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Generation of Beta Cells from Pancreatic Duct Cells and/or Stem Cells

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Stem Cell Therapy for Diabetes

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

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Abstract

Since diabetes is caused by the loss of the insulin-producing β cells, its reversal by replacement of these cells by transplantation or by replenishment from endogenous sources seems straightforward. In the pancreas, two mechanisms for β-cell growth are replication of preexisting β cells and neogenesis or the differentiation of new β cells from progenitor/stem cells that were not β cells. Replication and neogenesis are not mutually exclusive, and there is no biological reason for there to be only one mechanism for replenishment of the islet cells. This chapter focuses on the renewed interest in the identification, expansion, and differentiation of adult pancreatic progenitor/stem cells that can lead to more β cells, either in vivo or in vitro.

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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  CAS  Google Scholar 

  • Baertschiger RM, Bosco D, Morel P et al (2008) Mesenchymal stem cells derived from human exocrine pancreas express transcription factors implicated in beta-cell development. Pancreas 37:75–84

    Article  CAS  PubMed  Google Scholar 

  • Block GD, Locker J, Bowen WC et al (1996) Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGFβ in a chemically defined (HGM) medium. J Cell Biol 132:1133–1149

    Article  CAS  PubMed  Google Scholar 

  • Bock T, Pakkenberg B, Buschard K (2003) Increased islet volume but unchanged islet number in ob/ob mice. Diabetes 52:1716–1722

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S (2000) Perspective: postnatal pancreatic beta cell growth. Endocrinology 141:1926–1929

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S and Sharma A (2002) Pancreatic stem cells. J Pathol 197:519–526

    Article  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  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S, Taneja M, Weir GC et al (2000) In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 97:7999–8004

    Article  CAS  PubMed  Google Scholar 

  • Bonner-Weir S, Toschi E, Inada A et al (2004) The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatric Diabetes 5:15–22

    Article  Google Scholar 

  • Breault DT, Min IM, Carlone DL et al (2008) Generation of mTERT-GFP mice as a model to identify and study tissue progenitor cells. Proc Natl Acad Sci USA 105:10420–10425

    Article  CAS  PubMed  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 

  • Bruning JC, Winnay J, Bonner-Weir S et al (1997) Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88:561–572

    Article  CAS  PubMed  Google Scholar 

  • Bulotta A, Hui H, Anastasi E et al (2002) Cultured pancreatic ductal cells undergo cell cycle re-distribution and beta-cell-like differentiation in response to glucagon-like peptide-1. J Mol Endocrinol 29:347–360

    Article  CAS  PubMed  Google Scholar 

  • Butler AE, Janson J, Bonner-Weir S et al (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110

    Article  CAS  PubMed  Google Scholar 

  • Desai BM, Oliver-Krasinski J, De Leon DD et al (2007) Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration. J Clin Invest 117:971–977

    Article  CAS  PubMed  Google Scholar 

  • Dor Y and Melton DA (2008) Facultative endocrine progenitor cells in the adult pancreas. Cell 132:183–184

    Article  CAS  PubMed  Google Scholar 

  • Dor Y, Brown J, Martinez OI et al (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46

    Article  CAS  PubMed  Google Scholar 

  • Dore BA, Grogan WM, Madge GE et al (1981) Biphasic development of the postnatal mouse pancreas. Biol Neonate 40:209–217

    Article  CAS  PubMed  Google Scholar 

  • Edstrom C (1971) Further qauntitative structural studies of the pancreatic islet parenchyma in rats with duct ligation. Acta Soc Med Uppsal 76:127–138

    CAS  Google Scholar 

  • Fausto N and Campbell JS (2003) The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 120:117–130

    Article  CAS  PubMed  Google Scholar 

  • Ferraris C, Chevalier G, Favier B et al (2000) Adult corneal epithelium basal cells possess the capacity to activate epidermal, pilosebaceous and sweat gland genetic programs in response to embryonic dermal stimuli. Development 127:5487–5495

    CAS  PubMed  Google Scholar 

  • Gao R, Ustinov J, Pulkkinen MA et al (2003) Characterization of endocrine progenitor cells and critical factors for their differentiation in human adult pancreatic cell culture. Diabetes 52:2007–2015

    Article  CAS  PubMed  Google Scholar 

  • Gao R, Ustinov J, Korsgren O et al (2005) In vitro neogenesis of human islets reflects the plasticity of differentiated human pancreatic cells. Diabetologia 48:2296–2304

    Article  CAS  PubMed  Google Scholar 

  • Grompe M (2003) Pancreatic-hepatic switches in vivo. Mech Dev 120:99–106

    Article  CAS  PubMed  Google Scholar 

  • Gu D and Sarvetnick N (1993) Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development 118:33–46

    CAS  PubMed  Google Scholar 

  • Hale MA, Kagami H, Shi L et al (2005) The homeodomain protein PDX1 is required at mid-pancreatic development for the formation of the exocrine pancreas. Dev Biol 286:225–237

    Article  CAS  PubMed  Google Scholar 

  • Hao E, Tyrberg B, Itkin-Ansari P et al (2006) Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas. Nat Med 12:310–316

