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Address correspondence to Nora Sarvetnick, Dept. of Immunology (IMM-23), The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: (858) 784-9066. Fax: (858) 784-9083. email: noras{at}scripps.edu
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Abstract |
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Key Words: chemokines; proliferation; regeneration; duct; interferon
Abbreviations used in this paper: C-10, small inducible cytokine A6; Eotaxin, small inducible chemokine A 11; IP-10, IFN-
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Introduction |
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Although most chemokines and receptors have overlapping binding specificity with other family members, SDF-1 and its receptor CXCR4 bind only each other (Kim and Broxmeyer, 1999). CXCR4 has also been the focus of numerous papers because it is a coreceptor for the entry of HIV into T cells (Feng et al., 1996). SDF-1
is involved in the migration of hematopoietic cells to the marrow, and hematopoietic precursors from the bone marrow via the circulation into peripheral tissues (Aiuti et al., 1997; D'Apuzzo et al., 1997). A comprehensive study of the expression of SDF-1
and CXCR4 from gastrulation to organogenesis in the mouse embryo provides evidence of the continuous involvement of the SDF-1
/CXCR4 axis during embryogenesis (McGrath et al., 1999). Furthermore, disruption of the genes for SDF-1
or its receptor results in late embryonic lethality. Importantly, the SDF-1
deficient mouse and the corresponding CXCR4 mutants are the only known chemokine/chemokine receptor mutants that display embryonic lethality (Murphy et al., 2000). Genetically deficient embryos display severe defects in their gastrointestinal vasculature, cerebellar neuron migration, cardiac ventricular septal closure, B cell development, and hematopoietic bone marrow colonization (Nagasawa et al., 1996; Ma et al., 1998; Tachibana et al., 1998; Zou et al., 1998). The extensive consequences observed in different organ systems in the SDF-1
and CXCR4 knockout mice indicate that the SDF-1
CXCR4 axis is an essential component of differentiation of numerous tissues.
The terminal differentiation of the pancreatic endocrine cells from epithelial progenitor cells occurs during their migration from the duct wall into primitive islet-like structures (Slack, 1995). The process involves the remodeling of the cell surface and a change in the adhesive properties of these cells as they migrate (Cirulli et al., 2000). The signals governing this migration are not fully defined. Based on the demonstrated involvement of the SDF-1CXCR4 pair in the migration and proliferation of hematopoietic stem cells, we hypothesized that this ligandreceptor pair may be important during pancreatic endocrine cell development. However, because the genetically deficient mice suffer from widespread midgestational defects, it is difficult to address the requirement for CXCR4/SDF-1
during embryonic development. Therefore, we sought to determine the role of CXCR4 ligation during pancreatic islet regeneration.
In transgenic mice in which the cytokine IFN- is expressed under the control of the insulin promoter, the pancreas displays remarkable ductal hyperplasia and regeneration of new islets (Sarvetnick et al., 1988; Gu and Sarvetnick, 1993, 1994). Previous work suggests the pancreatic islet regeneration proceeds through the same intermediates as does islet formation during ontogeny (Gu and Sarvetnick, 1993, 1994; Kritzik et al., 1999, 2000). We have found that spontaneous islet regeneration in the IFN
transgenic mouse recapitulates the pancreatic developmental program in adults (Kritzik et al., 1999, 2000).
In this work, we tested the hypothesis that CXCR4 ligation is required for the differentiation of pancreatic islets during regeneration. Our results strongly support an essential role for the SDF-1CXCR4 pair during IFN
induced pancreatic regeneration.
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Results |
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In the NOD mouse pancreas, SDF-1 and CXCR4 expression was detected in islets by immunofluorescence (Fig. 3 A). In addition, SDF-1
expression was confirmed by Western blot analysis of proteins expressed by isolated pancreatic islets (unpublished data). The expression of SDF-1
in NOD mice appeared constitutive because in vitro treatment of the islets by IFN
(1,000 U/ml) for 24 h did not augment SDF-1
expression, as determined by Western blotting (n = 2; unpublished data). In the IFN
NOD mouse, SDF-1
staining was localized to cells within the islet mass (Fig. 3, B and C). In the duct epithelium, frequent cells, which express only CXCR4 (Fig. 3 E, green), and occasional cells, which coexpress CXCR4 and SDF-1
(Fig. 3 E, yellow), were observed. Thus, the majority of duct cells express CXCR4, suggesting that these cells may be migrating toward the SDF-1
expressing newly forming islets.
