Abstract
Glucose homeostasis relies on tightly regulated insulin secretion from pancreatic beta-cells, and its loss in diabetes is associated with the dysfunction of these cells. Beta-cells reside in the islets of Langerhans, which are highly vascularized by a dense capillary network comprised of endothelial cells and pericytes. While the requirement of the endothelium for the proper pancreatic function is well established, the role of pancreatic pericytes has only recently begun to unveil. Recent studies described multiple roles for pancreatic pericytes in glucose homeostasis, highlighting their function as both regulators of islet blood flow and as a source of critical signals that support proper beta-cell function and mass. Furthermore, recent findings point to the contribution of pericytic abnormalities to beta-cell dysfunction in type 2 diabetes, implicating the involvement of pancreatic pericytes in both the initiation and the progression of this disease. This newly gained data implicate pancreatic pericytes as critical components of the cellular network required for glucose regulation.
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References
Almaça 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 27:630–644.e4. https://doi.org/10.1016/j.cmet.2018.02.016
Apte M, Pirola RC, Wilson JS (2015) Pancreatic stellate cell: physiologic role, role in fibrosis and cancer. Curr Opin Gastroenterol 31:416–423. https://doi.org/10.1097/MOG.0000000000000196
Armulik A, Genové G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215. https://doi.org/10.1016/j.devcel.2011.07.001
Ashcroft FM, Rorsman P (2012) Diabetes mellitus and the β cell: the last ten years. Cell 148:1160–1171. https://doi.org/10.1016/j.cell.2012.02.010
Bonner-Weir S (1993) The microvasculature of the pancreas, with emphasis on that of the islets of Langerhans. In: Go VLW et al (eds) The pancreas: biology, pathobiology, and disease. Raven Press, New York, pp 759–768
Bonner-Weir S, Aguayo-Mazzucato C (2016) Physiology: pancreatic [beta]-cell heterogeneity revisited. Nature 535:365–366. https://doi.org/10.1038/nature18907
Bramswig NC, Kaestner KH (2014) Transcriptional and epigenetic regulation in human islets. Diabetologia 57:451–454. https://doi.org/10.1007/s00125-013-3150-3
Brissova M, Aamodt K, Brahmachary P, Prasad N, Hong J-Y, Dai C, Mellati M, Shostak A, Poffenberger G, Aramandla R, Levy SE, Powers AC (2014) Islet microenvironment, modulated by vascular endothelial growth factor-a signaling, promotes β cell regeneration. Cell Metab 19:498–511. https://doi.org/10.1016/j.cmet.2014.02.001
Cerasi E (2011) β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question. Medicographia 33:35–41
Chen X, Zhang X, Chen F, Larson CS, Wang L-J, Kaufman DB (2009) Comparative study of regenerative potential of beta cells from young and aged donor mice using a novel islet transplantation model. Transplantation 88:496–503. https://doi.org/10.1097/TP.0b013e3181b0d2ee
Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, Marselli L, Suleiman M, Ratner LE, Marchetti P, Accili D (2016) Evidence of β-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab 101:1044–1054. https://doi.org/10.1210/jc.2015-2860
Clevers H, Nusse R (2012) Wnt/β-catenin signaling and disease. Cell 149:1192–1205. https://doi.org/10.1016/j.cell.2012.05.012
Costes S, Langen R, Gurlo T, Butler PC (2013) β-Cell failure in type 2 diabetes: a case of asking too much of too few? Diabetes 62:327–335. https://doi.org/10.2337/db12-1326
