Ductal Cell Reprogramming to Insulin-Producing Beta-Like Cells as a Potential Beta Cell Replacement Source for Chronic Pancreatitis

Author(s): Aravinth P. Jawahar, Siddharth Narayanan, Gopalakrishnan Loganathan, Jithu Pradeep, Gary C. Vitale, Christopher M. Jones, Michael G. Hughes, Stuart K. Williams, Appakalai N. Balamurugan*.

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 1 , 2019

Become EABM
Become Reviewer

Abstract:

Islet cell auto-transplantation is a novel strategy for maintaining blood glucose levels and improving the quality of life in patients with chronic pancreatitis (CP). Despite the many recent advances associated with this therapy, obtaining a good yield of islet infusate still remains a pressing challenge. Reprogramming technology, by making use of the pancreatic exocrine compartment, can open the possibility of generating novel insulin-producing cells. Several lineage-tracing studies present evidence that exocrine cells undergo dedifferentiation into a progenitor-like state from which they can be manipulated to form insulin-producing cells. This review will present an overview of recent reports that demonstrate the potential of utilizing pancreatic ductal cells (PDCs) for reprogramming into insulin- producing cells, focusing on the recent advances and the conflicting views. A large pool of ductal cells is released along with islets during the human islet isolation process, but these cells are separated from the pure islets during the purification process. By identifying and improving existing ductal cell culture methods and developing a better understanding of mechanisms by which these cells can be manipulated to form hormone-producing islet-like cells, PDCs could prove to be a strong clinical tool in providing an alternative beta cell source, thus helping CP patients maintain their long-term glucose levels.

Keywords: Islets, ductal cells, auto-transplantation, neogenesis, chronic pancreatitis, cell reprogramming.