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Discussion |
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Importantly, neutralization with CXCR4 antibody elicited a fourfold increase in the proportion of apoptotic ductal cells. The role of CXCR4 in the regulation of apoptosis is context dependent. CXCR4 involvement in the stimulation of apoptosis by HIV envelope proteins in CD4+ T cells has been an area of extensive study (Herbein et al., 1998; Biard-Piechaczyk et al., 1999; Colamussi et al., 2001; Yao et al., 2001; Arthos et al., 2002). Similarly, CXCR4 regulation of the apoptotic effect of HIV coat proteins on neurons of the neocortex has also been reported (Corasaniti et al., 2001). In contrast, SDF-1 has been reported to promote survival by inhibiting apoptosis in hematopoietic progenitor cells (Lataillade et al., 2002). Furthermore, in fetal thymus organ culture, SDF-1
enhanced viability of serum-depleted cells in culture by down-regulating the pro-apoptotic bax protein and up-regulating the antiapoptotic bcl-2 protein (Hernandez-Lopez et al., 2002). Interestingly, transgenic mice expressing SDF-1
under a Rous sarcoma virus promoter display enhanced spleen and bone marrow myelopoiesis in vivo (Broxmeyer et al., 2003). Myeloid progenitors from the SDF-1
transgenic mice also exhibit prolonged survival in the absence of growth factors in vitro compared with progenitors from wild-type mice. In our pancreatic regeneration model, it appears that blocking the CXCR4 receptor resulted in an augmentation of apoptosis, indicating a role for the CXCR4 receptor in promoting survival of the ductal cell precursor pool in the regenerating ducts, similar to its role in hematopoietic progenitor cells. Our observation of diminished numbers of ductal cells expressing PDX1, a critical pancreatic progenitor marker, in mice treated with CXCR4 neutralizing antibody is consistent with the concurrent enhanced programmed cell death.
The endocrine progenitor cells in the ductal epithelium of the IFNNOD pancreas display primitive cell markers (unpublished data), and may be migrating in response to local changes in SDF-1
concentration and variations in CXCR4 expression in the cells in response to the cytokine IFN
. Once recruited to a niche where growth factors stimulate their proliferation and differentiation, these progenitors assume an endocrine cell lineage. The stimulatory effect of SDF-1
on the migration of CD34+ hematopoietic progenitor cells was established relatively early (Aiuti et al., 1997; Kim and Broxmeyer, 1998; Mohle et al., 1998). Of the many chemokines assayed SDF-1
was the first to have been shown to affect directed movement of myeloid progenitor cells (Broxmeyer et al., 1999). Wright et al. (2002) have reported recently that a purified population of hematopoietic stem cells expresses CXCR4 and migrates in response to SDF-1
in vitro. The mobilization of stem cells in and out of the bone marrow is important in therapeutic transplant procedures. However, what is more intriguing is whether these hematopoietic stem cells can migrate to sites of inflammation and differentiate into other tissue cell types (Krause et al., 2001). In vivo, SDF-1
is produced by bone marrow (Bleul et al., 1996) and the epithelial cells in many organs such as lung (Aiuti et al., 1997). Two recent papers provide evidence of CXCR4 expression in epithelial colon cells (Dwinell et al., 1999; Jordan et al., 1999). Interestingly, another class of cells of epithelial origin that express CXCR4 receptors are breast cancer cells, both primary and metastatic (Muller et al., 2001). Furthermore, using neutralizing antibodies for CXCR4 resulted in a significant reduction in metastatic ability indicating a clear effect of CXCR4 in the migration of breast cancer cells.
We present evidence that Src, MAPK, or Akt phosphorylation may potentially be involved in the stimulation of migration of the ductal cells by SDF-1. In vitro stimulation of the freshly isolated ductal cells with SDF-1
resulted in the phosphorylation of MAPK and Akt. The robust SDF-1
effect on Akt phosphorylation coupled with the in vivo results of an augmentation of apoptosis with CXCR4 neutralization suggests an involvement of Akt in the promotion of survival of duct cells. Therefore, it is possible for SDF-1
to have a direct effect on proliferation and survival. Alternatively, CXCR4 expression might induce migration of progenitor cells to niches where they can be stimulated to proliferate, and subsequently, differentiate into endocrine cells. Importantly, we have shown previously that inhibition of the infiltration of macrophages did not play a role in the observed proliferation and islet regeneration in the IFN
transgenic mice (Gu et al., 1995).
