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From the Department of Immunology, The Scripps Research Institute, La Jolla, California
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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transgenic mouse model of
pancreatic regeneration. To understand the role of KGF in pancreatic
differentiation, we generated insulin promoter-regulated KGF
transgenic mice. Remarkably, we have found that ectopic KGF
expression resulted in the emergence of hepatocytes within the islets
of Langerhans in the pancreas. Additionally, significant
intra-islet duct cell proliferation in the pancreata of transgenic KGF
mice was observed. The unexpected appearance of hepatocytes and
proliferation of intra-islet duct cells in the pancreata of these mice
evidently stemmed directly from local exposure to KGF.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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KGF belongs to the fibroblast growth factor (FGF) family, the members of which influence such processes as cell proliferation, migration, and differentiation.6 KGF is a mesenchymally derived mitogen that acts as a paracrine effector of epithelial cell growth.7 Indeed, the ability of KGF to induce epithelial cell proliferation has been demonstrated throughout the rat gastrointestinal tract.8 In addition, KGF is important in the wound-healing process9 as well as in epithelial cell differentiation.10-13 However, studies of mice in which the KGF gene was inactivated demonstrated that KGF was not necessary for development or viability; other than deficiencies in hair development, these mice had no significant abnormalities.14 Although other growth factors may compensate for the lack of KGF, this factor seems to play a role in mesenchymal stimulation of epithelial cell proliferation in vivo.15
To assess the influence of KGF on growth and development of the
pancreas, we developed a transgenic mouse model in which KGF was
overexpressed in pancreatic ß-cells. In this model (Ins-KGF
transgenic mice), the human insulin promoter was used to drive
expression of the murine KGF coding sequence. As a consequence, cells
with the morphology and antigenicity of hepatocytes formed within the
islets and intra-islet duct cells proliferated, as identified by
-fetoprotein (AFP) and carbonic anhydrase (CAII), respectively.
However, no pancreatic dysfunction followed despite the novel cellular
differentiation pathway induced in this model.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All animals were kept in a specific-pathogen-free (SPF) facility at The Scripps Research Institute in accordance with the rules and regulations of the Institutional Animal Care and Use Committee. Food and water were provided ad libitum, and animals were housed under a controlled 12-hour light and dark cycle.
Transgenic Mouse Generation
To prepare Ins-KGF transgenic mice, 585-bp KGF cDNA was obtained by RT-PCR of mRNA from mouse salivary glands and modified to include the Kozak consensus sequence. The KGF cDNA was cloned into a vector containing the human insulin promoter and the hepatitis B 3' untranslated sequence. The Ins-KGF fragment was isolated by low-melt agarose, purified using Geneclean (BIO101, La Jolla, CA) and NACS Prepac DNA purification columns (BRL, Gaithersburg, MD), and microinjected into fertilized zygotes from BALB/c x C57BL/6 F2 mice. Transgene-positive mice were then bred with BALB/c mice.
In Situ Hybridization
Hybridization was carried out as described previously.16 Antisense and sense riboprobes were prepared by in vitro transcription of a linearized plasmid containing KGF cDNA using [35S]UTP. After in situ hybridization, sections were covered with photographic emulsion and exposed for 4 weeks before developing.
