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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1852-1856
Copyright © 1997 by The Endocrine Society

Experimental Studies

Ex Vivo Expansion of Human Pancreatic Endocrine Cells1

Gillian M. Beattie, Vincenzo Cirulli2, Ana D. Lopez and Alberto Hayek

Whittier Institute, Department of Pediatrics, University of California-San Diego School of Medicine, La Jolla, California 92037

Address all correspondence and requests for reprints to: A. Hayek, M.D., Whittier Institute, Department of Pediatrics, 9894 Genesee Avenue, La Jolla, California 92037. E-mail ahayek{at}ucsd.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Cell transplantation as a therapy for type 1 diabetes is facilitated by ex vivo cell expansion of pancreatic ß-cells without loss of differentiative characteristics. The aim of this study was to determine the optimal conditions for in vitro growth of functional human pancreatic endocrine tissue. We examined the mitogenicity of matrixes from a variety of cell lines; proliferation was greater in cells growing on matrixes from bladder carcinoma cell lines, especially in monolayers grown on matrix from the human cell line HTB-9. After 14-day culture, there was a more than 100-fold proliferative increase, which was augmented to a more than 200-fold when hepatocyte growth factor/scatter factor was added; however, hepatocyte growth factor/scatter factor induced a rapid decrease in insulin content. Without the growth factor, fetal cell monolayers expanded 4-fold with no insulin loss; however, after 12-fold expansion, the insulin levels decreased to 40% of those in unexpanded cells. Adult islet cells expanded 3-fold without insulin loss. After 5-fold expansion, insulin levels decreased by 25% compared to those in free floating islets while retaining a normal response to secretagogues. Together, these results indicate that HTB-9 matrix provides the best stimulatory effect on replication of human endocrine cells, with little loss of in vitro function.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
WE HAVE RECENTLY reported that adult human ß-cells can be induced to undergo cell division using a combination of extracellular matrix and hepatocyte growth factor/scatter factor (HGF/SF) (1). In human fetal pancreatic islet cells, the regulation of proliferation and differentiation is also dependent on interactions between cell-cell and cell-matrix contacts and specific growth factors. However, the nature of these interactions is not fully understood, and the relative effects of matrix and growth factors on growth vs. differentiation remain unclear. Previously, we found that a combination of extracellular matrix from the rat bladder carcinoma line 804G (2) and the growth factor HGF/SF resulted in a 10-fold increase in cell number (3) when the fetal cells were expanded in monolayers. However, cell proliferation was associated with marked down-regulation of islet-specific gene expression. Cell transplantation experiments performed with this expanded cell mass, as a cell suspension, failed to produce mature endocrine cells, contrasting with our previous results following the transplantation of islet-like cell clusters into nude mice (4). However, after reaggregation of the cell suspension in the presence of nicotinamide, a potent inducer of endocrine differentiation (5), new islet formation was documented in all nude mice receiving grafts (3).

The experiments described here were performed to determine the relationship between matrix and growth factor effects on growth vs. differentiation. Specifically, we investigated whether human fetal and adult endocrine cells can be expanded in culture while minimizing the loss of hormone production. Previously, we have shown that complex matrixes deposited by cells in culture are preferable to simple matrixes such as collagen and Matrigel (Collaborative Research Inc., Cambridge, MA (6), and that the matrix generated by the rat bladder carcinoma line 804G is preferable to that made by bovine corneal endothelial cells (3, 7). However, growth of cells on 804G resulted in rapid loss of differentiated function. Therefore, we wanted to study whether, by using matrixes laid down by cells from other organs or tumors it would be possible to dissociate the effects of matrix on growth from the effects on differentiation. The use of HTB-9 matrix resulted in growth stimulation more potent than that induced by 804G matrix, with much less effect on insulin production.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Human pancreatic tissue

Human fetal pancreatic tissue was provided by the Anatomic Gift Foundation (Laurel, MD) and Advanced Bioscience Resources (Oakland, CA). Informed consent for tissue donation was obtained by the procurement centers, and our own institutional review board had reviewed and approved the use of fetal tissue for these studies. Tissue was processed as previously described (4), and the islet-like cell clusters (ICCs) formed were cultured for 3 days in the presence of HGF/SF. Human adult islets were provided by the Diabetes Research Institute (Miami, FL), and the Islet Isolation Core Facility (St. Louis, MO). They were isolated with an automated method, as described previously (8), and further purified by hand picking single islets (50–150 µm diameter) after dithizone staining (9).

