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Pancreatic Regeneration After Partial Pancreatectomy in Rodents

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Pancreatic Islet Biology

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

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Abstract

While the concept of beta cell replacement as a potential therapy for diabetes mellitus seems straightforward, a major obstacle for this strategy has been the limited amount of available islet tissue for transplantation. Besides replacement therapy using transplantation of cadaveric islets or cells derived from human embryonic stem cells or induced pluripotent (iPSc), efforts are being made to induce endogenous regeneration of the endocrine pancreas . Of the several models for pancreatic regeneration /islet cell replacement (some of which are described in other chapters), we favor the partial pancreatectomy . The physiological changes, cellular events and possible underlying molecular cues during the regeneration in this model are detailed herein.

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References

  • Ackermann Misfeldt A, Costa RH, Gannon M (2008) Beta-cell proliferation, but not neogenesis, following 60 % partial pancreatectomy is impaired in the absence of FoxM1. Diabetes 57:3069–3077

    Article  PubMed  PubMed Central  Google Scholar 

  • Allen FM (1922) Experimental studies in diabetes. Series III. The pathology of diabetes 1. Hydropic degeneration of islands of Langerhans after partial pancreatectomy. J Metab Res 1:5–41

    CAS  Google Scholar 

  • Apelqvist A, Ahlgren U, Edlund H (1997) Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr Biol 7:801–804

    Article  CAS  PubMed  Google Scholar 

  • Barker N (2014) Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol 15:19–33

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S, Trent DF, Weir GC (1983) Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J Clin Invest 71:1544–1553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonner-Weir S, Baxter LA, Schuppin GT et al (1993) A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 42:1715–1720

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S, Leahy JL, Weir GC (1988) Induced rat models of non-insulin-dependent diabetes mellitus. In: Shapiro E, Renold AE (eds) Lessons from animals diabetes II. John Libbey Publishers, London, pp 295–300

    Google Scholar 

  • Bonner-Weir S, Toschi E, Inada A et al (2004) The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes 5(Suppl2):16–22

    Article  PubMed  Google Scholar 

  • Bonner-Weir S, Li WC, Ouziel-Yahalom L et al (2010) Beta-cell growth and regeneration: replication is only part of the story. Diabetes 59:2340–2348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brockenbrough JS, Weir GC, Bonner-Weir S (1988) Discordance of exocrine and endocrine growth after 90 % pancreatectomy in rats. Diabetes 37:232–236

    Article  CAS  PubMed  Google Scholar 

  • Calderari S, Gangnerau MN, Thibault M et al (2007) Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto-Kakizaki rat model of type 2 diabetes. Diabetologia 50:1463–1471

    Article  CAS  PubMed  Google Scholar 

  • Calvo EL, Dusetti NJ, Cadenas MB et al (1991) Changes in gene expression during pancreatic regeneration: activation of c-myc and H-ras oncogenes in the rat pancreas. Pancreas 6:150–156

    Article  CAS  PubMed  Google Scholar 

  • Calvo EL, Bernatchez G, Pelletier G et al (1997) Downregulation of IGF-I mRNA expression during postnatal pancreatic development and overexpression after subtotal pancreatectomy and acute pancreatitis in the rat pancreas. J Mol Endocrinol 18:233–242

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Carter RL, Cho IK et al (2014) Cell-based therapies for Huntington’s diseases. Drug Discov Today 19:980–984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cleaver O, Krieg PA (2001) Notochord patterning of the endoderm. Dev Biol 234:1–12

    Article  CAS  PubMed  Google Scholar 

  • Collombat P, Hecksher-Sorensen J, Serup P et al (2006) Specifying pancreatic endocrine cell fates. Mech Dev 123:501–512

    Article  CAS  PubMed  Google Scholar 

  • Cras-Méneur C, Elghazi L, Czernichow P (2001) Epidermal growth factor increases undifferentiated pancreatic embryonic cells in vitro: a balance between proliferation and differentiation. Diabetes 50:1571–1579