Histological Analysis and Immunocytochemistry
Both pancreata and spleens were fixed overnight in 10% neutral buffered formalin (3.6% formaldehyde) and embedded in paraffin. Spleen sections were stained in conjunction with pancreatic slices as controls for pancreas-specific antibodies. The 5-µm paraffin sections were either stained with hematoxylin and eosin (H&E) for conventional histological evaluation or stained for the presence of insulin, glucagon, somatostatin, pancreatic polypeptide, amylase, CAII, Pdx-1, albumin, AFP, or BrdU using immunocytochemical techniques as described.17 Briefly, sections were deparaffinized and blocked with 2% normal goat serum before applying the primary antibodies for insulin, glucagon, somatostatin (all from DAKO, Carpinteria, CA), Pdx-1 (a generous gift from Dr. Helena Edlund, University of Umea, Umea, Switzerland), pancreatic peptide or AFP (both from ICN Immuno Biologicals, Costa Mesa, CA), albumin (Accurate Chemical and Scientific Corp., Westbury, NY), amylase (Sigma Chemical Co., St. Louis, MO), BrdU (Accurate/Sera-Lab, Westbury, NY), or CAII (Biodesign International, Kenne-bunk, ME). Binding of the primary antibody was detected using the appropriate secondary antibody (Vector Laboratories, Burlingame, CA) and the horseradish peroxidase (HRP)-labeled avidin-biotin complex (ABC kit, Vector Laboratories). HRP was visualized using 3,3'-diaminobenzidine as a substrate. Gill's hematoxylin was used as a counterstain for all sections. Masson's trichrome staining was used for the identification of fibrotic tissue. Briefly, paraffin-embedded sections were fixed in Bouin's fixative, stained successively with Weigert's iron hematoxylin and with Biebrich scarlet-acid fuchsin acid, and then counterstained with aniline blue. Blue staining by collagen and mucin indicated the presence of fibrosis, whereas cytoplasm stained red.
Islet Measurements
To determine the relative sizes of islets in Ins-KGF transgenic and their transgene-negative littermates, anti-insulin-stained sections were examined. Islets were measured at x10 power (Zeiss Axioscope), using the known 100-µm length of the crosshairs at x10 power for comparison. Islets were then classed as small (<100 µm diameter), medium (200 to 400 µm), or large (>400 µm). Sixteen Ins-KGF mice and twelve negative littermates were evaluated, and ten islets were counted for each mouse. The islet sizes of young (less than 3 months) and old (greater than 3 months) mice were compared using statistical analyses described below.
Blood Glucose Measurement
Blood was obtained from the eyes of anesthetized mice, and glucose levels were determined every 2 weeks using Glucofilm blood glucose test strips (Miles Diagnostic, Elkhart, IN). Typical, nonfasting blood glucose levels for Balb/c mice in our colony ranged from 80 to 150 mg/dl.
Bromodeoxyuridine (BrdU) Labeling and Assessment of Proliferation
For assessment of cellular proliferation, BrdU labeling was completed as previously described.18 Briefly, 100 µg/g body weight BrdU (Serva, Heidelberg, Germany) was injected intraperitoneally into mice 16 hours before sacrifice. Adult mice in our colony are, on average, 20 to 30 g. Paraffin-embedded pancreata were sectioned and stained with an anti-BrdU antibody (Accurate Chemical, Westbury, NY) as described above after treatment with 2.8 N HCl for 15 minutes. BrdU-positive cells were counted in transgenic and nontransgenic mice (n = 6 for each genotype). The mitotic index was calculated by dividing the number of positively stained nuclei of cells comprising the duct wall with that of total nuclei/duct wall in at least five randomly chosen fields in each pancreas. Ductal cells were identified by morphology and CAII staining.
Statistical Analysis
The unpaired t-test was used to compare differences between the groups using the Statview program by Abacus Concepts (Berkeley, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To assess the influence of a growth factor on pancreatic
development and function, we generated transgenic mice that
expressed KGF within ß-cells by using the human insulin promoter
(Ins-KGF mice). In situ hybridization of pancreatic sections
taken from two lines of these Ins-KGF mice demonstrated that expression
of the transgene was confined to their islets (Figure 1)
. The KGF signal appeared to be
consistent throughout all islets, including those with unusually high
levels of duct cells. In fact, no signal emanated from these duct
cells, even when anti-KGF monoclonal antibodies were used (data not
shown), presumably due to the lability of the KGF molecule or at least
the epitope recognized by these antibodies.