[1]
Lee B, Zhao Q, Habtezion A. Immunology of pancreatitis and environmental factors. Curr Opin Gastroenterol 2017; 33(5): 383-9.
[2]
Ewald N, Hardt PD. Diagnosis and treatment of diabetes mellitus in chronic pancreatitis. World J Gastroenterol 2013; 19(42): 7276-81.
[3]
Wynne K, Devereaux B, Dornhorst A. Diabetes of the exocrine pancreas. J Gastroenterol Hepatol 2018. [Epub ahead of print].
[4]
Makuc J. Management of pancreatogenic diabetes: challenges and solutions. Diabetes Metab Syndr Obes 2016; 9: 311-5.
[5]
Gruessner RW, Cercone R, Galvani C, et al. Results of open and robot-assisted pancreatectomies with autologous islet transplantations: treating chronic pancreatitis and preventing surgically induced diabetes. Transplant Proc 2014; 46(6): 1978-9.
[6]
Maeda H, Hanazaki K. Pancreatogenic diabetes after pancreatic resection. Pancreatology 2011; 11(2): 268-76.
[7]
Duggan SN, Ewald N, Kelleher L, Griffin O, Gibney J, Conlon KC. The nutritional management of type 3c (pancreatogenic) diabetes in chronic pancreatitis. Eur J Clin Nutr 2017; 71(1): 3-8.
[8]
Woodmansey C, McGovern AP, McCullough KA, et al. Incidence, Demographics, and Clinical Characteristics of Diabetes of the Exocrine Pancreas (Type 3c): A Retrospective Cohort Study. Diabetes Care 2017; 40(11): 1486-93.
[9]
Balamurugan A, Loganathan G, Lockridge A, et al. Islet Isolation from Pancreatitis Pancreas for Islet Autotransplantation Islets of Langerhans. Springer 2015; pp. 1199-227.
[10]
Morrison CP, Wemyss-Holden SA, Dennison AR, Maddern GJ. Islet yield remains a problem in islet autotransplantation. Arch Surg 2002; 137(1): 80-3.
[11]
Chinnakotla S, Radosevich DM, Dunn TB, et al. Long-term outcomes of total pancreatectomy and islet auto transplantation for hereditary/genetic pancreatitis. J Am Coll Surg 2014; 218(4): 530-43.
[12]
Balamurugan AN, Loganathan G, Bellin MD, et al. A new enzyme mixture to increase the yield and transplant rate of autologous and allogeneic human islet products. Transplantation 2012; 93(7): 693-702.
[13]
Sutherland DE, Radosevich DM, Bellin MD, et al. Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg 2012; 214(4): 409-24. discussion 24-6.
[14]
Afelik S, Rovira M. Pancreatic beta-cell regeneration: Facultative or dedicated progenitors? Mol Cell Endocrinol 2017; 445: 85-94.
[15]
Bonner-Weir S. Islet growth and development in the adult. J Mol Endocrinol 2000; 24(3): 297-302.
[16]
Corritore E, Lee YS, Sokal EM, Lysy PA. beta-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells. Ther Adv Endocrinol Metab 2016; 7(4): 182-99.
[17]
Bonner-Weir S, Guo L, Li WC, et al. Islet neogenesis: A possible pathway for beta-cell replenishment. Rev Diabet Stud 2012; 9(4): 407-16.
[18]
Bonner-Weir S, Inada A, Yatoh S, et al. Transdifferentiation of pancreatic ductal cells to endocrine beta-cells. Biochem Soc Trans 2008; 36(Pt 3): 353-6.
[19]
Aguayo-Mazzucato C, Bonner-Weir S. Pancreatic beta Cell Regeneration as a Possible Therapy for Diabetes. Cell Metab 2018; 27(1): 57-67.
[20]
Bonner-Weir S, Sharma A. Pancreatic stem cells. J Pathol 2002; 197(4): 519-26.
[21]
Ziv O, Glaser B, Dor Y. The plastic pancreas. Dev Cell 2013; 26(1): 3-7.
[22]
Cito M, Pellegrini S, Piemonti L, Sordi V. The potential and challenges of alternative sources of beta cells for the cure of type 1 diabetes. Endocr Connect 2018; 7(3): R114-25.
[23]
Zhou Q, Law AC, Rajagopal J, Anderson WJ, Gray PA, Melton DA. A multipotent progenitor domain guides pancreatic organogenesis. Dev Cell 2007; 13(1): 103-14.
[24]
Lysy PA, Weir GC, Bonner-Weir S. Making beta cells from adult cells within the pancreas. Curr Diab Rep 2013; 13(5): 695-703.
[25]
Pan FC, Wright C. Pancreas organogenesis: from bud to plexus to gland. Dev Dyn 2011; 240(3): 530-65.
[26]
Wandzioch E, Zaret KS. Dynamic signaling network for the specification of embryonic pancreas and liver progenitors. Science 2009; 324(5935): 1707-10.
[27]
Kopp JL, Dubois CL, Hao E, Thorel F, Herrera PL, Sander M. Progenitor cell domains in the developing and adult pancreas. Cell Cycle 2011; 10(12): 1921-7.
[28]
Li WC, Rukstalis JM, Nishimura W, et al. Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats. J Cell Sci 2010; 123(Pt 16): 2792-802.
[29]
Xu X, D’Hoker J, Stange G, et al. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 2008; 132(2): 197-207.
