Impact of pancreatic cell-engineered constructs on the islet apparatus in recipient rats with type I diabetes mellitus
https://doi.org/10.15825/1995-1191-2025-2-139-147
Abstract
Current research focuses on exploring strategies to stimulate the regenerative capacity of pancreatic beta cells as a potential therapeutic approach for diabetes mellitus (DM).
Objective: this study aims to perform a comparative histological analysis of the islet apparatus in rats with streptozotocin (STZ)-induced DM following the implantation of a pancreatic cell-engineered construct (PCEC). The PCEC consists of isolated allogeneic islets of Langerhans embedded within a scaffold derived from decellularized human pancreatic fragments.
Materials and methods. The pancreases of rats from the control group (n = 4; untreated type 1 DM – T1DM), experimental group 1 (n = 4; intraperitoneal injection of pancreatic islets), and experimental group 2 (n = 4; intraperitoneal injection of PCEC) underwent histological analysis. Immunohistochemical staining for insulin and glucagon was performed using specific antibodies and an imaging system.
Results. In the pancreatic islets of the control group, insulin- immunopositive beta cells were either absent or detected as isolated cells, with alpha cells predominating. In the pancreases of experimental group 1 rats, beta cells were observed in most islets and within the surrounding exocrine parenchyma, albeit in low numbers (1–2 per field of view), while alpha cells remained the dominant population. A significant increase in insulin-positive cells was observed in the pancreas of rats in experimental group 2, along with a reduction in glucagon-positive cell numbers.
Conclusion. Morphological examination of the pancreatic islet apparatus in the experimental animals revealed that implantation of the PCEC had a be- neficial effect on restoration of the recipient’s pool of functionally active beta cells, serving as a trigger for the regenerative process.
About the Authors
N. V. BaranovaRussian Federation
Natalia V. Baranova
1, Shchukinskaya str., Moscow, 123182
L. A. Kirsanova
Russian Federation
Moscow
G. N. Bubentsova
Russian Federation
Moscow
A. S. Ponomareva
Russian Federation
Moscow
A. O. Nikolskaya
Russian Federation
Moscow
Yu. B. Basok
Russian Federation
Moscow
V. I. Sevastianov
Russian Federation
Moscow
References
1. Wang KL, Tao M, Wei TJ, Wei R. Pancreatic β cell regeneration induced by clinical and preclinical agents. World J Stem Cells. 2021 Jan 26; 13 (1): 64–77. doi: 10.4252/wjsc.v13.i1.64.
2. Zhong F, Jiang Y. Endogenous Pancreatic β Cell Regeneration: A Potential Strategy for the Recovery of β Cell Deficiency in Diabetes. Front Endocrinol (Lausanne). 2019 Feb 20; 10: 101. doi: 10.3389/fendo.2019.00101.
3. Hogrebe NJ, Maxwell KG, Augsornworawat P, Millman JR. Generation of insulin-producing pancreatic β cells from multiple human stem cell lines. Nat Protoc. 2021 Sep; 16 (9): 4109–4143. doi: 10.1038/s41596-021-00560-y.
4. Spears E, Serafimidis I, Powers AC, Gavalas A. Debates in Pancreatic Beta Cell Biology: Proliferation Versus Progenitor Differentiation and Transdifferentiation in Restoring β Cell Mass. Front Endocrinol (Lausanne). 2021 Aug 6; 12: 722250. doi: 10.3389/fendo.2021.722250.
5. Pylaev TE, Smyshlyaeva IV, Popyhova EB. Regeneration of β-cells of the islet apparatus of the pancreas. Literature review. Diabetes mellitus. 2022; 25 (4): 395–404. (In Russ.). doi: 10.14341/DM12872.
6. Lu J, Jaafer R, Bonnavion R, Bertolino P, Zhang CX. Transdifferentiation of pancreatic α-cells into insulinsecreting cells: From experimental models to underlying mechanisms. World J Diabetes. 2014 Dec 15; 5 (6): 847–853. doi: 10.4239/wjd.v5.i6.847.