Dai C, Brissova M, Reinert RB, Nyman L, Liu EH, Thompson C, Shostak A, Shiota M, Takahashi T, Powers AC (2013) Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis. Diabetes 62:4144–4153. https://doi.org/10.2337/db12-1657
DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, Hu FB, Kahn CR, Raz I, Shulman GI, Simonson DC, Testa MA, Weiss R (2015) Type 2 diabetes mellitus. Nat Rev Dis Primers 1:15019. https://doi.org/10.1038/nrdp.2015.19
Diaferia GR, Jimenez-Caliani AJ, Ranjitkar P, Yang W, Hardiman G, Rhodes CJ, Crisa L, Cirulli V (2013) β1 integrin is a crucial regulator of pancreatic β-cell expansion. Development 140:3360–3372. https://doi.org/10.1242/dev.098533
Dor Y, Glaser B (2013) β-Cell dedifferentiation and type 2 diabetes. N Engl J Med 368:572–573. https://doi.org/10.1056/NEJMcibr1214034
Dor Y, Brown J, Martinez O, Melton D (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46. https://doi.org/10.1038/nature02520
Eberhard D, Lammert E (2009) The pancreatic beta-cell in the islet and organ community. Curr Opin Genet Dev 19:469–475. https://doi.org/10.1016/j.gde.2009.07.003
Epshtein A, Rachi E, Sakhneny L, Mizrachi S, Baer D, Landsman L (2017) Neonatal pancreatic pericytes support β-cell proliferation. Molecular Metabolism 6:1330–1338. https://doi.org/10.1016/j.molmet.2017.07.010
Finegood DT, Scaglia L, Bonner-Weir S (1995) Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 44:249–256
Fuchsberger C, Flannick J, Teslovich TM et al (2016) The genetic architecture of type 2 diabetes. Nature 536:41–47. https://doi.org/10.1038/nature18642
Georgia S, Bhushan A (2004) Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Investig 114:963–968. https://doi.org/10.1172/JCI200422098
Gittes GK (2009) Developmental biology of the pancreas: a comprehensive review. Dev Biol 326:4–35. https://doi.org/10.1016/j.ydbio.2008.10.024
Goulley J, Dahl U, Baeza N, Mishina Y, Edlund H (2007) BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion. Cell Metab 5:207–219. https://doi.org/10.1016/j.cmet.2007.01.009
Granot Z, Swisa A, Magenheim J, Stolovich-Rain M, Fujimoto W, Manduchi E, Miki T, Lennerz JK, Stoeckert CJ Jr, Meyuhas O, Seino S, Permutt MA, Piwnica-Worms H, Bardeesy N, Dor Y (2009) LKB1 regulates pancreatic β cell size, polarity, and function. Cell Metab 10:296–308. https://doi.org/10.1016/j.cmet.2009.08.010
Grant SFA, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323. https://doi.org/10.1038/ng1732
Gregg BE, Moore PC, Demozay D, Hall BA, Li M, Husain A, Wright AJ, Atkinson MA, Rhodes CJ (2012) Formation of a human β-cell population within pancreatic islets is set early in life. J Clin Endocrinol Metab 97:3197–3206. https://doi.org/10.1210/jc.2012-1206
Hammes H-P (2017) Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond. Diabetologia 61:1–10. https://doi.org/10.1007/s00125-017-4435-8
Harari N, Sakhneny L, Khalifa-Malka L, Busch A, Hertel KJ, Hebrok M, Landsman L (2019) Pancreatic pericytes originate from the embryonic pancreatic mesenchyme. Developmental Biology In press
Hayden MR, Sowers JR (2007) Isletopathy in type 2 diabetes mellitus: implications of islet RAS, islet fibrosis, islet amyloid, remodeling, and oxidative stress. Antioxid Redox Signal 9:891–910. https://doi.org/10.1089/ars.2007.1610
Hayden MR, Karuparthi PR, Habibi J, Wasekar C, Lastra G, Manrique C, Stas S, Sowers JR (2007) Ultrastructural islet study of early fibrosis in the Ren2 rat model of hypertension. Emerging role of the islet pancreatic pericyte-stellate cell. JOP 8:725–738
Hayden MR, Yang Y, Habibi J, Bagree SV, Sowers JR (2010) Pericytopathy oxidative stress and impaired cellular longevity in the pancreas and skeletal muscle in metabolic syndrome and type 2 diabetes. Oxidative Med Cell Longev 3:290–303. https://doi.org/10.4161/oxim.3.5.13653