[30]
Hoesli CA, Johnson JD, Piret JM. Purified human pancreatic duct cell culture conditions defined by serum-free high-content growth factor screening. PLoS One 2012; 7(3): e33999.
[31]
Bonner-Weir S, Taneja M, Weir GC, et al. In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 2000; 97(14): 7999-8004.
[32]
Kerr-Conte J, Pattou F, Lecomte-Houcke M, et al. Ductal cyst formation in collagen-embedded adult human islet preparations. A means to the reproduction of nesidioblastosis in vitro. Diabetes 1996; 45(8): 1108-14.
[33]
Ma D, Tang S, Song J, et al. Culturing and transcriptome profiling of progenitor-like colonies derived from adult mouse pancreas. Stem Cell Res Ther 2017; 8(1): 172.
[34]
Loomans CJM, Williams Giuliani N, Balak J, et al. Expansion of Adult Human Pancreatic Tissue Yields Organoids Harboring Progenitor Cells with Endocrine Differentiation Potential. Stem Cell Reports 2018; 10(3): 712-24.
[35]
Swales N, Martens GA, Bonne S, et al. Plasticity of adult human pancreatic duct cells by neurogenin3-mediated reprogramming. PLoS One 2012; 7(5): e37055.
[36]
Gomez DL, O’Driscoll M, Sheets TP, et al. Neurogenin 3 Expressing Cells in the Human Exocrine Pancreas Have the Capacity for Endocrine Cell Fate. PLoS One 2015; 10(8): e0133862.
[37]
Yamada T, Cavelti-Weder C, Caballero F, et al. Reprogramming Mouse Cells With a Pancreatic Duct Phenotype to Insulin-Producing beta-Like Cells. Endocrinology 2015; 156(6): 2029-38.
[38]
Bonner-Weir S, Li WC, Ouziel-Yahalom L, Guo L, Weir GC, Sharma A. Beta-cell growth and regeneration: replication is only part of the story. Diabetes 2010; 59(10): 2340-8.
[39]
Seeberger KL, Eshpeter A, Rajotte RV, Korbutt GS. Epithelial cells within the human pancreas do not coexpress mesenchymal antigens: epithelial-mesenchymal transition is an artifact of cell culture. Lab Invest 2009; 89(2): 110-21.
[40]
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15(3): 178-96.
[41]
Russ HA, Sintov E, Anker-Kitai L, et al. Insulin-producing cells generated from dedifferentiated human pancreatic beta cells expanded in vitro. PLoS One 2011; 6(9): e25566.
[42]
Bar Y, Russ HA, Sintov E, Anker-Kitai L, Knoller S, Efrat S. Redifferentiation of expanded human pancreatic beta-cell-derived cells by inhibition of the NOTCH pathway. J Biol Chem 2012; 287(21): 17269-80.
[43]
Corritore E, Dugnani E, Pasquale V, et al. Beta-Cell differentiation of human pancreatic duct-derived cells after in vitro expansion. Cell Reprogram 2014; 16(6): 456-66.
[44]
Zhang M, Lin Q, Qi T, et al. Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into beta cells in mice with reversal of diabetes. Proc Natl Acad Sci USA 2016; 113(3): 650-5.
[45]
Dorrell C, Tarlow B, Wang Y, et al. The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar. Stem Cell Res 2014; 13(2): 275-83.
[46]
Lee J, Sugiyama T, Liu Y, et al. Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells. Elife 2013; 2: e00940.
[47]
Sancho R, Gruber R, Gu G, Behrens A. Loss of Fbw7 reprograms adult pancreatic ductal cells into alpha, delta, and beta cells. Cell Stem Cell 2014; 15(2): 139-53.
[48]
Rovira M, Scott SG, Liss AS, Jensen J, Thayer SP, Leach SD. Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc Natl Acad Sci USA 2010; 107(1): 75-80.
[49]
Zhang T, Wang H, Saunee NA, Breslin MB, Lan MS. Insulinoma-associated antigen-1 zinc-finger transcription factor promotes pancreatic duct cell trans-differentiation. Endocrinology 2010; 151(5): 2030-9.
[50]
Assouline-Thomas B, Ellis D, Petropavlovskaia M, Makhlin J, Ding J, Rosenberg L. Islet Neogenesis Associated Protein (INGAP) induces the differentiation of an adult human pancreatic ductal cell line into insulin-expressing cells through stepwise activation of key transcription factors for embryonic beta cell development. Differentiation 2015; 90(4-5): 77-90.
[51]
Kikugawa R, Katsuta H, Akashi T, et al. Differentiation of COPAS-sorted non-endocrine pancreatic cells into insulin-positive cells in the mouse. Diabetologia 2009; 52(4): 645-52.
[52]
Klein D, Alvarez-Cubela S, Lanzoni G, et al. BMP-7 induces adult human pancreatic exocrine-to-endocrine conversion. Diabetes 2015; 64(12): 4123-34.
[53]
Criscimanna A, Speicher JA, Houshmand G, et al. Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice. Gastroenterology 2011; 141(4): 1451-62. 62 e1-6