Extracellular matrixes and monolayer formation

Extracellular matrices were derived from the rat bladder carcinoma cell lines 804G and NBT-11, a human bladder carcinoma cell line HTB-9, a human squamous carcinoma cell line SCC-25 (10), a human keratinocyte cell line HaCaT (11), a human lung carcinoma UCLA, and a human fetal pancreatic tumor line TRM-1 (12). The bladder carcinomas were chosen because we have previously shown that ICCs grow well as monolayers on the matrix from 804G (3), which is rich in laminin 5 (2). SSC-25 and HaCaT have also been shown to secrete high levels of laminin or laminin 5 (11, 13). UCLA was chosen as an epithelial cell line of human origin and TRM-1 because it comes from the same tissue as the ICCs. The cell lines NBT-11, HTB-9, and SCC-25 were all obtained from American Type Culture Collection (Rockville, MD), 804G cells were provided by Dr. V Quaranta (La Jolla, CA), UCLA cells were provided by Dr. R. Reisfeld (La Jolla, CA), and HaCaT cells were provided by Dr. D. Salomon (La Jolla, CA). TRM-1 cells were derived from human fetal pancreatic tissue in our laboratory (12). Extracellular matrixes were derived from monolayers of the cell lines as previously described (6, 14). Monolayers were derived from hand-picked epithelial-rich ICCs, 50–150 µm diameter (15). Fifty ICCs or adult islets were plated per well; four replicate wells were used for each determination. In the HGF/SF inhibition experiments, rabbit polyclonal antiserum specific for HGF/SF was used for neutralization at a 200-fold dilution (16, 17).

DNA synthesis and insulin content and secretion

Monolayers were pulsed with 1 µCi/mL [methyl-3H]thymidine (SA, 25 Ci/mmol; Amersham, Arlington, IL) in newly replenished medium. After 16 h, medium was collected to determine insulin secretion, and thymidine incorporation into DNA and insulin extractable from cells were quantified as previously described (5, 6). Acute insulin release after stimulation with glucose was assayed in static incubations as previously described (6). Insulin was measured with a solid phase RIA (Diagnostic Products Corp., Los Angeles, CA); DNA content was measured fluorometrically (18). Incorporation of [3H]thymidine was determined by liquid scintillation counting of trichloroacetic acid precipitates of the sonicated cells.

Statistical analysis

Experiments were carried out on at least three different preparations of human fetal ICCs or adult islets. The statistical significance of observed differences was analyzed by ANOVA and Fischer’s protected least significance difference test, with the 95% level as the limit of significance using StatView IV (Abacus Concepts, Berkeley, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Experiments with human fetal ICCs

Proliferative response. After 5 days of culture, proliferation was highest in monolayers growing on the matrixes derived from the bladder carcinoma cell lines 804G, NBT-11, and HTB-9; the addition of HGF/SF augmented the proliferative responses. However, thymidine incorporation was significantly higher in cells growing on HTB-9 matrix both with and without HGF/SF. Moreover, the proliferative response on HTB-9 matrix alone was comparable to that on 804G supplemented with HGF/SF (Fig. 1AGo).



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  		Figure 1. Comparison of effects of matrixes on proliferation and insulin production in ICC monolayers. ICCs were plated on selected matrixes. After 5 days of culture in the presence or absence of 10 ng/mL HGF/SF, monolayers were assayed for [3H]thymidine incorporation (A), 16-h release of insulin into the medium (B), and insulin content (C; n = 4). *, P < 0.05; **, P < 0.01; ***, P < 0.001.

 
Insulin content and release. As shown in Fig. 1Go, B and C, insulin content and release in the culture medium were significantly decreased in monolayers growing for 5 days on the bladder carcinoma matrixes when HGF/SF was added to the medium. However, in the absence of HGF/SF, both insulin content (Fig. 1BGo) and release (Fig. 1CGo) were significantly higher in the cells grown on HTB-9 (P < 0.001; n = 4).

