β cell regeneration and novel strategies for treatment of diabetes (Review)

Ji,Zengyang; Lu,Min; Xie,Huanhuan; Yuan,Honggang; Chen,Qing

doi:10.3892/br.2022.1555

β cell regeneration and novel strategies for treatment of diabetes (Review)

Authors:
- Zengyang Ji
- Min Lu
- Huanhuan Xie
- Honggang Yuan
- Qing Chen
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Affiliations: Department of Endocrinology, Changxing County Hospital of Traditional Chinese Medicine, Huzhou, Zhejiang 313199, P.R. China
Published online on: June 29, 2022 https://doi.org/10.3892/br.2022.1555
Article Number: 72

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Abstract

The etiology of diabetes is primarily attributed to the lack of functioning β cells, which in‑turn leads to insulin deficiency or insulin resistance, and this ultimately leads to β cell dysfunction. Restoring the number and function of β cells is an effective means of improving or even curing diabetes. β cell regeneration is a potential method for increasing the number of functioning β cells. In addition to self‑duplication of pancreatic β cells, β cells can be regenerated from embryonic stem cells, human induced pluripotent stem cells and pancreatic stem cells. Based on these mechanisms, proliferation and differentiation into functional β cells in vitro is one of the most promising strategies for treatment of diabetes. Although β cell regeneration has significant potential in the treatment of insulin‑deficient diabetes, and significant progress has been made in this regard, there remains challenges which prevent its use in the clinic.