Helgason A, Pálsson S, Thorleifsson G, Grant SFA, Emilsson V, Gunnarsdottir S, Adeyemo A, Chen Y, Chen G, Reynisdottir I, Benediktsson R, Hinney A, Hansen T, Andersen G, Borch-Johnsen K, Jørgensen T, Schäfer H, Faruque M, Doumatey A, Zhou J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Sigurdsson G, Hebebrand J, Pedersen O, Thorsteinsdottir U, Gulcher JR, Kong A, Rotimi C, Stefansson K (2007) Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet 39:218–225. https://doi.org/10.1038/ng1960
Hogan MF, Hull RL (2017) The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes. Diabetologia 60:952–959
Houtz J, Borden P, Ceasrine A, Minichiello L, Kuruvilla R (2016) Neurotrophin signaling is required for glucose-induced insulin secretion. Dev Cell 39:329–345. https://doi.org/10.1016/j.devcel.2016.10.003
Kragl M, Lammert E (2010) Basement membrane in pancreatic islet function. Adv Exp Med Biol 654:217–234. https://doi.org/10.1007/978-90-481-3271-3_10
Kragl M, Schubert R, Karsjens H, Otter S, Bartosinska B, Jeruschke K, Weiss J, Chen C, Alsteens D, Kuss O, Speier S, Eberhard D, Müller DJ, Lammert E (2016) The biomechanical properties of an epithelial tissue determine the location of its vasculature. Nat Commun 7:13560. https://doi.org/10.1038/ncomms13560
Lammert E, Cleaver O, Melton D (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294:564–567. https://doi.org/10.1126/science.1064344
Longnecker DS, Gorelick F, Thompson ED (2018) Anatomy, histology, and fine structure of the pancreas, 2nd ed. Wiley-Blackwell, Chichester
Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjögren M, Ling C, Eriksson K-F, Lethagen A-L, Mancarella R, Berglund G, Tuomi T, Nilsson P, Del Prato S, Groop L (2007) Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Investig 117:2155–2163. https://doi.org/10.1172/JCI30706
Mastracci TL, Sussel L (2012) The endocrine pancreas: insights into development, differentiation, and diabetes. Wiley Interdiscip Rev Developmental Biology 1:609–628. https://doi.org/10.1002/wdev.44
Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, Rizza RA, Butler PC (2008) Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes 57:1584–1594. https://doi.org/10.2337/db07-1369
Mandarino LJ, Finlayson J, Hassell JR (1994) High glucose downregulates glucose transport activity in retinal capillary pericytes but not endothelial cells. Invest Ophthalmol Vis Sci 35:964–972.
Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160:985–1000. https://doi.org/10.1016/S0002-9440(10)64920-6
Nikolova G, Jabs N, Konstantinova I, Domogatskaya A, Tryggvason K, Sorokin L, Fässler R, Gu G, Gerber H-P, Ferrara N, Melton DA, Lammert E (2006) The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation. Dev Cell 10:397–405. https://doi.org/10.1016/j.devcel.2006.01.015
Otonkoski T, Banerjee M, Korsgren O, Thornell L-E, Virtanen I (2008) Unique basement membrane structure of human pancreatic islets: implications for beta-cell growth and differentiation. Diabetes Obes Metab 10(Suppl 4):119–127. https://doi.org/10.1111/j.1463-1326.2008.00955.x
Ouaamari El A, Dirice E, Gedeon N, Hu J, Zhou J-Y, Shirakawa J, Hou L, Goodman J, Karampelias C, Qiang G, Boucher J, Martinez R, Gritsenko MA, De Jesus DF, Kahraman S, Bhatt S, Smith RD, Beer H-D, Jungtrakoon P, Gong Y, Goldfine AB, Liew CW, Doria A, Andersson O, Qian W-J, Remold-O’Donnell E, Kulkarni RN (2016) SerpinB1 promotes pancreatic β cell proliferation. Cell Metab 23:194–205. https://doi.org/10.1016/j.cmet.2015.12.001
