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PLOS ONE  2012 

Stellate Cells from Rat Pancreas Are Stem Cells and Can Contribute to Liver Regeneration

DOI: 10.1371/journal.pone.0051878

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Abstract:

The identity of pancreatic stem/progenitor cells is still under discussion. They were suggested to derive from the pancreatic ductal epithelium and/or islets. Here we report that rat pancreatic stellate cells (PSC), which are thought to contribute to pancreatic fibrosis, have stem cell characteristics. PSC reside in islets and between acini and display a gene expression pattern similar to umbilical cord blood stem cells and mesenchymal stem cells. Cytokine treatment of isolated PSC induced the expression of typical hepatocyte markers. The PSC-derived hepatocyte-like cells expressed endodermal proteins such as bile salt export pump along with the mesodermal protein vimentin. The transplantation of culture-activated PSC from enhanced green fluorescent protein-expressing rats into wild type rats after partial hepatectomy in the presence of 2-acetylaminofluorene revealed that PSC were able to reconstitute large areas of the host liver through differentiation into hepatocytes and cholangiocytes. This developmental fate of transplanted PSC was confirmed by fluorescence in situ hybridization of chromosome Y after gender-mismatched transplantation of male PSC into female rats. Transplanted PSC displayed long-lasting survival, whereas muscle fibroblasts were unable to integrate into the host liver. The differentiation potential of PSC was further verified by the transplantation of clonally expanded PSC. PSC clones maintained the expression of stellate cell and stem cell markers and preserved their differentiation potential, which indicated self-renewal potential of PSC. These findings demonstrate that PSC have stem cell characteristics and can contribute to the regeneration of injured organs through differentiation across tissue boundaries.