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Histological analysis revealed distinct morphological changes in
KGF-expressing islets of mice ranging in age from 6 weeks to 7.5
months. As Figure 2
illustrates, the
cellular composition of the islets changed in that, along with some
normal endocrine cells (ß, 
, and PP cells; data not shown), many
atypical cells were present (Figure 2, B–F)
. Found in approximately
one-fifth of the islets and localized in their peripheries, these novel
cells encompassed more than one-half the area of the islets (Figure 2, E and F)
. These cells were large, both in overall size and nuclear size
(Figure 2, E and 2F
, see arrows); in contrast, islets of nontransgenic
control mice contained cells of a smaller and more uniform size (data
not shown). Subsequent immunohistochemical analysis revealed that the
larger cells did not express insulin, glucagon, somatostatin,
pancreatic polypeptide, amylase, CAII, or Pdx-1 (a marker for the ß
and cell lineages in the adult), nor did they express Meca-32, a
marker for endothelial cells (Figure 3E
and data not shown). Thus, these atypical cells did not appear to be
endocrine, exocrine, ductal, or endothelial. However, the large cells
were similar in morphology to hepatocytes, appearing to take up the
eosin stain more intensely than the adjacent islet cells. We tested
this possibility by immunostaining pancreatic sections from transgenic
mice for the expression of AFP and albumin. Hepatocytes contain AFP
during liver development and regeneration19
and express
albumin during adulthood.20
Yet, all the larger cells
depicted here clearly expressed AFP (Figure 3)
, although only
two-thirds of them were also positive for albumin expression. Despite a
significant degree of background staining for albumin (especially in
the islets), the larger, putative hepatocytes stained much more
intensely for albumin (Figure 3F)
and were distinctly visible above
background. This background most likely resulted from albumin in the
serum, accentuated by the high degree of vascularization of the
pancreas. No AFP-expressing cells were detected in the nontransgenic
littermate controls (Figure 3A)
.
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. These comet-like clusters could imply poor association
with the other islet cells due to distinct membrane characteristics
leading to their exclusion to the periphery of the islet structure.
Some fibrosis was observed in trichrome-stained pancreata of the
Ins-KGF mouse, most commonly separating hepatocyte-like cells from
endocrine cells of the islets (Figure 4)
.
No morphological changes were evident in the livers, kidneys, or
intestines of Ins-KGF mice (data not shown).
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In general, the islets became progressively larger as the mice
aged and contained distended, folded intra-islet ductal structures
(Figure 2, C and D)
. No such morphological changes were observed in
nontransgenic littermate controls (data not shown). On average,
significantly more large islets (>400 µm diameter) were found in
Ins-KGF mice at 3 months of age and older than in nontransgenic
littermates (P = 0.017). Although the islets of
transgenic mice expressed insulin, glucagon, somatostatin, and
pancreatic polypeptide just as nontransgenic mice did, these hormones
in transgenic mice formed unique, small clusters surrounding the
distended intra islet ducts (see Figure 3E
for insulin). The cells
within the distended epithelia were confirmed as ductal cells by their
immunoreactivity to CAII (data not shown), a known component of
pancreatic duct cells.21
Evaluating serial sections of the
same pancreas also demonstrated that, although most islet cells stained
positive for Pdx-1, the intra-islet ducts did not (data not shown).
These epithelial cells manifested none of the endocrine hormones, nor
did they express amylase, which is normally present in acinar cells
(Figure 3E
and data not shown).
Often regions of the pancreas contained several highly folded ducts
immediately adjacent to one another, and duct cell proliferative
activity was demonstrable in experiments utilizing BrdU (Figure 5)
. A mitotic index of 1.6% was measured
for the duct cells of Ins-KGF mice, and that of the nontransgenic
littermates was 0.16%; this latter value is comparable to that
previously reported.22
The difference in these mitotic
indices is statistically significant (P <
0.001). Additionally, although the majority of BrdU-positive
(proliferating) cells were ductal, both the endocrine and exocrine
tissues of Ins-KGF mice contained more BrdU-positive cells than did
those of the nontransgenic mice. Despite these morphological changes,
transgenic mice had neither hyperglycemia nor hypoglycemia.