7. Aguayo-Mazzucato C, Bonner-Weir S. Pancreatic β Cell Regeneration as a Possible Therapy for Diabetes. Cell Metab. 2018 Jan 9; 27 (1): 57–67. doi: 10.1016/j.cmet.2017.08.007.
8. Courtney M, Gjernes E, Druelle N, Ravaud C, Vieira A, Ben-Othman N et al. The inactivation of Arx in pancreatic alpha-cells triggers their neogenesis and conversion into functional beta-like cells. PLoS Genet. 2013 Oct; 9 (10): e1003934. doi: 10.1371/journal.pgen.1003934.
9. Furuyama K, Chera S, van Gurp L, Oropeza D, Ghila L, Damond N et al. Diabetes Relief in Mice by GlucoseSensing Insulin-Secreting Human α-Cells. Nature. 2019 Mar; 567 (7746): 43–48. doi: 10.1038/s41586-019-0942-8.
10. Thorel F, Népote V, Avril I, Kohno K, Desgraz R, Chera S, Herrera PL. Conversion of adult pancreatic alphacells to beta-cells after extreme beta-cell loss. Nature. 2010 Apr 22; 464 (7292): 1149–1154. doi: 10.1038/nature08894.
11. Remedi MS, Emfinger C. Pancreatic β-cell identity in diabetes. Diabetes Obes Metab. 2016 Sep; 18 Suppl 1 (Suppl 1): 110–116. doi: 10.1111/dom.12727.
12. Bonner-Weir S, Toschi E, Inada A, Reitz P, Fonseca SY, Aye T, Sharma A. The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes. 2004; 5 (Suppl 2): 16–22. doi: 10.1111/j.1399-543X.2004.00075.x.
13. Bonner-Weir S, Inada A, Yatoh S, Li WC, Aye T, Toschi E, Sharma A. Transdifferentiation of pancreatic ductal cells to endocrine beta-cells. Biochem Soc Trans. 2008 Jun; 36 (Pt 3): 353–356. doi: 10.1042/BST0360353.
14. Li W-C, Rukstalis JM, Nishimura W, Tchipashvili V, Habener JF, Sharma A, Bonner-Weir S. Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats. J Cell Sci. 2010 Aug 15; 123 (Pt 16): 2792–2802. doi: 10.1242/jcs.065268.
15. Bouwens L. Transdifferentiation versus stem cell hypothesis for the regeneration of islet beta-cells in the pancreas. Microsc Res Tech. 1998 Nov 15; 43 (4): 332–336. doi: 10.1002/(SICI)1097-0029(19981115)43:43.0.CO;2-1.
16. Kim HS, Lee MK. β-Cell regeneration through the transdifferentiation of pancreatic cells: Pancreatic progenitor cells in the pancreas. J Diabetes Investig. 2016 May; 7 (3): 286–296. doi: 10.1111/jdi.12475.
17. Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stange G et al. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat Biotechnol. 2014 Jan; 32 (1): 76–83. doi: 10.1038/nbt.2747.
18. Miyazaki S, Tashiro F, Miyazaki J. Transgenic Expression of a Single Transcription Factor Pdx1 Induces Transdifferentiation of Pancreatic Acinar Cells to Endocrine Cells in Adult Mice. PLoS One. 2016 Aug 15; 11 (8): e0161190. doi: 10.1371/journal.pone.0161190.
19. Baeyens L, De Breuck S, Lardon J, Mfopou JK, Rooman I, Bouwens L. In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells. Diabetologia. 2005 Jan; 48 (1): 49–57. doi: 10.1007/s00125-004-1606-1.
20. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008 Oct 2; 455 (7213): 627–632. doi: 10.1038/nature07314.
21. Docherty FM, Sussel L. Islet Regeneration: Endogenous and Exogenous Approaches. Int J Mol Sci. 2021 Mar 24; 22 (7): 3306. doi: 10.3390/ijms22073306.