In the current paper, we report the limited expression of the chemokines C-10, MIG, TCA-4, Eotaxin, and SDF-1 in the 8-wk-old NOD pancreas. We had reported previously low level C-10 expression in the 10-wk-old NOD mouse pancreas (Bradley et al., 1999). In this earlier paper, Th1 cells harvested from primary cultures expressed high levels of lymphotactin, MIP-1
, MIP-1ß, and MCP-1, and low levels of IP-10 and RANTES, when stimulated with anti-CD3. In addition, Chen et al. (2001) have reported the expression of MCP-1 in pancreatic islets isolated from NOD mice at the peak of insulitis (810 wk) using RT-PCR; and Cameron et al. (2000) observed a progressive increase in MIP-1
production by the NOD pancreas peaking at 5 wk, and MCP-1 expression starting to rise by 10 wk. In the latter paper, chemokine expression was measured by ELISA. The discrepancies in the findings by different investigators may reflect differences in the time course of insulitis progression in the NOD mice, methods used to measure expression of the chemokines, and the genders of the NOD mice. Furthermore, as the analysis of whole pancreas RNA clearly masks important local differences in chemokine and chemokine receptor expression, the localization and potential significance of chemokines both in the pathogenesis of diabetes and islet regeneration still remain challenging fields of study.
In conclusion, this paper provides in vivo evidence for a role of the SDF-1CXCR4 chemotaxis axis in a model of tissue regeneration. Importantly, elucidating the molecular mechanisms involved in the stimulation of migration and proliferation and the diminution of apoptosis in the epithelial precursor cells in the regenerating pancreas will help devise effective means for islet replacement in the future.
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Materials and methods |
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RNase protection assays
Total RNA was extracted from pancreata from 8-wk-old male IFNNOD and NOD mice using an RNeasy Kit (QIAGEN) according to the manufacturer's instructions. Pancreatic RNA was pooled from three IFN
NOD transgenic mice and three NOD mice for the RNase protection assays. This process was repeated two independent times. In-house chemokine and chemokine receptor probes were used to perform the RNase protection assays as described previously (Asensio and Campbell, 1997; Boztug et al., 2002). The CHK1 chemokine probe detects lymphotactin, C-10, MIP-2, MCP-3, MIP-1ß, T cell activation gene 3, MCP-1, IP-10, MIP-1
, and RANTES. The CHK2 probe detects MIG, MCP-5, SDF-1
, TCA-4, growth-regulated oncogene
, Eotaxin, lipopolysaccharide-induced CXC chemokine, IFN-inducible T cell
chemoattractant, and Fractalkine. The probe for the CCR group of chemokine receptors included CCR6, CCR7, CCR8, CCR9, CCR4, CCR3, CCR1, CCR5, and CCR2. The probe for the CXCR group of receptors included CXCR4, CXCR2, CXCR5, DARC, CXCR1, CXCR3, and CX3CR1. Autoradiographs were analyzed by densitometry using NIH Image 1.63 for quantitation.
Immunohistochemistry and immunofluorescence
Pancreata from IFNNOD transgenic, NOD mice, and E18 NOD embryos were fixed in 10% neutral buffered formalin and embedded in paraffin. Paraffin embedded tissue was cut into 4-µm sections and stained using rabbit polyclonal antiSDF-1
antibody against mouse SDF-1
(Cell Sciences), goat polyclonal anti-CXCR4 antibody raised against the NH2-terminal extracellular domain of mouse CXCR4 receptor (Capralogics Inc.), or guinea pig antibody against insulin (DakoCytomation). Slides were counterstained with hematoxylin. For double immunofluorescent detection, biotinylated secondary goat, rabbit, and guinea pig antibodies (Vector Laboratories) were used, followed by streptavidin-conjugated Alexa Fluor 488 and 568 (Molecular Probes Inc.). The first streptavidin-conjugated Alexa Fluor (488) incubation was followed by avidin and biotin blocking (Vector Laboratories). After the Alexa Fluor (568) incubation, the sections were placed in mounting medium from The Slowfade Light Antifade Kit (Molecular Probes Inc.). Nuclei were visualized with TOPRO3 (Molecular Probes Inc.). Sections were analyzed on a scanning confocal microscope (model MRC 1024; BioRad Laboratories), mounted on an Axiovert TV-100 with 40 or 63X objectives (Carl Zeiss MicroImaging, Inc.).
Pancreatic ductal cell purification and islet isolation
Cells of the pancreatic ductal network were purified from 10- to 12-wk-old IFNNOD.scid mice for the migration experiments and IFN
NOD mice for the assessment of in vitro phosphorylation of signaling proteins. The pancreata were collagenase (1 mg/ml; Roche) digested for 45 min. The digest was filtered through a 200-µm mesh and the ductal network above the mesh was treated with 0.05% trypsin, 0.53 mM EDTA. The resulting cell suspension was filtered through a 70-µm cell strainer. The cells in the filtrate were resuspended in RPMI medium. Approximately one million duct cells were derived from each pancreas preparation. The viability of these duct cells ranges from 75 to 95%. Pancreatic islets were isolated and cultured as described previously (Flodstrom et al., 2002).