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To gain a more precise understanding of the timing and
distribution of the pancreatic hepatocyte and duct formation, we
analyzed 20 mice at 6 weeks to 12.5 months of age. Multiple pancreatic
sections from individual mice were scored for the presence of islets
containing either pancreatic hepatocytes or distinct duct cell
proliferation. As some islets did not contain either of these two
unusual phenotypes, the percentage of islets with atypical cells was
compared with the total number of islets (Table 1)
. Mice younger than 5 months of age had
significantly fewer islets (1.3%) containing pancreatic hepatocytes
(P = 0.0019) than mice between 5 and 8.99 months
of age (19.3%) or 9 and 12.5 months of age (17.5%). However, all
Ins-KGF mice, regardless of age, contained islets with proliferating
duct cells. Although some transgenic mice younger than 5 months of age
did not have pancreatic hepatocytes, these cells appeared much more
frequently in older mice. Strikingly, in 19 of the 20 mice examined,
any individual islet harbored either intra-islet duct cells or
hepatocytes, but not both. The exception was one mouse in which two
islets contained both islet hepatocytes and duct cell proliferation
(male, 5.5 months). Neither the age of mice nor their gender (9 females
and 11 males) had any bearing on their total number of islets or of
islets containing ductal cell proliferation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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KGF, which acts as a mitogen specific for epithelial cells, might participate in mesenchymal stimulation of epithelial cell proliferation in vivo.15 Despite the described influence of KGF in vivo and in vitro, knockout mice lacking KGF do not display significant developmental abnormalities, and pancreatic and liver development appear entirely normal.14 Thus, although KGF can induce epithelial cell proliferation and the differentiation of hepatocytes in vivo, other growth factors must also be able to perform these functions during ontogeny.
Here we observed the induction of islet hepatocytes and
hyperproliferation of duct cells associated with islet production of
KGF. Other growth factors have been shown to influence pancreatic
growth as well. Systemic treatment with EGF in pigs induced pancreatic
duct cell proliferation,23
and transgenic mice
overexpressing TGF- displayed significant histological changes in
the pancreas, including the formation of tubular complexes containing
actively dividing duct cells.24
However, no individual
growth factor has previously been demonstrated to induce the formation
of pancreatic hepatocytes.
The induction of hepatocytes in our transgenic model was not expected;
however, KGF itself formerly induced the proliferation of hepatocytes
in vitro and in vivo.8,25
Previous
studies in rodents demonstrated that hepatocytes could develop in the
pancreas after a variety of exogenous treatments, including the
administration of ciprofibrate, TCDD, or cadmium, as well as
maintenance on a copper-deficient diet followed by transfer to a normal
diet.26-30
Furthermore, we observed hepatocyte-like cells
in the pancreata of transgenic mice overexpressing interferon- in
the islets of Langerhans.17
In contrast to these models,
Ins-KGF mice formed most of the hepatocytes we detected within the
pancreatic islets, at the perimeter or in comet-like structures that
extended from the islets. It is significant that the hepatocyte-like
cells identified here produced AFP, an embryo-specific protein not
found in fully differentiated liver cells in the
pancreas.19,20
All of the pancreatic hepatocyte-like cells
observed in our Ins-KGF mice expressed AFP, whereas only two-thirds
expressed albumin. As AFP is typically expressed earlier during
development than albumin,19
possibly cells expressing AFP
but not albumin represent an earlier hepatocyte precursor than the
cells expressing both these markers.