    Article  PubMed  Google Scholar 

  • Criscimanna A, Speicher JA, Houshmand G, Shiota C, Prasadan K, Ji B, Logsdon CD, Gittes GK, Esni F (2011) Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice. Gastroenterology 141:1451–1462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farkas G Jr, Takács T, Mándi Y et al (1997) TGF-beta 1 and IL-6–new aspects in pancreas regeneration? Acta Chir Hung 36:89–91

    PubMed  Google Scholar 

  • Figeac F, Ilias A, Bailbe D et al (2012) Local in vivo GSK3β knockdown promotes pancreatic β cell and acinar cell regeneration in 90 % pancreatectomized rat. Mol Ther 20:1944–1952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foglia VG (1944) Caracteristicas de la diabetes en la rata. Rev Soc Argent Biol 20:21–37

    CAS  Google Scholar 

  • Fuchs E, Nowak JA (2008) Building epithelial tissues from skin stem cells. Cold Spring Harb Symp Quant Biol 73:333–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gittes GK (2009) Developmental biology of the pancreas: a comprehensive review. Dev Biol 326:4–35

    Article  CAS  PubMed  Google Scholar 

  • Grapin-Botton A, Majithia AR, Melton DA (2001) Key events of pancreas formation are triggered in gut endoderm by ectopic expression of pancreatic regulatory genes. Genes Dev 15:444–454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hardikar AA, Karandikar MS, Bhonde RR (1999) Effect of partial pancreatectomy on diabetic status in BALB/c mice. J Endocrinol 162:189–195

    Article  CAS  PubMed  Google Scholar 

  • Hebrok M, Kim SK, Melton DA (1998) Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev 12:1705–1713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hebrok M (2003) Hedgehog signaling in pancreas development. Mech Dev 120:45–57

    Article  CAS  PubMed  Google Scholar 

  • Houssay BA, Rodriquez RR, Cardeza AF (1954) Prevention of experimental diabetes with adrenal steroids. Endocrinology 54:550–552

    Article  CAS  PubMed  Google Scholar 

  • Inada A, Nienaber C, Katsuta H et al (2008) Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci USA 105:19915–19919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jansson L, Sandler S (1989) Pancreatic and islet blood flow in the regenerating pancreas after a partial pancreatectomy in adult rats. Surgery 106:861–866

    CAS  PubMed  Google Scholar 

  • Jensen JN, Cameron E, Garay MV et al (2005) Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology 128:728–741

    Article  CAS  PubMed  Google Scholar 

  • Jetton TL, Liu YQ, Trotman WE et al (2001) Enhanced expression of insulin receptor substrate-2 and activation of protein kinase B/Akt in regenerating pancreatic duct epithelium of 60 %-partial pancreatectomy rats. Diabetologia 44:2056–2065

    Article  CAS  PubMed  Google Scholar 

  • Jonas J-C, Sharma A, Hasenkamp W, Ilkova H, Patane G, Laybutt R, Bonner-Weir S, Weir GC (1999) Chronic hyperglycemia triggers loss of pancreatic beta cell differentiation in an animal model of diabetes. J Biol Chem 274:14112–14121

    Article  CAS  PubMed  Google Scholar 

  • Katsuta H, Koyanagi-Katsuta R, Shiiba M et al (2005) cDNA microarray analysis after laser microdissection in proliferating islets of partially pancreatectomized mice. Med Mol Morphol 38:30–35

    Article  CAS  PubMed  Google Scholar 

  • Kim SK, Hebrok M, Melton DA (1997) Notochord to endoderm signaling is required for pancreas development. Development 124:4243–4252

    CAS  PubMed  Google Scholar 

  • Kim SW, Kim KH, Park SJ et al (2001) Endogenous gastrin stimulates regeneration of remnant pancreas after partial pancreatectomy. Dig Dis Sci 46:2134–2139

