The non-β endocrine cells in pancreatic islets play an essential counterpart and regulatory role to the insulin-producing β-cells in the regulation of blood-glucose homeostasis. While significant progress has been made towards the understanding of β-cell regeneration in adults, very little is known about the regeneration of the non-β endocrine cells such as glucagon-producing α-cells and somatostatin producing δ-cells. Previous studies have noted the increase of α-cell composition in diabetes patients and in animal models. It is thus our hypothesis that non-β-cells such as α-cells and δ-cells in adults can regenerate, and that the regeneration accelerates in diabetic conditions. To test this hypothesis, we examined islet cell composition in a streptozotocin (STZ)-induced diabetes mouse model in detail. Our data showed the number of α-cells in each islet increased following STZ-mediated β-cell destruction, peaked at Day 6, which was about 3 times that of normal islets. In addition, we found δ-cell numbers doubled by Day 6 following STZ treatment. These data suggest α- and δ-cell regeneration occurred rapidly following a single diabetes-inducing dose of STZ in mice. Using in vivo BrdU labeling techniques, we demonstrated α- and δ-cell regeneration involved cell proliferation. Co-staining of the islets with the proliferating cell marker Ki67 showed α- and δ-cells could replicate, suggesting self-duplication played a role in their regeneration. Furthermore, Pdx1+/Insulin？ cells were detected following STZ treatment, indicating the involvement of endocrine progenitor cells in the regeneration of these non-β cells. This is further confirmed by the detection of Pdx1+/glucagon+ cells and Pdx1+/somatostatin+ cells following STZ treatment. Taken together, our study demonstrated adult α- and δ-cells could regenerate, and both self-duplication and regeneration from endocrine precursor cells were involved in their regeneration.
References
[1]
Bernardo AS, Hay CW, Docherty K (2008) Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic beta cell. Mol Cell Endocrinol 294: 1–9.
[2]
Murtaugh LC, Melton DA (2003) Genes, signals, and lineages in pancreas development. Annu Rev Cell Dev Biol 19: 71–89.
[3]
Oliver-Krasinski JM, Stoffers DA (2008) On the origin of the beta cell. Genes Dev 22: 1998–2021.
[4]
Alpert S, Hanahan D, Teitelman G (1988) Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell 53: 295–308.
[5]
Herrera PL, Huarte J, Sanvito F, Meda P, Orci L, et al. (1991) Embryogenesis of the murine endocrine pancreas; early expression of pancreatic polypeptide gene. Development 113: 1257–1265.
[6]
Teitelman G, Alpert S, Polak JM, Martinez A, Hanahan D (1993) Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon and the neuronal proteins tyrosine hydroxylase and neuropeptide Y, but not pancreatic polypeptide. Development 118: 1031–1039.
[7]
Bonner-Weir S, Li WC, Ouziel-Yahalom L, Guo L, Weir GC, et al. (2010) Beta-cell growth and regeneration: replication is only part of the story. Diabetes 59: 2340–2348.
[8]
Petrik J, Arany E, McDonald TJ, Hill DJ (1998) Apoptosis in the pancreatic islet cells of the neonatal rat is associated with a reduced expression of insulin-like growth factor II that may act as a survival factor. Endocrinology 139: 2994–3004.
[9]
Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S (1997) Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 138: 1736–1741.
[10]
Parsons JA, Brelje TC, Sorenson RL (1992) Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology 130: 1459–1466.
[11]
Weir GC, Laybutt DR, Kaneto H, Bonner-Weir S, Sharma A (2001) Beta-cell adaptation and decompensation during the progression of diabetes. Diabetes 50: Suppl 1S154–159.
[12]
Rankin MM, Kushner JA (2009) Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes 58: 1365–1372.
[13]
Unger RH, Orci L (2010) Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci U S A 107: 16009–16012.
[14]
Maruyama H, Hisatomi A, Orci L, Grodsky GM, Unger RH (1984) Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest 74: 2296–2299.
D'Alessio DA, Sieber C, Beglinger C, Ensinck JW (1989) A physiologic role for somatostatin 28 as a regulator of insulin secretion. J Clin Invest 84: 857–862.
[17]
Mandarino L, Stenner D, Blanchard W, Nissen S, Gerich J, et al. (1981) Selective effects of somatostatin-14, -25 and -28 on in vitro insulin and glucagon secretion. Nature 291: 76–77.