Migration assays
Chemotaxis was assessed using uncoated or collagen-coated culture plate inserts (12-µm pore; 12-mm diam; Millipore) placed into 24-well plates. Half the inserts were coated with 3.48 mg/ml collagen type I (BD Biosciences), diluted threefold with 95% ethanol, 2 h at RT, and blocked with 1% BSA. Freshly isolated ductal network cells resuspended in serum-free RPMI 1640 medium (200,000 cells in 200 µl) were added to the upper chambers. 600 µl of RPMI 1640 medium with 0, 100, or 300 ng/ml of SDF-1 (PeproTech) was added to the bottom chambers and the cells were allowed to migrate for 24 h at 37°C. At the end of the assay, the cells from the upper chamber were aspirated and the membranes were fixed in 10% neutral buffered formalin, stained with hematoxylin and eosin, and mounted on slides upside down. Images of eight fields were captured from each membrane (at a magnification of 20) and the number of cells in or associated with the pores was counted.
Experimental protocol for the CXCR4 antibody neutralization study
12-wk-old IFNNOD mice were divided into two groups of eight. Rabbit IgG or a rabbit polyclonal CXCR4 neutralizing antibody (20 µg/mouse; Gonzalo et al., 2000; Millennium Pharmaceuticals, Inc.) was injected intravenously every third day for a period of 2 wk. The total number of injections per mouse was five. On day 13 of treatment, 100 µg/g BrdU (Sigma-Aldrich) was administered intraperitoneally. 15 h after the BrdU injection, pancreatic tissue was fixed in BOUIN's. Monoclonal rat anti-BrdU antibody (Accurate Chemical) was used to assess proliferation.
In pancreata from a subgroup of mice (n = 2 per group) treated with CXCR4 neutralizing antibody or control IgG, TUNEL staining was performed using the in situ cell death detection POD kit (Roche) according to the manufacturer's instructions. TUNEL staining was repeated on sections from two different levels of the pancreas for each animal.
Pancreata from mice treated with IgG or CXCR4 neutralizing antibody (n = 4 per group) were evaluated for PDX1 staining using rabbit polyclonal anti-PDX1 antibody (CHEMICON International, Inc.). Images were captured from at least six ductal areas from each mouse and the PDX1-positive duct cell number and the total duct cell number in these areas were quantified. In seven of the mice from each group, the percentage of small ducts (defined as ducts comprising <15 cells) and large ducts were quantified by counting duct cells from at least 10 images captured from one hematoxylin stained section from each mouse.
Assessment of SDF-1stimulated Src, MAPK, and Akt phosphorylation
Freshly isolated cells from the pancreatic ductal network from IFNNOD transgenic mice were serum-starved overnight, and stimulated with 100 or 300 ng/ml SDF-1
or 10 ng/ml EGF for 5 min at 37°C. Cells were lysed with RIPA buffer containing 20 mmol/liter Tris, pH 7.5, 1 mmol/liter EDTA, 140 mmol/liter NaCl, 1% NP-40, 1 mmol/liter orthovanadate, 1 mmol/liter PMSF, and 10 µg/ml aprotinin. Cell lysates were prepared for Western blot analysis. Rabbit polyclonal antibodies to phospho-Src (Tyr 416), dually phosphorylated phospho-MAPK (Thr202/Tyr204), and phospho-Akt (Ser473) were used for immunodetection (Cell Signaling Technology). In a second stimulation experiment, the cells were isolated and serum starved as above and treated with 300 ng/ml SDF-1
for 0, 2, 5, 10, 30, and 60 min.
Pancreatic islets were precultured for 56 d before a 24-h exposure to 1,000 U/ml IFN (BD Biosciences) or vehicle. After exposure, the islets were homogenized in RIPA buffer, and lysates prepared for Western blot analysis and were immunoblotted with SDF-1
antibody. All membranes were stripped and reblotted with a mouse mAb to actin to confirm equal protein loading (ICN Biomedicals).
Statistical analysis
Analysis of variance was used to analyze data in Fig. 5. The t test was used to analyze data in Figs. 69.
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Acknowledgments |
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This work was supported by the National Institute of Health grant DK55230 to N. Sarvetnick and grants MH62231, MH62261, and NS36979 to I.L. Campbell. This is manuscript number 15665-IMM from the Scripps Research Institute.
Submitted: 29 April 2003
Accepted: 29 September 2003
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