Time course of growth and insulin production on HTB-9 matrix. During the log phase of growth of ICCs on HTB-9, the doubling times were 22 and 32 h in the presence or absence of HGF/SF, respectively. After 14 days there was a more than 100-fold increase in DNA content, which was augmented to more than 200-fold when HGF/SF was added to the medium (Fig. 2AGo). However, in the presence of HGF/SF, insulin release and content diminished rapidly. After 4 days, insulin release was decreased by 38%; after 14 days, it was barely detectable (Fig. 2BGo). The effect on insulin content was even more dramatic, being reduced by 68% after 4 days and barely detectable at 14 days (Fig. 2CGo). In contrast, when monolayers derived from ICCs were grown in the absence of HGF/SF, insulin release and content remained at the level of free floating ICCs for 4 days; thereafter, the levels dropped, and by day 14 were similar to those in the presence of HGF/SF. The differences in insulin levels observed on day 4 in the presence and absence of HGF/SF were significant (P < 0.05 for insulin release and P < 0.001 for insulin content). By day 7 the observed differences were still significant for content (P < 0.05), and by day 14 under both conditions the levels were barely detectable.



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  		Figure 2. Time course of growth and insulin production of ICC monolayers on HTB-9 matrix. ICCs were grown on HTB-9 matrix in the presence or absence of 10 ng/mL HGF/SF. Monolayers were assayed for total DNA content (A), insulin release (B), and insulin content (C) at various time points for 14 days (n = 4). *, P < 0.05; ***, P < 0.001.

 
When HGF/SF-specific antiserum was added to the cultures for 1 week, we were able to completely block the proliferative effect of HGF/SF, but not the proliferative effect of the matrix alone (Fig. 3Go).



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  		Figure 3. Effect of neutralizing levels of antiserum specific for HGF/SF on the proliferation of monolayers on HTB-9 matrix. ICCs were cultured for 1 week as monolayers on HTB-9 matrix in the presence or absence of both HGF/SF and antiserum specific for HGF/SF. Total DNA contents were compared after 1 week (n = 4). ***, P < 0.001.

 
Experiments with human adult islets

Because of the differences in function between fetal and adult endocrine cells, it was important to determine whether the effects of HTB-9 matrix would be the same in adult islets.

Proliferation. There was a 3-fold increase in islet DNA after 1 week in monolayer and a 5-fold increase after 2 weeks when using HTB-9 matrix alone. The proliferative effect of the matrix was enhanced with the addition of HGF/SF to 4- and 6-fold after 1 and 2 weeks, respectively (Fig. 4AGo). The increase in DNA was accompanied by a concomitant increase in cell number and [3H]thymidine incorporation (data not shown). There was no increase in DNA content in control islets kept free floating in petri dishes (Fig. 4AGo) or plated on tissue-coated dishes alone (data not shown).



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  		Figure 4. Time course of growth and insulin production of monolayers of adult islets on HTB-9 matrix. Adult islets were cultured on HTB-9 matrix in the presence or absence of 25 ng/mL HGF/SF. Monolayers were assayed for total DNA content (A) and insulin content (B) at various time points for 14 days. Free floating islets were used as controls (n = 4). *, P < 0.05; ***, P < 0.001.

 
Insulin content and release. After 7 days of culture, the insulin content of monolayers grown with matrix alone was similar to that of control islets kept free floating. However, there was a significant loss of insulin from the monolayers grown with HGF/SF (P < 0.05; n = 4). After 2 weeks, insulin content had decreased in the presence or absence of HGF/SF, but the observed insulin loss was significantly higher in the presence of HGF/SF (Fig. 4BGo; P < 0.001; n = 4).

After 5 days in culture, overnight insulin release in 5.5 mmol/L glucose was reduced in monolayers in both the presence and absence of HGF/SF compared to that in free floating islets. However, their ability to respond to acute stimulation with 16.7 mmol/L glucose was comparable to that of free floating islets (Fig. 5Go).



