Abstract
Previously, we reported elevated numbers of macrophages in the pancreas of NOD mice, a spontaneous animal model for T1D, during the early postnatal period. Extracellular matrix plays an important role in the tissue trafficking and retention of macrophages as well as in postnatal pancreas development. Therefore, we have examined the expression and distribution of laminin and fibronectin, two major extracellular matrix proteins and their corresponding integrin receptors, in the pre-weaning pancreases of NOD mice and control mouse strains. In addition, we have characterized the pancreas morphology during this period, since the morphology of the pre-weaning pancreas before the onset of lymphocytic peri-insulitis, when the pancreas is still subject to developmental changes, has been poorly documented. We show that laminin labeling is mainly associated with exocrine tissue, whereas fibronectin labeling was mostly localized at the islet-ductal pole, islet periphery and in intralobular septa. Moreover, the protein expression level of fibronectin was increased in NOD pancreases at the early stage of postnatal development, as compared to pancreases of C57BL/6 and BALB/c mouse strains. Interestingly, pancreatic macrophages were essentially found at sites of intense fibronectin labeling. The increased fibronectin content in NOD neonatal pancreas coincided with altered islet morphology, histologically reflected by enlarged and irregular shaped islets and increased percentages of total endocrine area as compared to that of control strains. In conclusion, increased levels of the extracellular matrix protein fibronectin were found in the early postnatal NOD pancreas, and this is associated with an enhanced accumulation of macrophages and altered islet morphology.
Similar content being viewed by others
Abbreviations
- BMDMs:
-
Bone marrow-derived macrophages
- ECM:
-
Extracellular matrix
- HE:
-
Hematoxylin-eosin
- M-CSF:
-
Macrophage-colony stimulating factor
- NOD:
-
Non-obese diabetic
- T1D:
-
Type 1 diabetes
References
Adams JC, Watt FM (1993) Regulation of development and differentiation by the extracellular matrix. Development 117:1183–1198
Amrani A, Durant S, Throsby M, Coulaud J, Dardenne M, Homo-Delarche F (1998) Glucose homeostasis in the nonobese diabetic mouse at the prediabetic stage. Endocrinology 139:1115–1124
Bosco D, Meda P, Halban PA, Rouiller DG (2000) Importance of cell-matrix interactions in rat islet beta-cell secretion in vitro. Role of α6α1 integrin. Diabetes 49:233–243
de Bruijn MF, Slieker WA, van der Loo JC, Voerman JS, van Ewijk W, Leenen PJM (1994) Distinct mouse bone marrow macrophage precursors identified by differential expression of ER-MP12 and ER-MP20 antigens. Eur J Immunol 24:2279–2284
Charré S, Rosmalen JG, Pelegri C, Alves V, Leenen PJ, Drexhage HA, Homo-Delarche F (2002) Abnormalities in dendritic cell and macrophage accumulation in the pancreas of nonobese diabetic (NOD) mice during the early neonatal period. Histol Histopathol 17:393–401
Cirulli V, Beattie GM, Klier G, Ellisman M, Salomon DR (2000) Expression and function of αVα3 and αVα5 integrins in the developing pancreas: roles in the adhesion and migration of putative endocrine progenitor cells. J Cell Biol 150:1445–1459
Delovitch TL, Singh B (1997) The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7:727–738
Fowden AL, Hill DJ (2001) Intra-uterine programming of the endocrine pancreas. Br Med Bull 60:123–142
Giavazzi R, Hart IR (1983) Mononuclear phagocyte adherence in the presence of laminin. A possible marker of cellular differentiation. Exp Cell Res 146:391–399
Gomez Dumm CL, Console GM, Luna GC, Dardenne M, Goya RG (1995) Quantitative immunohistochemical changes in the endocrine pancreas of nonobese diabetic (NOD) mice. Pancreas 11:396–401
Gu D, Sarvetnick N (1993) Epithelial cell proliferation and islet neogenesis in IFN-gamma transgenic mice. Development 118:33–46
Hulinsky I, Harrington J, Cooney S, Silink M (1995a) Insulin secretion and DNA synthesis of cultured islets of Langerhans are influenced by the matrix. Pancreas 11:309–314
