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18.05.2020 | Article

Islet pericytes convert into profibrotic myofibroblasts in a mouse model of islet vascular fibrosis

verfasst von: Luciana Mateus Gonçalves, Elizabeth Pereira, João Pedro Werneck de Castro, Ernesto Bernal-Mizrachi, Joana Almaça

Erschienen in: Diabetologia | Ausgabe 8/2020

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Abstract

Aims/hypothesis

Islet vascular fibrosis may play an important role in the progression of type 2 diabetes, but there are no mouse models allowing detailed mechanistic studies to understand how a dysfunctional islet microvasculature contributes to diabetes pathogenesis. Here we report that the transgenic AktTg mouse, unlike other mouse strains, shows an increased deposition of extracellular matrix (ECM) proteins in perivascular regions, allowing us to study the cellular mechanisms that lead to islet vascular fibrosis.

Methods

Using immunohistochemistry, we labelled the islet microvasculature and ECM in pancreas sections of AktTg mice and human donors and performed lineage tracing to follow the fate of islet pericytes. We compared islet microvascular responses in living pancreas slices from wild-type and AktTg mice.

Results

We found that vascular pericytes proliferate extensively, convert into profibrotic myofibroblasts and substantially contribute to vascular fibrosis in the AktTg mouse model. The increased deposition of collagen I, fibronectin and periostin within the islet is associated with diminished islet perfusion as well as impaired capillary responses to noradrenaline (norepinephrine) and to high glucose in living pancreas slices.

Conclusions/interpretation

Our study thus illustrates how the AktTg mouse serves to elucidate a cellular mechanism in the development of islet vascular fibrosis, namely a change in pericyte phenotype that leads to vascular dysfunction. Because beta cells in the AktTg mouse are more numerous and larger, and secrete more insulin, in future studies we will test the role beta cell secretory products play in determining the phenotype of pericytes and other cells residing in the islet microenvironment under physiological and pathophysiological conditions.

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Brunicardi FC, Stagner J, Bonner-Weir S et al (1996) Microcirculation of the islets of Langerhans. Long Beach Veterans Administration Regional Medical Education Center Symposium. Diabetes 45(4):385–392. https://doi.org/10.2337/diab.45.4.385 CrossRefPubMed

Nikolova G, Jabs N, Konstantinova I et al (2006) The vascular basement membrane: a niche for insulin gene expression and β cell proliferation. Dev Cell 10(3):397–405. https://doi.org/10.1016/j.devcel.2006.01.015 CrossRefPubMed

Gepts W (1957) Contribution to the morphological study of the islands of Langerhans in diabetes; study of the quantitative variations of the different insular constituents. Ann Soc R Sci Med Nat Brux 10(1):5–108 [article in French]

Halban PA, Polonsky KS, Bowden DW et al (2014) β-Cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care 37(6):1751–1758. https://doi.org/10.2337/dc14-0396 CrossRefPubMedPubMedCentral

Gepts W, Lecompte PM (1981) The pancreatic islets in diabetes. Am J Med 70(1):105–115. https://doi.org/10.1016/0002-9343(81)90417-4 CrossRefPubMed

Portha B, Lacraz G, Kergoat M et al (2009) The GK rat beta-cell: a prototype for the diseased human beta-cell in type 2 diabetes? Mol Cell Endocrinol 297(1–2):73–85. https://doi.org/10.1016/j.mce.2008.06.013 CrossRefPubMed

Ko SH, Kwon HS, Kim SR et al (2004) Ramipril treatment suppresses islet fibrosis in Otsuka Long-Evans Tokushima fatty rats. Biochem Biophys Res Commun 316(1):114–122. https://doi.org/10.1016/j.bbrc.2004.02.023 CrossRefPubMed

Movassat J, Saulnier C, Serradas P, Portha B (1997) Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat. Diabetologia 40(8):916–925. https://doi.org/10.1007/s001250050768 CrossRefPubMed

Shima K, Shi K, Sano T, Iwami T, Mizuno A, Noma Y (1993) Is exercise training effective in preventing diabetes mellitus in the Otsuka-Long-Evans-Tokushima fatty rat, a model of spontaneous non-insulin-dependent diabetes mellitus? Metab Clin Exp 42(8):971–977. https://doi.org/10.1016/0026-0495(93)90009-d CrossRefPubMed

10.

Mizuno A, Noma Y, Kuwajima M, Murakami T, Zhu M, Shima K (1999) Changes in islet capillary angioarchitecture coincide with impaired B-cell function but not with insulin resistance in male Otsuka-Long-Evans-Tokushima fatty rats: dimorphism of the diabetic phenotype at an advanced age. Metab Clin Exp 48(4):477–483. https://doi.org/10.1016/S0026-0495(99)90107-5 CrossRefPubMed

11.