[54]
Thorel F, Nepote V, Avril I, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 2010; 464(7292): 1149-54.
[55]
Li W, Nakanishi M, Zumsteg A, et al. In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes. Elife 2014; 3: e01846.
[56]
Wang Y, Dorrell C, Naugler WE, et al. Long-term correction of diabetes in mice by in vivo reprogramming of pancreatic ducts. Mol Ther 2018; 26(5): 1327-42.
[57]
Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE. A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 1993; 42(12): 1715-20.
[58]
Inada A, Nienaber C, Katsuta H, et al. Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci USA 2008; 105(50): 19915-9.
[59]
Tellez N, Montanya E. Gastrin induces ductal cell dedifferentiation and beta-cell neogenesis after 90% pancreatectomy. J Endocrinol 2014; 223(1): 67-78.
[60]
Suarez-Pinzon WL, Lakey JR, Brand SJ, Rabinovitch A. Combination therapy with epidermal growth factor and gastrin induces neogenesis of human islet beta-cells from pancreatic duct cells and an increase in functional beta-cell mass. J Clin Endocrinol Metab 2005; 90(6): 3401-9.
[61]
Yamaguchi J, Liss AS, Sontheimer A, et al. Pancreatic duct glands (PDGs) are a progenitor compartment responsible for pancreatic ductal epithelial repair. Stem Cell Res 2015; 15(1): 190-202.
[62]
El-Gohary Y, Wiersch J, Tulachan S, et al. Intraislet Pancreatic Ducts Can Give Rise to Insulin-Positive Cells. Endocrinology 2016; 157(1): 166-75.
[63]
Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008; 455(7213): 627-32.
[64]
Rankin MM, Wilbur CJ, Rak K, Shields EJ, Granger A, Kushner JA. beta-Cells are not generated in pancreatic duct ligation-induced injury in adult mice. Diabetes 2013; 62(5): 1634-45.
[65]
Cavelti-Weder C, Shtessel M, Reuss JE, et al. Pancreatic duct ligation after almost complete beta-cell loss: exocrine regeneration but no evidence of beta-cell regeneration. Endocrinology 2013; 154(12): 4493-502.
[66]
Solar M, Cardalda C, Houbracken I, et al. Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev Cell 2009; 17(6): 849-60.
[67]
Rezanejad H, Ouziel-Yahalom L, Keyzer CA, et al. Heterogeneity of SOX9 and HNF1beta in Pancreatic Ducts Is Dynamic. Stem Cell Reports 2018; 10(3): 725-38.
[68]
Furuyama K, Kawaguchi Y, Akiyama H, et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 2011; 43(1): 34-41.
[69]
Kopp JL, Dubois CL, Schaffer AE, et al. Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 2011; 138(4): 653-65.
[70]
Pan FC, Bankaitis ED, Boyer D, et al. Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development 2013; 140(4): 751-64.
[71]
Al-Hasani K, Pfeifer A, Courtney M, et al. Adult duct-lining cells can reprogram into beta-like cells able to counter repeated cycles of toxin-induced diabetes. Dev Cell 2013; 26(1): 86-100.
[72]
Courtney M, Gjernes E, Druelle N, et al. The inactivation of Arx in pancreatic alpha-cells triggers their neogenesis and conversion into functional beta-like cells. PLoS Genet 2013; 9(10): e1003934.
[73]
Collombat P, Xu X, Ravassard P, et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell 2009; 138(3): 449-62.
[74]
Kopinke D, Murtaugh LC. Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas. BMC Dev Biol 2010; 10: 38.
[75]
Ricordi C, Goldstein JS, Balamurugan AN, et al. National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities. Diabetes 2016; 65(11): 3418-28.
[76]
Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343(4): 230-8.
[77]
Brennan DC, Kopetskie HA, Sayre PH, et al. Long-Term Follow-Up of the Edmonton Protocol of Islet Transplantation in the United States. Am J Transplant 2016; 16(2): 509-17.
[78]
Hering BJ, Clarke WR, Bridges ND, et al. Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care 2016; 39(7): 1230-40.
[79]
Bottino R, Knoll MF, Knoll CA, Bertera S, Trucco MM. The Future of Islet Transplantation Is Now. Front Med (Lausanne) 2018; 5: 202.
[80]
Bellin MD, Abu-El-Haija M, Morgan K, et al. A multicenter study of total pancreatectomy with islet autotransplantation (TPIAT): POST (Prospective Observational Study of TPIAT). Pancreatology 2018; 18(3): 286-90.
[81]
Morgan K, Owczarski SM, Borckardt J, Madan A, Nishimura M, Adams DB. Pain control and quality of life after pancreatectomy with islet autotransplantation for chronic pancreatitis. J Gastrointest Surg 2012; 16(1): 129-33. discussion 33-4.