    Article  CAS  PubMed  Google Scholar 

  • Ko SH, Suh SH, Kim BJ et al (2004) Expression of the intermediate filament vimentin in proliferating duct cells as a marker of pancreatic precursor cells. Pancreas 28:121–128

    Article  CAS  PubMed  Google Scholar 

  • Lammert E, Cleaver O, Melton DA (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294:564–567

    Article  CAS  PubMed  Google Scholar 

  • Laybutt DR, Sharma A, Sgroi DC, Gaudet J, Bonner-Weir S, Weir GC (2002) Genetic regulation of metabolic pathways in β-cells disrupted by hyperglycemia. J Biol Chem 277:10912–10921

    Article  CAS  PubMed  Google Scholar 

  • Laybutt DR, Glandt M, Xu G, Ahn YB, Trivedi N, Bonner-Weir S, Weir GC (2003) Critical reduction in β-cell mass results in two distinct outcomes over time: adaptation with impaired glucose tolerance or decompensated diabetes. J Biol Chem 278:2997–3005

    Article  CAS  PubMed  Google Scholar 

  • Leahy JL, Bonner-Weir S, Weir GC (1988) Minimal chronic hyperglycemia is a critical determinant of impaired insulin secretion following incomplete pancreatectomy in the rat. J Clin Investig 81:1407–1414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee AY, Mahler N, Best C et al (2014) Regenerative implants for cardiovascular tissue engineering. Transl Res 163:321–341

    Article  CAS  PubMed  Google Scholar 

  • Lee CS, De León DD, Kaestner KH et al (2006) Regeneration of pancreatic islets after partial pancreatectomy in mice does not involve the reactivation of neurogenin-3. Diabetes 55:269–272

    CAS  PubMed  Google Scholar 

  • Lee SH, Hao E, Levine F (2011) β-Cell replication and islet neogenesis following partial pancreatectomy. Islets 3:188–195

    Article  PubMed  Google Scholar 

  • Lehv M, Fitzgerald PJ (1968) Pancreatic acinar cell regeneration. IV. Regeneration after resection. Am J Pathol 53:513–535

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li WC, Rukstalis JM, Nishimura W et al (2010) Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats. J Cell Sci 123:2792–2802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim HW, Lee JE, Shin SJ et al (2002) Identification of differentially expressed mRNA during pancreas regeneration of rat by mRNA differential display. Biochem Biophys Res Commun 299:806–812

    Article  CAS  PubMed  Google Scholar 

  • Liu YQ, Nevin PW, Leahy JL (2000) Beta-cell adaptation in 60 % pancreatectomy rats that preserves normoinsulinemia and normoglycemia. Am J Physiol Endocrinol Metab 279:E68–E73

    CAS  PubMed  Google Scholar 

  • Lukens FDW, Dohan FC (1942) Pituitarydiabetes in the cat; recovery following insulin or dietary treatment. Endocrinology 30:175–202

    Article  CAS  Google Scholar 

  • Martin JM, Lacy PE (1963) The prediabetic period in partially pancreatectomized rats. Diabetes 12:238–242

    Article  Google Scholar 

  • Michalopoulos GK (2013) Principles of liver regeneration and growth homeostasis. Compr Physiol 3:485–513

    PubMed  Google Scholar 

  • Min BH, Kim BM, Lee SH et al (2003) Clusterin expression in the early process of pancreas regeneration in the pancreatectomized rat. J Histochem Cytochem 51:1355–1365

    Article  CAS  PubMed  Google Scholar 

  • Miyasaka K, Ohta M, Masuda M et al (1997) Retardation of pancreatic regeneration after partial pancreatectomy in a strain of rats without CCK-A receptor gene expression. Pancreas 14:391–399

    Article  CAS  PubMed  Google Scholar 

  • Morisset J, Aliaga JC, Calvo EL et al (1999) Expression and modulation of p42/p44 MAPKs and cell cycle regulatory proteins in rat pancreas regeneration. Am J Physiol 277:G953–G959