Hulinsky I, Cooney S, Harrington J, Silink M (1995b) In vitro growth of neonatal rat islet cells is stimulated by adhesion to matrix. Horm Metab Res 27:209–215
Jiang FX, Cram DS, Deaizpurua HJ, Harrison LC (1999) Laminin-1 promotes differentiation of fetal mouse pancreatic beta-cells. Diabetes 48:722–730
Jiang FX, Naselli G, Harrison LC (2002) Distinct distribution of laminin and its integrin receptors in the pancreas. J Histochem Cytochem 50:1625–1632
Judware R, McCormick TS, Mohr S, Yun JK, Lapetina EG (1998) Propensity for macrophage apoptosis is related to the pattern of expression and function of integrin extracellular matrix receptors. Biochem Biophys Res Commun 246:507–512
Kremlev SG, Chapoval AI, Evans R (1998) Cytokine release by macrophages after interacting with CSF-1 and extracellular matrix proteins: characteristics of a mouse model of inflammatory responses in vitro. Cell Immunol 185:59–64
Maldonado TS, Crisera CA, Kadison AS, Alkasab SL, Longaker MT, Gittes GK (2000) Basement membrane exposure defines a critical window of competence for pancreatic duct differentiation from undifferentiated pancreatic precursor cells. Pancreas 21:93–96
Miralles F, Battelino T, Czernichow P, Scharfmann R (1998) TGF-beta plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2. J Cell Biol 143:827–836
Pelegri C, Rosmalen JG, Durant S, Throsby M, Alves V, Coulaud J, Esling A, Pleau JM, Drexhage HA, Homo-Delarche F (2000) Islet endocrine-cell behaviour from birth onward in mice with the nonobese diabetic genetic background. Mol Med 7:311–319
Pictet RL, Clark WR, Williams RH, Rutter WJ (1972) An ultrastructural analysis of the developing embryonic pancreas. Dev Biol 29:436–467
Rosmalen JG, Leenen PJ, Pelegri C, Drexhage HA, Homo-Delarche F (2002) Islet abnormalities in the pathogenesis of autoimmune diabetes. Trends Endocrinol Metab 13:209–214
Shaw LM, Mercurio AM (1994) Regulation of interactions with laminin by integrin cytoplasmic domains: the A and B structural variants of the alpha 6 beta 1 integrin differentially modulate the adhesive strength, morphology and migration of macrophages. Mol Biol Cell 5:679–690
Shima M, Teitelbaum SL, Holers VM, Ruzicka C, Osmack P, Ross FP (1995) Macrophage-colony-stimulating factor regulates expression of the integrins alpha 4 beta 1 and alpha 5 beta 1 by murine bone marrow macrophages. Proc Natl Acad Sci USA 92:5179–5183
Sreenan S, Pick AJ, Levisetti M, Baldwin AC, Pugh W, Polonsky KS (1999) Increased beta-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse. Diabetes 48:989–996
Stoffers DA, Kieffer TJ, Hussain MA, Drucker DJ, Bonner-Weir S, Habener JF, Egan JM (2000) Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 49:741–748
St Onge L, Wehr R, Gruss P (1999) Pancreas development and diabetes. Curr Opin Gen Dev 9:295–300
Trudeau JD, Dutz JP, Arany E, Hill DJ, Fieldus WE, Finegood DT (2000) Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes? Diabetes 49:1–7
Van de Wiel-van Kemenade E, van Kooyk Y, de Boer AJ, Huijbens RJ, Weder P, van de Kasteele W, Melief CJ, Figdor CG (1992) Adhesion of T and B lymphocytes to extracellular matrix and endothelial cells can be regulated through the beta subunit of VLA. J Cell Biol 117:461–470
Acknowledgements
The authors would like to thank Mrs. V. Alves, J. Coulaud, I. Cisse, Mr. H. de Wit and Mr. O. Babin for technical assistance; Dr. P. Leenen for providing the ER-MP23 antibody, Mr. T. van Os for assistance with preparing the illustrations, and Dr. J.J. Bajramovic for the opportunity of using laboratory facilities, helpful discussions and critically reading this manuscript.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by the Centre Nationale de la Recherche Scientifique, Université Paris V and grants from the 5th PCRD “MONODIAB.”
Rights and permissions
About this article
Cite this article
Geutskens, S.B., Homo-Delarche, F., Pleau, JM. et al. Extracellular matrix distribution and islet morphology in the early postnatal pancreas: anomalies in the non-obese diabetic mouse. Cell Tissue Res 318, 579–589 (2004). https://doi.org/10.1007/s00441-004-0989-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-004-0989-0