    Article  CAS  PubMed  Google Scholar 

  • Hardikar AA, Marcus-Samuels B, Geras-Raaka E et al (2003) Human pancreatic precursor cells secrete FGF2 to stimulate clustering into hormone-expressing islet-like cell aggregates. Proc Natl Acad Sci USA 100:7117–7122

    Article  CAS  PubMed  Google Scholar 

  • Hultquist GT, Karlsson U, Hallner AC (1979) The regenerative capacity of the pancreas in duct-ligated rats. Exp Pathol 17:44–52

    CAS  Google Scholar 

  • Inada A, Nienaber C, Fonseca S et al (2006) Timing and expression pattern of carbonic anhydrase II in pancreas. Dev Dyn 235:1571–1577

    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  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 

  • Jhappan C, Stahle C, Harkins RN et al (1990) TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 61:1137–1146

    Article  CAS  PubMed  Google Scholar 

  • Jiang J, Au M, Lu K et al (2007) Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells 25:1940–1953

    Article  CAS  PubMed  Google Scholar 

  • Kikugawa RKH, Akashi T, Yatoh S et al (2009) Differentiation of COPAS-sorted non-endocrine pancreatic cells into insulin-positive cells in the mouse. Diabetologia 52: in press

    Google Scholar 

  • Kloppel G, Löhr M, Habich K et al (1985) Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res 4:110–125

    CAS  PubMed  Google Scholar 

  • Kritzik MR, Jones E, Chen Z et al (1999) Pdx1 and Msx-2 expression in the regenerating and developing pancreas. J Endocrinol 163:523–530

    Article  CAS  PubMed  Google Scholar 

  • Kritzik MR, Krahl T, Good A et al (2000) Transcription factor expression during pancreatic islet regeneration. Mol Cell Endocrinol 164:99–107

    Article  CAS  PubMed  Google Scholar 

  • Kroon E, Martinson LA, Kadoya K et al (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26:443–452

    Article  CAS  PubMed  Google Scholar 

  • Lardon J, Huyens N, Rooman I et al (2004) Exocrine cell transdifferentiation in dexamethasone-treated rat pancreas. Virchows Arch 444:61–65

    Article  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 

  • Li L, Seno M, Yamada H et al (2003) Betacellulin improves glucose metabolism by promoting conversion of intraislet precursor cells to beta-cells in streptozotocin-treated mice. Am J Physiol Endocrinol Metab 285:E577–583

    CAS  PubMed  Google Scholar 

  • Li WC, Horb ME, Tosh D et al (2005) In vitro transdifferentiation of hepatoma cells into functional pancreatic cells. Mech Dev 122:835–847

    Article  CAS  PubMed  Google Scholar 

  • Mashima H, Ohnishi H, Wakabayashi K et al (1996a) Betacellulin and activin A coordinately convert amylase-secreting pancreatic AR42J cells into insulin-secreting cells. J Clin Invest 97:1647–1654

    Article  CAS  PubMed  Google Scholar 

  • Mashima H, Shibata H, Mine T et al (1996b) Formation of insulin producing cells from pancreatic acinar AR42J cells by hepatocyte growth factor. Endocrinol 137:3969–3976

    Article  CAS  Google Scholar 

  • Meier JJ, Butler AE, Saisho Y et al (2008) Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes 57:1584–1594

    Article  CAS  PubMed  Google Scholar 

  • Michalopoulos GK (2007) Liver regeneration. J Cell Physiol 213:286–300

    Article  CAS  PubMed  Google Scholar 

  • Noguchi H, Kaneto H, Weir GC et al (2003) PDX1 protein containing its own antennapedia-like protein transduction domain can transduce pancreatic duct and islet cells. Diabetes 52:1732–1737

    Article  CAS  PubMed  Google Scholar 

  • Oshima Y, Suzuki A, Kawashimo K et al (2007) Isolation of mouse pancreatic ductal progenitor cells expressing CD133 and c-met by flow cytometric cell sorting. Gastroenterology 132:720–732

    Article  CAS  PubMed  Google Scholar 

  • Parsons JA, Bartke A, Sorenson RL (1995) Number and size of islets of Langerhans in pregnant human growth hormone-expressing transgenic, and pituitary dwarf mice: effect of lactogenic hormones. Endocrinol 136:2013–2021

    Article  CAS  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 

  • Peters K, Panienka R, Li J et al (2005) Expression of stem cell markers and transcription factors during the remodeling of the rat pancreas after duct ligation. Virchows Arch 446:56–63

    Article  CAS  PubMed  Google Scholar 

  • Portha B (2005) Programmed disorders of beta-cell development and function as one cause for type 2 diabetes? The GK rat paradigm. Diabetes Metab Res Rev 21: 495–504

    Article  CAS  PubMed  Google Scholar 

  • Ramiya VK, Maraist M, Arfors KE et al (2000) Reversal of insulin dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med 6:278–282

    Article  CAS  PubMed  Google Scholar 

  • Rao MS, Dwivedi RS, Yeldandi AV et al (1989) Role of periductal and ductular epithelial cells of the adult rat pancreas in pancreatic hepatocyte lineage. Am J Physiol 134:1069–1086