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1	Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA and Butler PC: Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 52:102–110. 2003.PubMed/NCBI View Article : Google Scholar
2	Wang P, Fiaschi-Taesch NM, Vasavada RC, Scott DK, García-Ocaña A and Stewart AF: Diabetes mellitus-advances and challenges in human β-cell proliferation. Nat Rev Endocrinol. 11:201–212. 2015.PubMed/NCBI View Article : Google Scholar
3	Campbell-Thompson M, Fu A, Kaddis JS, Wasserfall C, Schatz DA, Pugliese A and Atkinson MA: Insulitis and beta-cell mass in the natural history of type 1 diabetes. Diabetes. 65:719–731. 2016.PubMed/NCBI View Article : Google Scholar
4	Burke GW III, Vendrame F, Virdi SK, Ciancio G, Chen L, Ruiz P, Messinger S, Reijonen HK and Pugliese A: Lessons from pancreas transplantation in type 1 diabetes: Recurrence of islet autoimmunity. Curr Diab Rep. 15(121)2015.PubMed/NCBI View Article : Google Scholar
5	Afelik S and Rovira M: Pancreatic beta-cell regeneration: Advances in understanding the genes and signaling pathways involved. Genome Med. 9(42)2017.PubMed/NCBI View Article : Google Scholar
6	Levine F and Itkin-Ansari P: Beta-cell Regeneration: Neogenesis, replication or both? J Mol Med (Berl). 86:247–258. 2008.PubMed/NCBI View Article : Google Scholar
7	Aguayo-Mazzucato C and Bonner-Weir S: Pancreatic β cell regeneration as a possible therapy for diabetes. Cell Metab. 27:57–67. 2018.PubMed/NCBI View Article : Google Scholar
8	Benthuysen JR, Carrano AC and Sander M: Advances in beta cell replacement and regeneration strategies for treating diabetes. J Clin Invest. 126:3651–3660. 2016.PubMed/NCBI View Article : Google Scholar
9	Xu X, D'Hoker J, Stangé G, Bonné S, De Leu N, Xiao X, Van de Casteele M, Mellitzer G, Ling Z, Pipeleers D, et al: Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 132:197–207. 2008.PubMed/NCBI View Article : Google Scholar
10	Li WC, Rukstalis JM, Nishimura W, Tchipashvili V, Habener JF, Sharma A and Bonner-Weir S: Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats. J Cell Sci. 123 (Pt 16):2792–2802. 2010.PubMed/NCBI View Article : Google Scholar
11	Dor Y, Brown J, Martinez OI and Melton DA: Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature. 429:41–46. 2004.PubMed/NCBI View Article : Google Scholar
12	Teta M, Rankin MM, Long SY, Stein GM and Kushner JA: Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell. 12:817–826. 2007.PubMed/NCBI View Article : Google Scholar
13	Thorel F, Népote V, Avril I, Kohno K, Desgraz R, Chera S and Herrera PL: Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 464:1149–1154. 2010.PubMed/NCBI View Article : Google Scholar
14	Chera S, Baronnier D, Ghila L, Cigliola V, Jensen JN, Gu G, Furuyama K, Thorel F, Gribble FM, Reimann F and Herrera PL: Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. Nature. 514:503–507. 2014.PubMed/NCBI View Article : Google Scholar
15	Avrahami D, Li C, Yu M, Jiao Y, Zhang J, Naji A, Ziaie S, Glaser B and Kaestner KH: Targeting the cell cycle inhibitor p57Kip2 promotes adult human β cell replication. J Clin Invest. 124:670–674. 2014.PubMed/NCBI View Article : Google Scholar
16	Courtney M, Gjernes E, Druelle N, Ravaud C, Vieira A, Ben-Othman N, Pfeifer A, Avolio F, Leuckx G, Lacas-Gervais S, et al: The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells. PLoS Genet. 9(e1003934)2013.PubMed/NCBI View Article : Google Scholar
17	Lilly MA, Davis MF, Fabie JE, Terhune EB and Gallicano GI: Current stem cell based therapies in diabetes. Am J Stem Cells. 5:87–98. 2016.PubMed/NCBI
18	Domínguez-Bendala J, Lanzoni G, Klein D, Álvarez-Cubela S and Pastori RL: The human endocrine pancreas: New insights on replacement and regeneration. Trends Endocrinol Metab. 27:153–162. 2016.PubMed/NCBI View Article : Google Scholar
19	D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK and Baetge EE: Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol. 24:1392–1401. 2006.PubMed/NCBI View Article : Google Scholar
20	Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J, et al: Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 26:443–452. 2008.PubMed/NCBI View Article : Google Scholar
21	Rezania A, Bruin JE, Riedel MJ, Mojibian M, Asadi A, Xu J, Gauvin R, Narayan K, Karanu F, O'Neil JJ, et al: Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes. 61:2016–2029. 2012.PubMed/NCBI View Article : Google Scholar
22	Pagliuca FW, Millman JR, Gürtler M, Segel M, Van Dervort A, Ryu JH, Peterson QP, Greiner D and Melton DA: Generation of functional human pancreatic beta cells in vitro. Cell. 159:428–439. 2014.PubMed/NCBI View Article : Google Scholar
23	Bruin JE, Rezania A, Xu J, Narayan K, Fox JK, O'Neil JJ and Kieffer TJ: Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice. Diabetologia. 56:1987–1998. 2013.PubMed/NCBI View Article : Google Scholar
24	Kirk K, Hao E, Lahmy R and Itkin-Ansari P: Human embryonic stem cell derived islet progenitors mature inside an encapsulation device without evidence of increased biomass or cell escape. Stem Cell Res. 12:807–814. 2014.PubMed/NCBI View Article : Google Scholar
25	Vegas AJ, Veiseh O, Gürtler M, Millman JR, Pagliuca FW, Bader AR, Doloff JC, Li J, Chen M, Olejnik K, et al: Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med. 22:306–311. 2016.PubMed/NCBI View Article : Google Scholar
26	Xie R, Everett LJ, Lim HW, Patel NA, Schug J, Kroon E, Kelly OG, Wang A, D'Amour KA, Robins AJ, et al: Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell. 12:224–237. 2013.PubMed/NCBI View Article : Google Scholar
27	Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, O'Dwyer S, Quiskamp N, Mojibian M, Albrecht T, et al: Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 32:1121–1133. 2014.PubMed/NCBI View Article : Google Scholar
28	Millman JR, Xie C, Van Dervort A, Gürtler M, Pagliuca FW and Melton DA: Generation of stem cell-derived beta-cells from patients with type 1 diabetes. Nat Commun. 7(11463)2016.PubMed/NCBI View Article : Google Scholar
29	Navarro-Tableros V, Gomez Y, Brizzi MF and Camussi G: Generation of human stem cell-derived pancreatic organoids (POs) for regenerative medicine. Adv Exp Med Biol. 1212:179–220. 2020.PubMed/NCBI View Article : Google Scholar