Not completely clear from the foregoing results is how the hepatocytes became localized to the pancreatic islets. Undoubtedly, the in situ proximity of a growth signal played a role in the resulting morphology. Others have proposed that small numbers of uncommitted stem cells in adults retain the ability to differentiate.31,32 The potential existence of stem cells within internal organs of adults may be of great significance in understanding the effects of exogenous KGF expression within ß-cells. The liver and the pancreas both arise from evagination of the primitive gut wall, or endoderm. In fact, a candidate for the liver stem cell (reviewed in Ref. 33 ) has been described. Although still debated, much evidence supports the existence of such cells and their capacity to differentiate into either bile duct cells or hepatocytes (reviewed in 31, 33, and 34). Considering the common embryonic origin of the liver and pancreas, conceivably stem cells can be induced in both these organs of adults. Such cells might also maintain the ability to act as bipotential precursors that can differentiate into hepatocytes or duct cells whether occupying the liver or pancreas. The molecules involved in activating and regulating stem cells are likely to be the same as those known to regulate cell proliferation and morphogenesis of the liver. Of such molecules thus far described, growth factors, including members of the FGF family, perform this activity (reviewed in Ref. 31 ). The pancreatic duct epithelial cell could even be the precursor for developing hepatocytes in the pancreas. For example, analysis of pancreatic hepatocyte development in rats during recovery from a copper-deficient diet suggested that these hepatocytes originate from duct cells as well as interstitial cells.28 Other observations in the regenerating hamster pancreas indicated that pancreatic duct cells gave rise to hepatocytes.35 Thus, the origin of pancreatic hepatocytes and proliferating ductal cells offers several alternatives. A low-frequency stem cell within the pancreas might have the capacity to differentiate toward either a pancreatic hepatocyte or a duct cell, and exposure to KGF could determine the lineage commitment. Or, two stem cells (one for each cell type) might exist at extremely low frequency, then differentiate along their precommitted pathway upon exposure to KGF. Although hepatic cells supposedly can arise from ducts, we found no lineage connection between these two cells in the Ins-KGF mouse. Finally, the islet cell types described here might also arise through trans-differentiation of existing differentiated cell types. Acinar cells have been proposed to be the cellular origin of pancreatic hepatocytes in some systems.
In former studies,5 KGF administered daily maintained duct cell proliferation, which ceased after KGF was withdrawn. In that study, intralobular ducts adjacent to or within the islets of Langerhans were proliferating. Although such localized influence of KGF would be expected in our transgenic mice, it is not clear why systemic KGF treatment would yield such a restricted effect. Nevertheless, several authors have suggested that duct cell proliferation can contribute to the tissue damage of such pancreatic diseases as chronic pancreatitis, pancreatic cancer, and cystic fibrosis.1-4 In addition, the proliferation and differentiation of pancreatic duct cells play critical roles in the transgenic mouse model of islet regeneration that we developed and characterized.36 Indeed, the observation that endocrine cell differentiation frequently accompanies pancreatic duct cell carcinomas suggests that duct cell proliferation can lead to islet neogenesis,37,38 even though no clinical symptoms were evident in our KGF transgenic mice described here.
Clearly, transgenic expression of KGF in the liver during development resulted in substantial morphological changes to the liver, the pancreas, and other sites as well as changes in epithelial growth in multiple organ systems.39 Yet, we saw no changes in any organ other than the pancreas, a distinction that may reflect the absolute level of KGF expressed in our transgenic mice or differences in the promoters used in these two studies.
In summary, we have generated a transgenic mouse in which the differentiation of pancreatic cells to hepatocytes as well as proliferation of duct cell are induced by the expression of a discrete growth factor, KGF. Such characterization of factors influencing and controlling the proliferation and differentiation of duct epithelial cells and hepatocytes bears on the understanding of tissue breakdown in disease and the potential for recovery.
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Acknowledgements |
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Footnotes |
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M. L. Krakowski is supported by a NMSS postdoctoral fellowship, E. M. Jones was supported by NIH postdoctoral fellowship DK09355-01, D. Gu was supported by a postdoctoral fellowship from the Juvenile Diabetes Foundation, and N. Sarvetnick is supported by a Diabetes Interdisciplinary Research Center from the Juvenile Diabetes Foundation and by NIH grant HD-29764 and JDFI 995010. This is publication 11056-IMM from the Department of Immunology, the Scripps Research Institute.
Accepted for publication December 6, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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transgenic mice. Development 1993, 118:33-46[Abstract]
overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 1990, 61:1137-1146[Medline]
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