcr4-/- and sdf1-/- SMG was normal, unlike development of AMD3100- or CCX733-treated explants. This suggests the existence of other ligands that could bind CXCR7, or alternative signaling pathways with which SDF-1/CXCR4/7 might interact in this organ. It has been reported that migrating muscle progenitors cells reach the anlage of the tongue in cxcr4-/- or gab1-/-, but not in the double-mutant mice. A crosstalk between G-protein-coupled receptors and tyrosine kinase receptors may contribute to compensatory mechanisms .
Finally, when SDF-1 signaling was blocked, the size of the epithelium was reduced in the SMG but not in the pancreas. Although SDF-1 is important for survival of insulin-producing β-cells , we did not observe any effect of SDF-1 signaling on cell survival early in pancreas development, even when e12.5 explants were cultured in the absence of serum (data not shown). This indicates that the survival signals are different in the two organs. A role for SDF-1 in cell survival has already been described in several systems [35, 51]. We excluded the possibility that the role of SDF-1 in cell survival in SMG coincided with its role in branching morphogenesis, thereby indicating that SDF-1 plays distinct roles in the SMG.
In conclusion, the present work shows that the formation of primitive ducts in the pancreas depends on remodeling of a globular mass of epithelial cells, as described earlier in SMG. Our data also identify SDF-1 as a factor that may promote the transition from a mass of epithelial cells towards monolayers in the pancreas and SMG. Understanding the mechanisms of such epithelial transition is relevant to carcinogenesis, which is associated with loss of epithelial polarity and formation of a mass of cells that fills the ductal lumen.
C57BL/6J cxcr4 +/- mice were obtained from, and genotyped according to The Jackson Laboratory (Bar Harbor, MA). The generation of SDF-1-/- mice has been described . All other mice were of the CD1 strain. The animals were raised and treated according to the principles of laboratory animal care of the University Animal Welfare Committee.
Dissection and culture of explants
Pancreatic and SMG explants were microdissected from mouse embryos at e12.5 and e13.5 respectively and cultured on microporous membranes . M199 medium was supplemented with 10% fetal calf serum for the pancreas and Universal complement Insulin/Transferrin/Selenite (BD Biosciences) for SMG culture. The medium of pancreatic cultures was changed every day. Recombinant mouse SDF-1a (R&D systems, Lille, France) was dissolved in PBS containing 0.15% bovine serum albumin (BSA) to 14 mg/ml (stock solution) and was added at the final concentration of 300 ng/ml. AMD3100 (Sigma, Bornem, Belgium) was dissolved in water to 10 mM (stock solution) and was added at 20 μM in the culture medium. CCX733, in DMSO, was used at 20 μM . The general caspase inhibitor VI (Calbiochem/VWR, Leuven, Belgium) was dissolved in DMSO to 16.5 mM (stock solution) and was added at the final concentration of 25 μM. Control explants were exposed to the same concentration of vehicle as the test samples.
Mouse embryos were fixed overnight at 4°C in 60% ethanol, 30% formaldehyde and 10% acetic acid before paraffin embedding. Full-length cDNAs of SDF-1 and of CXCR4 were generated via RT-PCR using as template reverse transcribed total RNA derived from mouse embryo heads. DIG-labeled antisense RNA probes were produced by in vitro transcription of the SDF-1 and CXCR4 cDNAs, and hybridizations were performed on 16 μm-thick sections as described .
For whole mount immunolocalization, pancreata dissected from embryos were fixed in 4% paraformaldehyde in PBS for 2 h at 4°C and treated as described . For immunofluorescence on sections, embryos or explants were fixed, embedded and processed as described . Antibodies and dilutions used in this study are given in Additional file 6. Sections were stained with bis-benzimide (Sigma, Bornem, Belgium) or with TOPRO in PBS during incubation with the secondary antibodies. Fluorescence was observed with a Zeiss Axiovert 200 inverted fluorescence microscope or with a Biorad confocal microscope or with a Zeiss LSM510 multiphoton confocal microscope.
List of abbreviations
- The abbreviations used are CXCR4:
chemokine CXC-motif receptor 4
Stromal cell-derived factor-1
We thank Patrick Vandersmissen for imaging, all members of the HORM and CELL units for discussion. Chemocentryx is acknowledged for providing the CXCR7 inhibitor, CCX733. This work was supported by the Région bruxelloise (confocal microscopy) and grants from the Belgian State Program on Interuniversity Poles of Attraction to FPL and PV, and from the Belgian Fund for Scientific Medical Research. JvE. held and A-CH. holds a fellowship from the Fonds pour la formation à la Recherche dans l'Industrie et dans l'Agriculture (Belgium), LP is a Research Fellow of the Fonds National de la Recherche Scientifique (FNRS, Belgium) and CEP and PV are Research Associates of the FNRS.
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