30	Van de Casteele M, Leuckx G, Baeyens L, Cai Y, Yuchi Y, Coppens V, De Groef S, Eriksson M, Svensson C, Ahlgren U, et al: Neurogenin 3+ cells contribute to β-cell neogenesis and proliferation in injured adult mouse pancreas. Cell Death Dis. 4(e523)2013.PubMed/NCBI View Article : Google Scholar
31	Lee SH, Hao E and Levine F: β-Cell replication and islet neogenesis following partial pancreatectomy. Islets. 3:188–195. 2011.PubMed/NCBI View Article : Google Scholar
32	Gao R, Ustinov J, Korsgren O and Otonkoski T: In vitro neogenesis of human islets reflects the plasticity of differentiated human pancreatic cells. Diabetologia. 48:2296–2304. 2005.PubMed/NCBI View Article : Google Scholar
33	Lechner A, Nolan AL, Blacken RA and Habener JF: Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue. Biochem Biophys Res Commun. 327:581–588. 2005.PubMed/NCBI View Article : Google Scholar
34	Gershengorn MC, Hardikar AA, Wei C, Geras-Raaka E, Marcus-Samuels B and Raaka BM: Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells. Science. 306:2261–2264. 2004.PubMed/NCBI View Article : Google Scholar
35	Seaberg RM, Smukler SR, Kieffer TJ, Enikolopov G, Asghar Z, Wheeler MB, Korbutt G and van der Kooy D: Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat Biotechnol. 22:1115–1124. 2004.PubMed/NCBI View Article : Google Scholar
36	Bonner-Weir S, Toschi E, Inada A, Reitz P, Fonseca SY, Aye T and Sharma A: The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes. 5 (Suppl 2):S16–S22. 2004.PubMed/NCBI View Article : Google Scholar
37	Otonkoski T, Gao R and Lundin K: Stem cells in the treatment of diabetes. Ann Med. 37:513–520. 2005.PubMed/NCBI View Article : Google Scholar
38	Corritore E, Lee YS, Sokal EM and Lysy PA: β-cell replacement sources for type 1 diabetes: A focus on pancreatic ductal cells. Ther Adv Endocrinol Metab. 7:182–199. 2016.PubMed/NCBI View Article : Google Scholar
39	Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB and Cornelius JG: Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med. 6:278–282. 2000.PubMed/NCBI View Article : Google Scholar
40	Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A and O'Neil JJ: In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA. 97:7999–8004. 2000.PubMed/NCBI View Article : Google Scholar
41	Gmyr V, Belaich S, Muharram G, Lukowiak B, Vandewalle B, Pattou F and Kerr-Conte J: Rapid purification of human ductal cells from human pancreatic fractions with surface antibody CA19-9. Biochem Biophys Res Commun. 320:27–33. 2004.PubMed/NCBI View Article : Google Scholar
42	Lee J, Sugiyama T, Liu Y, Wang J, Gu X, Lei J, Markmann JF, Miyazaki S, Miyazaki J, Szot GL, et al: Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells. Elife. 2(e00940)2013.PubMed/NCBI View Article : Google Scholar
43	Yatoh S, Dodge R, Akashi T, Omer A, Sharma A, Weir GC and Bonner-Weir S: Differentiation of affinity-purified human pancreatic duct cells to beta-cells. Diabetes. 56:1802–1809. 2007.PubMed/NCBI View Article : Google Scholar
44	Rescan C, Le Bras S, Lefebvre VH, Frandsen U, Klein T, Foschi M, Pipeleers DG, Scharfmann R, Madsen OD and Heimberg H: EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade. Lab Invest. 85:65–74. 2005.PubMed/NCBI View Article : Google Scholar
45	Hoesli CA, Johnson JD and Piret JM: Purified human pancreatic duct cell culture conditions defined by serum-free high-content growth factor screening. PLoS One. 7(e33999)2012.PubMed/NCBI View Article : Google Scholar
46	Abdel Aziz MT, El-Asmar MF, Rezq AM, Mahfouz SM, Wassef MA, Fouad HH, Ahmed HH and Taha FM: The effect of a novel curcumin derivative on pancreatic islet regeneration in experimental type-1 diabetes in rats (long term study). Diabetol Metab Syndr. 5(75)2013.PubMed/NCBI View Article : Google Scholar
47	Stolovich-Rain M, Hija A, Grimsby J, Glaser B and Dor Y: Pancreatic beta cells in very old mice retain capacity for compensatory proliferation. J Biol Chem. 287:27407–27414. 2012.PubMed/NCBI View Article : Google Scholar
48	Al-Hasani K, Pfeifer A, Courtney M, Ben-Othman N, Gjernes E, Vieira A, Druelle N, Avolio F, Ravassard P, Leuckx G, et al: Adult duct-lining cells can reprogram into β-like cells able to counter repeated cycles of toxin-induced diabetes. Dev Cell. 26:86–100. 2013.PubMed/NCBI View Article : Google Scholar
49	Collombat P, Xu X, Ravassard P, Sosa-Pineda B, Dussaud S, Billestrup N, Madsen OD, Serup P, Heimberg H and Mansouri A: The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell. 138:449–462. 2009.PubMed/NCBI View Article : Google Scholar
50	Pfeifer A, Courtney M, Ben-Othman N, Al-Hasani K, Gjernes E, Vieira A, Druelle N, Avolio F, Faurite B, Mansouri A and Collombat P: Induction of multiple cycles of pancreatic β-cell replacement. Cell Cycle. 12:3243–3244. 2013.PubMed/NCBI View Article : Google Scholar
51	Gu D and Sarvetnick N: Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development. 118:33–46. 1993.PubMed/NCBI View Article : Google Scholar
52	Wang TC, Bonner-Weir S, Oates PS, Chulak M, Simon B, Merlino GT, Schmidt EV and Brand SJ: Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells. J Clin Invest. 92:1349–1356. 1993.PubMed/NCBI View Article : Google Scholar
53	Sancho R, Gruber R, Gu G and Behrens A: Loss of Fbw7 reprograms adult pancreatic ductal cells into α, δ, and β cells. Cell Stem Cell. 15:139–153. 2014.PubMed/NCBI View Article : Google Scholar
54	Baeyens L, De Breuck S, Lardon J, Mfopou JK, Rooman I and Bouwens L: In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells. Diabetologia. 48:49–57. 2005.PubMed/NCBI View Article : Google Scholar
55	Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, Shemer R, Nord C, Scheel DW, Pan FC, et al: Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat Biotechnol. 32:76–83. 2014.PubMed/NCBI View Article : Google Scholar
56	Rong Z, Wang M, Hu Z, Stradner M, Zhu S, Kong H, Yi H, Goldrath A, Yang YG, Xu Y and Fu X: An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell. 14:121–130. 2014.PubMed/NCBI View Article : Google Scholar