    CAS  Google Scholar 

  • Reddy JK, Rao MS, Yeldandi AV et al (1991) Pancreatic hepatocytes: an in vivo model for cell lineage in pancreas of adult rat. Digest Dis Science 36:502–509

    Article  CAS  Google Scholar 

  • Rooman I, Lardon J, Bouwens L (2002) Gastrin stimulates beta-cell neogenesis and increases islet mass from transdifferentiated but not from normal exocrine pancreas tissue. Diabetes 51: 686–690

    Article  CAS  PubMed  Google Scholar 

  • Sarvetnick NE and Gu D (1992) Regeneration of pancreatic endocrine cells in interferon-gamma transgenic mice. Adv Exp Med Biol 321:85–89

    CAS  PubMed  Google Scholar 

  • Scaglia L, Cahill CJ, Finegood DT et al (1997) Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinol 138:1736–1741

    Article  CAS  Google Scholar 

  • Seaberg RM, Smukler SR, Kieffer TJ et al (2004) Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat Biotechnol 22:1115–1124

    Article  CAS  PubMed  Google Scholar 

  • Seymour PA, Freude KK, Tran MN et al (2007) Sox9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci USA 104:1865–1870

    Article  CAS  PubMed  Google Scholar 

  • Sharma A, Zangen DH, Reitz P et al (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 

  • Song SY, Gannon M, Washington MK et al (1999) Expansion of PDX1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor a. Gastroenterology 117:1416–1426

    Article  CAS  PubMed  Google Scholar 

  • Suarez-Pinzon WL, Lakey JR, Brand SJ et al (2005) Combination therapy with epidermal growth factor and gastrin induces neogenesis of human islet β-cells from pancreatic duct cells and an increase in functional β-cell mass. J Clin Endocrinol Metab 90:3401–3409

    Article  CAS  PubMed  Google Scholar 

  • Sugiyama T, Rodriguez RT, McLean GW et al (2007) Conserved markers of fetal pancreatic epithelium permit prospective isolation of islet progenitor cells by FACs. Proc Natl Acad Sci USA 104:175–180

    Article  CAS  PubMed  Google Scholar 

  • Suzuki A, Nakauchi H, Taniguchi H (2004) Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting. Diabetes 53:2143–2152

    Article  CAS  PubMed  Google Scholar 

  • Teta M, Rankin MM, Long SY et al (2007) Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell 12:817–826

    Article  CAS  PubMed  Google Scholar 

  • Tyrberg B, Ustinov J, Otonkoski T et al (2001) Stimulated endocrine cell proliferation and differentiation in transplanted human pancreatic islets: effects of the ob gene and compensatory growth of the implantation organ. Diabetes 50:301–307

    Article  CAS  PubMed  Google Scholar 

  • Wang TC, Bonner-Weir S, Oates PS et al (1993) Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells. J Clin Invest 92:1349–1356

    Article  CAS  PubMed  Google Scholar 

  • Wang RN Klöppel 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 

  • Wang X, Foster M, Al-Dhalimy M et al (2003) The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci USA 100(Suppl 1):11881–11888

    Article  CAS  PubMed  Google Scholar 

  • Wang CY, Gou SM, Liu T et al (2008) Differentiation of CD24- pancreatic ductal cell-derived cells into insulin-secreting cells. Dev Growth Differ 50:633–643

    Article  CAS  PubMed  Google Scholar 

  • Xu G, Stoffers DA, Habener JF et al (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 X, D‘Hoker J, Stangé G et al (2008) Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132:197–207

    Article  CAS  PubMed  Google Scholar 

  • Yatoh S, Dodge R, Akashi T et al (2007) Differentiation of affinity-purified human pancreatic duct cells to β-cells. Diabetes 56:1802–1809

    Article  CAS  PubMed  Google Scholar 

  • Yoon KH, Ko SH, Cho JH et al (2003) Selective β-cell loss and α-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endoc Metab 88:2300–2308.

    Article  CAS  Google Scholar 

  • Zhao M, Amiel SA, Christie MR et al (2005) Insulin-producing cells derived from human pancreatic non-endocrine cell cultures reverse streptozotocin-induced hyperglycaemia in mice. Diabetologia 48:2051–2061

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Wang X, Pineyro MA et al (1999) Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells. Diabetes 48:2358–2366

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Pineyro MA, Wang X et al (2002) Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX1 and HNF3bα transcription factors. J Cell Physiol 192:304–314

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank those scientists who have worked with us through the years for their discussions and contributions. The research was supported by grants from NIH and JDRF.

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Authors and Affiliations

  1. Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Joslin Diabetes Center, 02215, Boston, MA, USA

    Susan Bonner-Weir & Arun Sharma

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  1. Susan Bonner-Weir
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  2. Arun Sharma
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Correspondence to Susan Bonner-Weir .

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  1. Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Shimon Efrat

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Bonner-Weir, S., Sharma, A. (2010). Generation of Beta Cells from Pancreatic Duct Cells and/or Stem Cells. In: Efrat, S. (eds) Stem Cell Therapy for Diabetes. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-60761-366-4_8

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