Heydinger DK, Lacy PE (1974) Islet cell changes in the rat following injection of homogenized islets. Diabetes 23(7):579–582. https://doi.org/10.2337/diab.23.7.579 CrossRefPubMed

12.

Gepts W (1981) Islet changes in human diabetes. In: Cooperstein SJ, Watkins D (eds) The islet of Langerhans: biochemistry, physiology and pathology. Academic Press, Cambridge MA, pp 321–356. https://doi.org/10.1016/B978-0-12-187820-7.50019-X CrossRef

13.

Hayden MR, Karuparthi PR, Habibi J et al (2008) Ultrastructure of islet microcirculation, pericytes and the islet exocrine interface in the HIP rat model of diabetes. Exp Biol Med (Maywood) 233(9):1109–1123. https://doi.org/10.3181/0709-rm-251 CrossRef

14.

Brissova M, Shostak A, Fligner CL et al (2015) Human islets have fewer blood vessels than mouse islets and the density of islet vascular structures is increased in type 2 diabetes. J Histochem Cytochem 63(8):637–645. https://doi.org/10.1369/0022155415573324 CrossRefPubMedPubMedCentral

15.

Cohrs CM, Chen C, Jahn SR et al (2017) Vessel network architecture of adult human islets promotes distinct cell-cell interactions in situ and is altered after transplantation. Endocrinology 158(5):1373–1385. https://doi.org/10.1210/en.2016-1184 CrossRefPubMed

16.

Virtanen I, Banerjee M, Palgi J et al (2008) Blood vessels of human islets of Langerhans are surrounded by a double basement membrane. Diabetologia 51(7):1181–1191. https://doi.org/10.1007/s00125-008-0997-9 CrossRefPubMed

17.

Van Deijnen JH, Van Suylichem PT, Wolters GH, Van Schilfgaarde R (1994) Distribution of collagens type I, type III and type V in the pancreas of rat, dog, pig and man. Cell Tissue Res 277(1):115–121. https://doi.org/10.1007/bf00303087 CrossRefPubMed

18.

Bernal-Mizrachi E, Wen W, Stahlhut S, Welling CM, Permutt MA (2001) Islet β cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia. J Clin Invest 108(11):1631–1638. https://doi.org/10.1172/jci13785 CrossRefPubMedPubMedCentral

19.

Dulauroy S, Di Carlo SE, Langa F, Eberl G, Peduto L (2012) Lineage tracing and genetic ablation of ADAM12⁺ perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med 18(8):1262–1270. https://doi.org/10.1038/nm.2848 CrossRefPubMed

20.

Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisen J (2011) A pericyte origin of spinal cord scar tissue. Science 333(6039):238–242. https://doi.org/10.1126/science.1203165 CrossRefPubMed

21.

Humphreys BD, Lin SL, Kobayashi A et al (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176(1):85–97. https://doi.org/10.2353/ajpath.2010.090517 CrossRefPubMedPubMedCentral

22.

Lin SL, Kisseleva T, Brenner DA, Duffield JS (2008) Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 173(6):1617–1627. https://doi.org/10.2353/ajpath.2008.080433 CrossRefPubMedPubMedCentral

23.

Schrimpf C, Xin C, Campanholle G et al (2012) Pericyte TIMP3 and ADAMTS1 modulate vascular stability after kidney injury. J Am Soc Nephrol 23(5):868–883. https://doi.org/10.1681/asn.2011080851 CrossRefPubMedPubMedCentral

24.

Hayden MR, Karuparthi PR, Habibi J et al (2007) Ultrastructural islet study of early fibrosis in the Ren2 rat model of hypertension. Emerging role of the islet pancreatic pericyte-stellate cell. JOP 8(6):725–738PubMed

25.

Junqueira LC, Bignolas G, Brentani RR (1979) Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem J 11(4):447–455. https://doi.org/10.1007/bf01002772 CrossRefPubMed

26.

Almaca J, Weitz J, Rodriguez-Diaz R, Pereira E, Caicedo A (2018) The pericyte of the pancreatic islet regulates capillary diameter and local blood flow. Cell Metab 27(3):630–644 e634. https://doi.org/10.1016/j.cmet.2018.02.016 CrossRefPubMedPubMedCentral

27.

Fischer MJ, Uchida S, Messlinger K (2010) Measurement of meningeal blood vessel diameter in vivo with a plug-in for ImageJ. Microvasc Res 80(2):258–266. https://doi.org/10.1016/j.mvr.2010.04.004 CrossRefPubMed

28.