    CAS  PubMed  Google Scholar 

  • Murtaugh LC (2007) Pancreas and beta-cell development: from the actual to the possible. Development 134:427–438

    Article  CAS  PubMed  Google Scholar 

  • Oberg-Welsh C, Sandler S, Andersson A, Welsh M (1997) Effects of vascular endothelial growth factor on pancreatic duct cell replication and the insulin production of fetal islet-like cell clusters in vitro. Mol Cell Endocrinol 126:125–132

    Google Scholar 

  • Pearson KW, Scott D, Torrance B (1977) Effects of partial surgical pancreatectomy in rats. I. Pancreatic regeneration. Gastroenterology 72:469–473

    CAS  PubMed  Google Scholar 

  • Peshavaria M, Larmie BL, Lausier J et al (2006) Regulation of pancreatic beta-cell regeneration in the normoglycemic 60 % partial-pancreatectomy mouse. Diabetes 55:3289–3298

    Article  CAS  PubMed  Google Scholar 

  • Sharma A, Zangen DH, Reitz P (1999) The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration. Diabetes 48:507–513

    Article  CAS  PubMed  Google Scholar 

  • Shin JS, Lee JJ, Lee EJ et al (2005) Proteome analysis of rat pancreas induced by pancreatectomy. Biochim Biophys Acta 1749:23–32

    Article  CAS  PubMed  Google Scholar 

  • Slack JM (2003) Regeneration research today. Dev Dyn 226:162–166

    Article  CAS  PubMed  Google Scholar 

  • Smith FE, Rosen KM, Villa-Komaroff L et al (1991) Enhanced insulin-like growth factor I gene expression in regenerating rat pancreas. Proc Natl Acad Sci USA 88:6152–6156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith FE, Bonner-Weir S, Leahy JL et al (1994) Pancreatic Reg/pancreatic stone protein (PSP) gene expression does not correlate with beta-cell growth and regeneration in rats. Diabetologia 37:994–999

    Article  CAS  PubMed  Google Scholar 

  • Sommer H (1987) Functional recovery of the exocrine pancreas in rats after partial resection. Eur Surg Res 19:318–322

    Article  CAS  PubMed  Google Scholar 

  • Sumi S, Tamura K (2000) Frontiers of pancreas regeneration. J Hepatobiliary Pancreat Surg 7:286–294

    Article  CAS  PubMed  Google Scholar 

  • Tanigawa K, Nakamura S, Kawaguchi M et al (1997) Effect of aging on B-cell function and replication in rat pancreas after 90 % pancreatectomy. Pancreas 15:53–59

    Article  CAS  PubMed  Google Scholar 

  • Téllez N, Joanny G, Escoriza J et al (2011) Gastrin treatment stimulates β-cell regeneration and improves glucose tolerance in 95 % pancreatectomized rats. Endocrinology 152:2580–2588

    Article  PubMed  Google Scholar 

  • Tellez N, Montanya E (2014) Gastrin induces ductal cell dedifferentiation and β-cell neogenesis after 90 % pancreatectomy. J Endocrinol 223:67–78

    Google Scholar 

  • Terazono K, Yamamoto H, Takasawa S et al (1988) A novel gene activated in regenerating islets. J Biol Chem 263:2111–2114

    CAS  PubMed  Google Scholar 

  • Terazono K, Uchiyama Y, Ide M et al (1990) Expression of reg protein in rat regenerating islets and its co-localization with insulin in the beta cell secretory granules. Diabetologia 33:250–252

    Article  CAS  PubMed  Google Scholar 

  • Thorel F, Damond N, Chera S, Wiederkehr A, Thorens B, Meda P, Wollheim CB, Herrera PL (2011) Normal glucagon signaling and β-cell function after near-total α-cell ablation in adult mice. Diabetes 60:2872–2882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Togashi Y, Shirakawa J, Orime K et al (2014) β-Cell proliferation after a partial pancreatectomy is independent of IRS-2 in mice. Endocrinology 155:1643–1652