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  		Figure 5. Effects of HTB-9 and HGF/SF on insulin release from adult islet monolayers. Chronic (A) and acute (B) insulin release from adult islet monolayers were measured after 5 days in culture on HTB-9 matrix in the presence or absence of HGF/SF. Free floating islets were used as controls (n = 4). **, P < 0.05; ***, P < 0.001.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These studies show that cell monolayers derived from ICCs on HTB-9 matrix plus HGF/SF achieved a 4-fold increase in DNA without a decrease in insulin content. Even after a 12-fold increase in DNA, 40% of the insulin content was still present. Maximal expansion using the same matrix in the presence of HGF/SF reached a 200-fold increase, but a simultaneous loss of cellular insulin content was observed. The culture of adult islets on HTB-9 matrix without the growth factor produced a 3-fold increase in DNA content with no loss of insulin expression or response to glucose, and a 5-fold increase in DNA content with only a 25% loss of insulin expression. Together, these data show that matrixes derived from bladder carcinoma cell lines, especially those of human origin, significantly stimulate the proliferation of human pancreatic endocrine cells. The data also show that the mitogenic response of fetal pancreatic cells, most likely endocrine precursor cells, is particularly susceptible to the matrix effect, and both fetal and adult cells show an increment in replication when HGF/SF is added to the culture medium. Although the mitogenic effect is mostly seen in precursor cells in fetal tissue and in endocrine cells in adult islets, other cells, including fibroblasts and endothelial cells, may contribute to the total DNA pool measured. In differentiated cells, the combined synergistic effects of the matrix and the growth factor on proliferation are paralleled by the diminished expression of islet-specific genes and the loss of function, as measured in the decreased insulin content and release (3).

The extracellular matrix is a complex of glycoproteins, including fibronectins, laminins, heparan, and dermatan sulfate proteoglycans and collagens (14), serving as the scaffolding in tissue organization and migration, especially of embryonic cells during development (19). More recently, it has been shown that components of extracellular matrix play an important role in tissue-specific gene expression (20). Growth factors secreted and stored in extracellular matrix by bladder carcinoma cells in vitro include endothelial cell growth factor (21), transforming growth factor-ß1 (22), and, under certain conditions, HGF/SF (23). To our knowledge, there are no reports that HGF/SF is secreted by HTB-9 cells. Our data using neutralizing antibodies to HGF/SF suggest that the proliferative effect of HTB-9 matrix is not due to HGF/SF storage in matrix by HTB-9 cells. It is likely that signal transduction pathways are differentially activated by extracellular matrix and growth factors. Our previous study in which we demonstrated that adult islets could be induced to divide on matrix with HGF/SF did not measure effects on the differentiation state over a period of time in culture (1). The significant finding of the current study is that it is possible to separate mitogenic from differentiation effects mediated by extracellular matrixes.

In summary, the matrix produced by HTB-9 cells and HGF/SF added to medium are powerful mitogenic stimuli to human pancreatic endocrine cells.


   Acknowledgments
 
We thank Dr. J. Rubin for providing HGF/SF and its specific antiserum, and Drs. F. Levine and M. Mally for helpful discussions.


   Footnotes
 
1 This work was supported by Juvenile Diabetes Foundation Grant 196046 and the Herbert O. Perry Fund. Back

2 Recipient of a Career Development Award from the Juvenile Diabetes Foundation. Back

Received December 17, 1996.

Revised February 5, 1997.