[82]
Solomina J, Golebiewska J, Kijek MR, et al. Pain control, glucose control, and quality of life in patients with chronic pancreatitis after total pancreatectomy with islet autotransplantation: A preliminary report. Transplant Proc 2017; 49(10): 2333-9.
[83]
Bellin MD, Parazzoli S, Oseid E, et al. Defective glucagon secretion during hypoglycemia after intrahepatic but not nonhepatic islet autotransplantation. Am J Transplant 2014; 14(8): 1880-6.
[84]
Chinnakotla S, Beilman GJ, Dunn TB, et al. Factors predicting outcomes after a total pancreatectomy and islet autotransplantation lessons learned from over 500 cases. Ann Surg 2015; 262(4): 610-22.
[85]
Takita M, Lara LF, Naziruddin B, et al. Effect of the duration of chronic pancreatitis on pancreas islet yield and metabolic outcome following islet autotransplantation. J Gastrointest Surg 2015; 19(7): 1236-46.
[86]
McEachron KR, Bellin MD. Total pancreatectomy and islet autotransplantion for chronic and recurrent acute pancreatitis. Curr Opin Gastroenterol 2018; 34(5): 367-73.
[87]
Wilson GC, Sutton JM, Abbott DE, et al. Long-term outcomes after total pancreatectomy and islet cell autotransplantation: Is it a durable operation? Ann Surg 2014; 260(4): 659-65. discussion 65- 7
[88]
Lin YK, Faiman C, Johnston PC, et al. Spontaneous Hypoglycemia After Islet Autotransplantation for Chronic Pancreatitis. J Clin Endocrinol Metab 2016; 101(10): 3669-75.
[89]
Shindo Y, Kanak MA. Total pancreatectomy with islet autotransplantation: Recent updates and outcomes. Curr Opin Organ Transplant 2017; 22(5): 444-51.
[90]
Zhou J, Pineyro MA, Wang X, Doyle ME, Egan JM. Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors. J Cell Physiol 2002; 192(3): 304-14.
[91]
Hardikar AA, Marcus-Samuels B, Geras-Raaka E, Raaka BM, Gershengorn MC. Human pancreatic precursor cells secrete FGF2 to stimulate clustering into hormone-expressing islet-like cell aggregates. Proc Natl Acad Sci USA 2003; 100(12): 7117-22.
[92]
Baron M, Veres A, Wolock SL, et al. A Single-Cell Transcriptomic Map of the Human and Mouse Pancreas Reveals Inter- and Intracell Population Structure. Cell Syst 2016; 3(4): 346-60 e4.
[93]
Dorrell C, Schug J, Canaday PS, et al. Human islets contain four distinct subtypes of beta cells. Nat Commun 2016; 7: 11756.
[94]
Segerstolpe A, Palasantza A, Eliasson P, et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab 2016; 24(4): 593-607.
[95]
Xin Y, Kim J, Okamoto H, et al. RNA sequencing of single human islet cells reveals type 2 diabetes genes. Cell Metab 2016; 24(4): 608-15.
[96]
Zou C, Lu Y, Teng X, et al. MRI tracking of autologous pancreatic progenitor-derived insulin-producing cells in monkeys. Sci Rep 2017; 7(1): 2505.
[97]
Yasunaga K, Ito T, Miki M, et al. Using CRISPR/Cas9 to Knock out Amylase in Acinar Cells Decreases Pancreatitis-Induced Autophagy.BioMed Research International. (8719397)8 pages. 2018; 2018 : p.
[98]
Donadel G, Pastore D, Della-Morte D, et al. FGF-2b and h-PL transform duct and non-endocrine human pancreatic cells into endocrine insulin secreting cells by modulating differentiating genes. Int J Mol Sci 2017; 18(11): 2234.
[99]
Lima MJ, Muir KR, Docherty HM, et al. Generation of functional beta-like cells from human exocrine pancreas. PLoS One 2016; 11(5): e0156204.
[100]
Vieira A, Druelle N, Avolio F, et al. Beta-Cell Replacement Strategies: The Increasing Need for a “beta-Cell Dogma”. Front Genet 2017; 8: 75.
[101]
Sheets TP, Park KE, Park CH, et al. Targeted Mutation of NGN3 Gene Disrupts Pancreatic Endocrine Cell Development in Pigs. Sci Rep 2018; 8(1): 3582.
[102]
Zhao JB, Liao DH, Nissen TD. Animal models of pancreatitis: can it be translated to human pain study? World J Gastroenterol 2013; 19(42): 7222-30.
[103]
Aghdassi AA, Mayerle J, Christochowitz S, Weiss FU, Sendler M, Lerch MM. Animal models for investigating chronic pancreatitis. Fibrogenesis Tissue Repair 2011; 4(1): 26.
[104]
Xiao X, Guo P, Shiota C, et al. Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes. Cell Stem Cell 2018; 22(1): 78-90 e4..


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 14
ISSUE: 1
Year: 2019
Page: [65 - 74]
Pages: 10
DOI: 10.2174/1574888X13666180918092729
Price: $65

Article Metrics

PDF: 30
HTML: 5