References

[1]  Fitzgerald PJ, Alvizouri M (1952) Rapid restitution of the rat pancreas following acinar cell necrosis subsequent to ethionine. Nature 170: 929–930.
[2]  Pour P (1978) Islet cells as a component of pancreatic ductal neoplasms. I. Experimental study: ductular cells, including islet cell precursors, as primary progenitor cells of tumors. Am J Pathol 90: 295–316.
[3]  Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, et al. (2000) Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med 6: 278–282.
[4]  Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, et al. (2001) Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 50: 521–533.
[5]  Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, et al. (2000) In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 97: 7999–8004.
[6]  Bonner-Weir S, Toschi E, Inada A, Reitz P, Fonseca SY, et al. (2004) The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes 5: 16–22.
[7]  Kordes C, Sawitza I, Müller-Marbach A, Ale-Agha N, Keitel V, et al. (2007) CD133+ hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 352: 410–417.
[8]  Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, et al. (1998) Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 43: 128–133.
[9]  Bachem MG, Schneider E, Gro? H, Weidenbach H, Schmid RM, et al. (1998) Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115: 421–432.
[10]  Ikejiri N (1990) The vitamin A-storing cells in the human and rat pancreas. Kurume Med J 37: 67–81.
[11]  Yokoi Y, Namihisa T, Kuroda H, Komatsu I, Miyazaki A, et al. (1984) Immunocytochemical detection of desmin in fat-storing cells (Ito cells). Hepatology 4: 709–714.
[12]  Gard A, White F, Dutton G (1985) Extra-neural glial fibrillary acidic protein (GFAP) immunoreactivity in perisinusoidal stellate cells of rat liver. J Neuroimmunol 8: 359–375.
[13]  Uyama N, Zhao L, Van Rossen E, Hirako Y, Reynaert H, et al. (2006) Hepatic stellate cells express synemin, a protein bridging intermediate filaments to focal adhesions. Gut 55: 1276–1289.
[14]  Zhao L, Burt AD (2007) The diffuse stellate cell system. J Mol Histol 38: 53–64.
[15]  Niki T, Pekny M, Hellemans K, Bleser PD, Berg KV, et al. (1999) Class VI intermediate filament protein nestin is induced during activation of rat hepatic stellate cells. Hepatology 29: 520–527.
[16]  Lardon J, Rooman I, Bouwens L (2001) Nestin expression in pancreatic stellate cells and angiogenic endothelial cells. Histochem Cell Biol 117: 535–540.
[17]  Wiese C, Rolletschek A, Kania G, Blyszczuk P, Tarasov KV, et al. (2005) Nestin expression - a property of multi-lineage progenitor cells? Cell Mol Life Sci 61: 2510–2522.
[18]  Rao MS, Dwiwedi RS, Yeldandi AV, Subbarao V, Tan XD, et al. (1989) Role of periductal and ductular epithelial cells of the adult rat pancreas in pancreatic hepatocyte lineage: A change in the differentiation commitment. Am J Pathol 134: 1069–1086.
[19]  Reddy JK, Rao MS, Yeldandi AV, Tan XD, Dwivedi RS (1991) Pancreatic hepatocytes: an in vivo model for cell lineage in pancreas of adult rat. Dig Dis Sci 36: 502–509.
[20]  Bisgaard HC, Thorgeirsson SS (1991) Evidence for a common cell of origin for primitive epithelial cells isolated from rat liver and pancreas. J Cell Physiol 147: 333–343.
[21]  Rao MS, Yukawa M, Omori M, Thorgeirsson SS, Reddy JK (1996) Expression of transcription factors and stem cell factor precedes hepatocyte differentiation in rat pancreas. Gene Expr 6: 15–22.
[22]  Hendriks HFJ, Verhoofstad WA, Brouwer A, de Leeuw AM, Knook DL (1985) Perisinusoidal fat-storing cells are the main vitamin A storage sites in rat liver. Exp Cell Res 160: 138–149.
[23]  Lange C, Bassler P, Lioznov MV, Bruns H, Kluth D, et al. (2005) Hepatocytic gene expression in cultured rat mesenchymal stem cells. Transplant Proc 37: 276–279.
[24]  Kubitz R, Sütfels G, Kühlkamp T, K?lling R, H?ussinger D (2004) Trafficking of the bile salt export pump from the Golgi to the canalicular membrane is regulated by the p38 MAP kinase. Gastroenterology 126: 541–553.
[25]  Higgins GM, Anderson RM (1931) Experimental pathology of the liver. I. Restoration of the liver of the white rat following partial surgical removal. Arch Pathol Lab Med 12: 186–202.
[26]  Tatematsu M, Ho RH, Kaku T, Ekem JK, Farber E (1984) Studies on the proliferation and fate of oval cells in the liver of rats treated with 2-acetylaminofluorene and partial hepatectomy. Am J Pathol 114: 418–430.
[27]  Bani-Yaghoub M, Kubu CJ, Cowling R, Rochira J, Nikopoulos GN, et al. (2007) A switch in numb isoforms is a critical step in cortical development. Dev Dyn 236: 696–705.
[28]  Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH (2004) Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10: 55–63.
[29]  Qihao Z, Xigu C, Guanghui C, Weiwei Z (2007) Spheroid formation and differentiation into hepatocyte-like cells of rat mesenchymal stem cell induced by co-culture with liver cells. DNA Cell Biol 26: 497–503.
[30]  Nyfeler Y, Kirch RD, Mantei N, Leone DP, Radtke F, et al. (2005) Jagged1 signals in the postnatal subventricular zone are required for neural stem cell self-renewal. EMBO J 24: 3504–3515.
[31]  Karanu FN, Yuefei L, Gallacher L, Sakano S, Bhatia M (2003) Differential response of primitive human CD34? and CD34+ hematopoetic cells to the Notch ligand Jagged-1. Leukemia 17: 1366–1374.
[32]  Evarts RP, Nagy P, Marsden ER, Thorgeirsson SS (1987) A precursor - product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis 8: 1737–1740.
[33]  Hatch HM, Zheng D, Jorgensen ML, Petersen BE (2002) SDF-1alpha/CXCR4: a mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats. Cloning Stem Cells 4: 339–351.
[34]  Tondreau T, Lagneaux L, Dejeneffe M, Massy M, Mortier C, et al. (2004) Bone marrow-derived mesenchymal stem cells already express specific neural proteins before any differentiation. Differentiation 72: 319–326.
[35]  Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, et al. (2004) In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology 40: 1275–1284.
[36]  Chamberlain G, Fox J, Ashton B, Middleton J (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25: 2739–2749.
[37]  Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, et al. (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3: 301–313.
[38]  Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, et al. (2011) Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 43: 34–41.
[39]  Hanley KP, Oakley F, Sugden S, Wilson DI, Mann DA, et al. (2008) Ectopic SOX9 mediates extracellular matrix deposition characteristic of organ fibrosis. J Biol Chem 283: 14063–14071.

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