Accepted March 6, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Hayek A, Beattie GM, Cirulli V, Lopez AD, Ricordi C, Rubin JS. 1995 Growth factor/matrix-induced proliferation of human adult ß-cells. Diabetes. 44:1458–1460.[Abstract]
  2. Langhofer M, Hopkinson SB, Jones JCR. 1993 The matrix secreted by 804G cells contains laminin-related components that participate in hemidesmosome assembly in vitro. J Cell Sci. 105:753–764.[Abstract]
  3. Beattie GM, Rubin JS, Mally MI, Otonkoski T, Hayek A. 1996 Regulation of proliferation and differentiation of human fetal pancreatic islet cells by extracellular matrix, hepatocyte growth factor and cell-cell contact. Diabetes. 45:1223–1228.[Abstract]
  4. Beattie GM, Levine F, Mally M, et al. 1994 Acid ß-galactosidase: a developmentally regulated marker of endocrine cell precursors in the human fetal pancreas. J Clin Endocrinol Metab. 78:1232–1240.[Abstract]
  5. Otonkoski T, Beattie GM, Mally MI, Ricordi C, Hayek A. 1993 Nicotinamide is a potent inducer of endocrine differentiation in cultured human fetal pancreatic cells. J Clin Invest. 92:1459–1466.
  6. Beattie GM, Lappi DA, Baird A, Hayek A. 1991 Functional impact of attachment and purification in the short term culture of human pancreatic islets. J Clin Endocrinol Metab. 73:93–98.[Abstract/Free Full Text]
  7. Hayek A, Lopez AD, Beattie G M. 1989 Enhancement of pancreatic islet cell monolayer growth by endothelial cell matrix and insulin. In Vitro. 25:146–150.
  8. Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW. 1988 Automated method for isolation of human pancreatic islets. Diabetes. 37:413–420.[Abstract]
  9. Latif ZA, Noel J, Alejandro R. 1988 A simple method of staining fresh and cultured islets. Transplantation. 45:827–830.[Medline]
  10. Matsuit C, Wang CK, Nelson CF, Bauer EA, Hoeffer WK. 1995 The assembly of laminin-5 subunits. J Biol Chem. 270:23496–23503.[Abstract/Free Full Text]
  11. Ryle C, Breitkreutz D, Stark H, et al. 1989 Density-dependent modulation of synthesis of keratins 1 + 10 in the human keratinocyte line HaCat and in ras-transfected tumorigenic clones. Differentiation. 40:42–54.[CrossRef][Medline]
  12. Wang S, Beattie GM, Mally MI, et al. 1997 Isolation and characterization of a cell line from the epithelial cells of the human fetal pancreas. Cell Transplant. 6:59–67.[CrossRef][Medline]
  13. Richardson KEY, Spooner BS. 1977 Mammalian pancreas development: regeneration and differentiation in vitro. Dev Biol. 58:402–420.[CrossRef][Medline]
  14. Gospodarowicz D. 1984 Preparation of extracellular matrices produced by cultured bovine corneal endothelial cells and PF-HR-9 endodermal cells: their use in cell culture. In: Barnes DW, Sirbasku DA, Sato GH, eds. Cell Culture methods for molecular and cell biology. New York: Liss; 275–295.
  15. Levine F, Beattie GM, Hayek A. 1994 Differential integrin expression facilitates isolation of human fetal pancreatic epithelial cells. Cell Transplant. 3:307–313.[Medline]
  16. Rubin JS, Chan A, Bottaro DP, et al. 1991 A broad-spectrum human lung-derived mitogen is a variant of hepatocyte growth factor. Proc Natl Acad Sci USA. 88:415–419.[Abstract/Free Full Text]
  17. Otonkoski T, Cirulli V, Beattie GM, et al. 1996 A role for hepatocyte growth factor/scatter factor in fetal mesenchyme-induced pancreatic ß-cell growth. Endocrinology. 137:3131–3139.[Abstract]
  18. Hinegardner RT. 1971 An improved fluorometric assay for DNA. Anal Biochem. 39:197–201.[CrossRef][Medline]
  19. Adamson ED. 1982 The effect of collagen on cell division, cellular differentiation and embryonic development. In: Weiss JB, Jayson MIV, eds. Collagen in Health and Disease. Edinburgh: Churchill Livingstone; 218–243.
  20. Bissell MJ, Barcellos-Hoff H. 1987 The influence of extracellular matrix on gene expression: is structure the message? J Cell Sci. 8:327–343.
  21. Akaogi K, Okabe Y, Funahashi K, et al. 1994 Cell adhesion activity of a 30-kDa major secreted protein from human bladder carcinoma cells. Biochem Biophys Res Commun. 198:1046–1053.[CrossRef][Medline]
  22. Bourdrel L, Lin CH, Lauren SL, et al. 1993 Recombinant human transforming growth factor-beta 1: expression by chinese hamster ovary cells, isolation, and characterization. Protein Express Purification. 4:130–140.
  23. Bellusci S, Moens G, Thiery JP, Jouanneau J. 1994 A scatter factor-like factor is produced by a metastatic variant of a rat bladder carcinoma cell line. J Cell Sci. 107:1277–1287.[Abstract]



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