Kanisicak O, Khalil H, Ivey MJ et al (2016) Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat Commun 7(1):12260. https://doi.org/10.1038/ncomms12260 CrossRefPubMedPubMedCentral

29.

Henderson JR, Moss MC (1985) A morphometric study of the endocrine and exocrine capillaries of the pancreas. Q J Exp Physiol 70(3):347–356. https://doi.org/10.1113/expphysiol.1985.sp002920 CrossRefPubMed

30.

Bachem MG, Schneider E, Gross H et al (1998) Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115(2):421–432. https://doi.org/10.1016/S0016-5085(98)70209-4 CrossRefPubMed

31.

Lee E, Ryu GR, Ko SH, Ahn YB, Song KH (2017) A role of pancreatic stellate cells in islet fibrosis and β-cell dysfunction in type 2 diabetes mellitus. Biochem Biophys Res Commun 485(2):328–334. https://doi.org/10.1016/j.bbrc.2017.02.082 CrossRefPubMed

32.

Weitz JR, Makhmutova M, Almaca J et al (2018) Mouse pancreatic islet macrophages use locally released ATP to monitor beta cell activity. Diabetologia 61(1):182–192. https://doi.org/10.1007/s00125-017-4416-y CrossRefPubMed

33.

Tuttle RL, Gill NS, Pugh W et al (2001) Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Akt1/PKBα. Nat Med 7(10):1133–1137. https://doi.org/10.1038/nm1001-1133 CrossRefPubMed

34.

Shepro D, Morel NM (1993) Pericyte physiology. FASEB J 7(11):1031–1038. https://doi.org/10.1096/fasebj.7.11.8370472 CrossRefPubMed

35.

Koyama Y, Brenner DA (2017) Liver inflammation and fibrosis. J Clin Invest 127(1):55–64. https://doi.org/10.1172/jci88881 CrossRefPubMedPubMedCentral

36.

Shook BA, Wasko RR, Rivera-Gonzalez GC et al (2018) Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science (New York, NY) 362(6417):2971. https://doi.org/10.1126/science.aar2971

37.

King GL, Buzney SM, Kahn CR et al (1983) Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels. J Clin Invest 71(4):974–979. https://doi.org/10.1172/jci110852 CrossRefPubMedPubMedCentral

38.

King GL, Goodman AD, Buzney S, Moses A, Kahn CR (1985) Receptors and growth-promoting effects of insulin and insulinlike growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest 75(3):1028–1036. https://doi.org/10.1172/jci111764 CrossRefPubMedPubMedCentral

39.

Yang J, Waldron RT, Su HY et al (2016) Insulin promotes proliferation and fibrosing responses in activated pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol 311(4):G675–G687. https://doi.org/10.1152/ajpgi.00251.2016 CrossRefPubMedPubMedCentral

40.

Kim JW, Ko SH, Cho JH et al (2008) Loss of beta-cells with fibrotic islet destruction in type 2 diabetes mellitus. Front Biosci 13(13):6022–6033. https://doi.org/10.2741/3133 CrossRefPubMed

41.

Donath MY, Boni-Schnetzler M, Ellingsgaard H, Ehses JA (2009) Islet inflammation impairs the pancreatic β-cell in type 2 diabetes. Physiology (Bethesda) 24(6):325–331. https://doi.org/10.1152/physiol.00032.2009 CrossRef

42.

Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214(2):199–210. https://doi.org/10.1002/path.2277 CrossRefPubMedPubMedCentral

43.

Agudo J, Ayuso E, Jimenez V et al (2012) Vascular endothelial growth factor-mediated islet hypervascularization and inflammation contribute to progressive reduction of β-cell mass. Diabetes 61(11):2851–2861. https://doi.org/10.2337/db12-0134 CrossRefPubMedPubMedCentral

44.

Erkan M, Adler G, Apte MV et al (2012) StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 61(2):172–178. https://doi.org/10.1136/gutjnl-2011-301220 CrossRefPubMed

45.

Richards OC, Raines SM, Attie AD (2010) The role of blood vessels, endothelial cells, and vascular pericytes in insulin secretion and peripheral insulin action. Endocr Rev 31(3):343–363. https://doi.org/10.1210/er.2009-0035 CrossRefPubMedPubMedCentral

Titel: Islet pericytes convert into profibrotic myofibroblasts in a mouse model of islet vascular fibrosis
verfasst von: Luciana Mateus Gonçalves
Elizabeth Pereira
João Pedro Werneck de Castro
Ernesto Bernal-Mizrachi
Joana Almaça
Publikationsdatum: 18.05.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 8/2020
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-020-05168-7

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