[18]
Strowski MZ, Parmar RM, Blake AD, Schaeffer JM (2000) Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice. Endocrinology 141: 111–117.
[19]
Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429: 41–46.
[20]
Meier JJ, Lin JC, Butler AE, Galasso R, Martinez DS, et al. (2006) Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia 49: 1838–1844.
[21]
Teta M, Rankin MM, Long SY, Stein GM, Kushner JA (2007) Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell 12: 817–826.
[22]
Liu H, Guz Y, Kedees MH, Winkler J, Teitelman G (2010) Precursor cells in mouse islets generate new beta-cells in vivo during aging and after islet injury. Endocrinology 151: 520–528.
[23]
Xu X, D'Hoker J, Stange G, Bonne S, De Leu N, et al. (2008) Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132: 197–207.
[24]
Thorel F, Nepote V, Avril I, Kohno K, Desgraz R, et al. (2010) Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464: 1149–1154.
[25]
Chung CH, Hao E, Piran R, Keinan E, Levine F (2010) Pancreatic beta-cell neogenesis by direct conversion from mature alpha-cells. Stem Cells 28: 1630–1638.
[26]
Li Z, Karlsson FA, Sandler S (2000) Islet loss and alpha cell expansion in type 1 diabetes induced by multiple low-dose streptozotocin administration in mice. J Endocrinol 165: 93–99.
[27]
O'Reilly LA, Gu D, Sarvetnick N, Edlund H, Phillips JM, et al. (1997) alpha-Cell neogenesis in an animal model of IDDM. Diabetes 46: 599–606.
[28]
Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, et al. (2003) Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 88: 2300–2308.
[29]
Liu Z, Kim W, Chen Z, Shin YK, Carlson OD, et al. (2011) Insulin and glucagon regulate pancreatic alpha-cell proliferation. PLoS One 6: e16096.
[30]
Iki K, Pour PM (2007) Distribution of pancreatic endocrine cells including IAPP-expressing cells in non-diabetic and type 2 diabetic cases. J Histochem Cytochem 55: 111–118.
[31]
Brissova M, Fowler MJ, Nicholson WE, Chu A, Hirshberg B, et al. (2005) Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem 53: 1087–1097.
[32]
Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, et al. (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A 103: 2334–2339.
[33]
Chen X, Zhang X, Chen F, Larson CS, Wang LJ, et al. (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.
[34]
Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H (1998) beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 12: 1763–1768.
[35]
Gannon M, Ables ET, Crawford L, Lowe D, Offield MF, et al. (2008) pdx-1 function is specifically required in embryonic beta cells to generate appropriate numbers of endocrine cell types and maintain glucose homeostasis. Dev Biol 314: 406–417.
[36]
Holland AM, Hale MA, Kagami H, Hammer RE, MacDonald RJ (2002) Experimental control of pancreatic development and maintenance. Proc Natl Acad Sci U S A 99: 12236–12241.
[37]
Jonsson J, Carlsson L, Edlund T, Edlund H (1994) Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371: 606–609.
[38]
Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, et al. (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122: 983–995.
[39]
Gromada J, Franklin I, Wollheim CB (2007) Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28: 84–116.
[40]
Rahier J, Goebbels RM, Henquin JC (1983) Cellular composition of the human diabetic pancreas. Diabetologia 24: 366–371.
[41]
Pechhold K, Koczwara K, Zhu X, Harrison VS, Walker G, et al. (2009) Blood glucose levels regulate pancreatic beta-cell proliferation during experimentally-induced and spontaneous autoimmune diabetes in mice. PLoS One 4: e4827.
[42]
Kaneto H, Miyatsuka T, Kawamori D, Yamamoto K, Kato K, et al. (2008) PDX-1 and MafA play a crucial role in pancreatic beta-cell differentiation and maintenance of mature beta-cell function. Endocr J 55: 235–252.
[43]
Thyssen S, Arany E, Hill DJ (2006) Ontogeny of regeneration of beta-cells in the neonatal rat after treatment with streptozotocin. Endocrinology 147: 2346–2356.
[44]
Bonner-Weir S, Trent DF, Honey RN, Weir GC (1981) Responses of neonatal rat islets to streptozotocin: limited B-cell regeneration and hyperglycemia. Diabetes 30: 64–69.