    Article  PubMed  Google Scholar 

  • Wang RN, Kloppel G, Bouwens L (1995) Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats. Diabetologia 38:1405–1411

    Article  CAS  PubMed  Google Scholar 

  • Watanabe T, Yonemura Y, Yonekura H et al (1994) Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein. Proc Natl Acad Sci USA 91:3589–3592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe H, Saito H, Rychahou PG et al (2005) Aging is associated with decreased pancreatic acinar cell regeneration and phosphatidylinositol 3-kinase/Akt activation. Gastroenterology 128:1391–1404

    Article  CAS  PubMed  Google Scholar 

  • Watanabe H, Saito H, Ueda J et al (2008a) Regulation of pancreatic duct cell differentiation by phosphatidylinositol-3 kinase. Biochem Biophys Res Commun 370:33–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe H, Saito H, Nishimura H et al (2008b) Activation of phosphatidylinositol-3 kinase regulates pancreatic duodenal homeobox-1 in duct cells during pancreatic regeneration. Pancreas 36:153–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wells JM, Melton DA (1999) Vertebrate endoderm development. Annu Rev Cell Dev Biol 15:393–410

    Article  CAS  PubMed  Google Scholar 

  • Wu F, Guo L, Jakubowski A et al (2013) TNF-like weak inducer of apoptosis (TWEAK) promotes beta cell neogenesis from pancreatic ductal epithelium in adult mice. PLoS ONE 8:e72132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu G, Stoffers DA, Habener JF, Bonner-Weir S (1999) Exendin-4 stimulates both β-cell replication and neogenesis resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48:2270–2276

    Article  CAS  PubMed  Google Scholar 

  • Xu G, Sumi S, Koike M et al (1996) Role of endogenous hypergastrinemia in regenerating endocrine pancreas after partial pancreatectomy. Dig Dis Sci 41:2433–2439

    Article  CAS  PubMed  Google Scholar 

  • Xu X, D’Hoker J, Stangé G, Bonné S, De Leu N, Xiao X, Van de Casteele M, Mellitzer G, Ling Z, Pipeleers D, Bouwens L, Scharfmann R, Gradwohl G, Heimberg H (2008) Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132:197–207

    Article  CAS  PubMed  Google Scholar 

  • Yang M, Liu W, Wang CY et al (2006) Proteomic analysis of differential protein expression in early process of pancreatic regeneration in pancreatectomized rats. Acta Pharmacol Sin 27:568–578

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors appreciate al the discussions with past laboratory members that contributed to the studies discussed here. Much of the work was originally supported by grants from the US National Institutes of Health R01 DK 066056 (S.B.-W.), P30 DK036836 as well as the Diabetes Research and Wellness Foundation and an important group of private donors. W.-C.L. was supported by a JDRF postdoctoral fellowship (3-2008-72).

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Authors and Affiliations

  1. Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan

    Wan-Chun Li & Chang-Yi Chen

  2. Department of Endocrinology and Metabolism, Taipei City Hospital, Ren-Ai Branch, Taipei, Taiwan

    Hung-Yu Chien

  3. Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA

    Susan Bonner-Weir

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  1. Wan-Chun Li
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  2. Chang-Yi Chen
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  3. Hung-Yu Chien
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  4. Susan Bonner-Weir
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Correspondence to Susan Bonner-Weir .

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Editors and Affiliations

  1. NHMRC Clinical Trials Centre Diabetes and Islet-biology Group, The University of Sydney Faculty of Medicine, Sydney, New South Wales, Australia

    Anandwardhan A. Hardikar

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Li, WC., Chen, CY., Chien, HY., Bonner-Weir, S. (2016). Pancreatic Regeneration After Partial Pancreatectomy in Rodents. In: A. Hardikar, A. (eds) Pancreatic Islet Biology. Stem Cell Biology and Regenerative Medicine. Springer, Cham. https://doi.org/10.1007/978-3-319-45307-1_5

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