Prentki M, Matschinsky FM, Madiraju SRM (2013) Metabolic signaling in fuel-induced insulin secretion. Cell Metab 18:162–185. https://doi.org/10.1016/j.cmet.2013.05.018
Reinert RB, Brissova M, Shostak A, Pan FC, Poffenberger G, Cai Q, Hundemer GL, Kantz J, Thompson CS, Dai C, McGuinness OP, Powers AC (2013) Vascular endothelial growth factor-a and islet vascularization are necessary in developing, but not adult, pancreatic islets. Diabetes 62:4154–4164. https://doi.org/10.2337/db13-0071
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 31:343–363. https://doi.org/10.1210/er.2009-0035
Riley KG, Pasek RC, Maulis MF, Dunn JC, Bolus WR, Kendall PL, Hasty AH, Gannon M (2015) Macrophages are essential for CTGF-mediated adult β-cell proliferation after injury. Mol Metab 4:584–591. https://doi.org/10.1016/j.molmet.2015.05.002
Rorsman P, Braun M (2013) Regulation of insulin secretion in human pancreatic islets. Annu Rev Physiol 75:155–179. https://doi.org/10.1146/annurev-physiol-030212-183754
Sakhneny L, Rachi E, Epshtein A, Guez HC, Wald-Altman S, Lisnyansky M, Khalifa-Malka L, Hazan A, Baer D, Priel A, Weil M, Landsman L (2018) Pancreatic Pericytes support β-cell function in a Tcf7l2-dependent manner. Diabetes 67:437–447. https://doi.org/10.2337/db17-0697
Salpeter SJ, Klein AM, Huangfu D, Grimsby J, Dor Y (2010) Glucose and aging control the quiescence period that follows pancreatic beta cell replication. Development 137:3205–3213. https://doi.org/10.1242/dev.054304
Sasson A, Rachi E, Sakhneny L, Baer D, Lisnyansky M, Epshtein A, Landsman L (2016) Islet Pericytes are required for β-cell maturity. Diabetes 65:3008–3014. https://doi.org/10.2337/db16-0365
Schaeffer M, Hodson DJ, Lafont C, Mollard P (2011) Endocrine cells and blood vessels work in tandem to generate hormone pulses. J Mol Endocrinol 47:R59–R66. https://doi.org/10.1530/JME-11-0035
Stolovich-Rain M, Hija A, Grimsby J, Glaser B, Dor Y (2012) Pancreatic beta cells in very old mice retain capacity for compensatory proliferation. J Biol Chem 287:27407–27414. https://doi.org/10.1074/jbc.M112.350736
Stratman AN, Davis GE (2012) Endothelial cell-pericyte interactions stimulate basement membrane matrix assembly: influence on vascular tube remodeling, maturation, and stabilization. Microsc Microanal 18:68–80. https://doi.org/10.1017/S1431927611012402
Talchai C, Xuan S, Lin HV, Sussel L, Accili D (2012) Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150:1223–1234. https://doi.org/10.1016/j.cell.2012.07.029
Tang S-C, Chiu Y-C, Hsu C-T, Peng S-J, Fu Y-Y (2013) Plasticity of Schwann cells and pericytes in response to islet injury in mice. Diabetologia 56:2424–2434. https://doi.org/10.1007/s00125-013-2977-y
Tarussio D, Metref S, Seyer P, Mounien L, Vallois D, Magnan C, Foretz M, Thorens B (2014) Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis. J Clin Investig 124:413–424. https://doi.org/10.1172/JCI69154
van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, Van Den Born M, Soete G, Pals S, Eilers M, Medema R, Clevers H (2002) The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111:241–250
Wang P, Fiaschi-Taesch NM, Vasavada RC, Scott DK, García-Ocaña A, Stewart AF (2015) Diabetes mellitus--advances and challenges in human β-cell proliferation. Nat Rev Endocrinol 11:201–212. https://doi.org/10.1038/nrendo.2015.9
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Landsman, L. (2019). Pancreatic Pericytes in Glucose Homeostasis and Diabetes. In: Birbrair, A. (eds) Pericyte Biology in Different Organs. Advances in Experimental Medicine and Biology, vol 1122. Springer, Cham. https://doi.org/10.1007/978-3-030-11093-2_2
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