22. Jörns A, Klempnauer J, Tiedge M, Lenzen S. Recovery of pancreatic beta cells in response to long-term normoglycemia after pancreas or islet transplantation in severely streptozotocin diabetic adult rats. Pancreas. 2001 Aug; 23 (2): 186–196. doi: 10.1097/00006676-200108000-00009.
23. Mikhailichenko VYu, Stolyarov SS. Effect tranplantation of pancreas islet cell cultures at alloxan diabetes at rats in experiment. International Journal of Applied and fundamental research. 2015; 9 (4): 670–672.
24. Jung HS, Ahn YR, Oh SH, Kim YS, No H, Lee MK, Kim KW. Enhancement of beta-cell regeneration by islet transplantation after partial pancreatectomy in mice. Transplantation. 2009 Aug 15; 88 (3): 354–359. doi: 10.1097/TP.0b013e3181b07a02.
25. Baranova NV, Ponomareva AS, Kirsanova LA, Nikolskaya AO, Bubentsova GN, Basok YuB, Sevastianov VI. Functional efficiency of pancreatic cell-engineered construct in an animal experimental model for type I diabetes. Russian Journal of Transplantology and Artificial Organs. 2024; 26 (2): 94–104. [In Russ, English abstract]. doi: 10.15825/1995-1191-2024-2-94-104.
26. Ponomareva AS, Kirsanova LA, Baranova NV, Surguchenko VA, Bubentsova GN, Basok YuB et al. Decellularization of donor pancreatic fragment to obtain a tissue-specific matrix scaffold. Russian Journal of Transplantology and Artificial Organs. 2020; 22 (1): 123–133. [In Russ, English abstract]. doi: 10.15825/1995-1191-2020-1-123-133.
27. Sevastianov VI, Basok YB. Biomimetics of Extracellular Matrices for Cell and Tissue Engineered Medical Products. Newcastle upon Tyne, UK: Cambridge Scholars Publishing, 2023; 339.
28. Sevastianov VI, Ponomareva AS, Baranova NV, Kirsanova LA, Basok YuB, Nemets EA et al. Decellularization of Human Pancreatic Fragments with Pronounced Signs of Structural Changes. Int J Mol Sci. 2023 Dec 21; 24 (1): 119. doi: 10.3390/ijms24010119.
29. Sevastianov VI, Ponomareva AS, Baranova NV, Belova AD, Kirsanova LA, Nikolskaya AO et al. A Tissue-Engineered Construct Based on a Decellularized Scaffold and the Islets of Langerhans: A Streptozotocin-Induced Diabetic Model. Life (Basel). 2024 Nov 19; 14 (11): 1505. doi: 10.3390/life14111505.
30. Sanchez A, Lawzewitsch J. Histological study of endocrine pancreas: cell differentiation process in Langerhans islets of bovine fetus and adult bovines. Commun Biol. 1985; 5 (3): 345–365.
31. Riadinskaia NI, Siraziev RZ. [Histological and histochemical characteristics of pancreas of deer at the Altay]. Tsitologiia. 2008; 50 (8): 719–724. [In Russ]. PMID: 18822792.
32. Kirsanova LA, Bliumkin VN. [Some characteristics of the histological structure of the fetal bovine pancreas]. Biull Eksp Biol Med. 1990 Sep; 110 (9): 330–332. [In Russ]. PMID: 2268733.
33. Skaletskaya GN, Skaletskiy NN, Kirsanova LA, Bubentsova GN, Volkova EA, Sevastyanov VI. Experimental implantation of tissue-engineering pancreatic construct. Russian Journal of Transplantology and Artificial Organs. 2019; 21 (2): 104–111. [In Russ, English abstract]. doi: 10.15825/1995-1191-2019-2-104-111.
Review
For citations:
Baranova N.V., Kirsanova L.A., Bubentsova G.N., Ponomareva A.S., Nikolskaya A.O., Basok Yu.B., Sevastianov V.I. Impact of pancreatic cell-engineered constructs on the islet apparatus in recipient rats with type I diabetes mellitus. Russian Journal of Transplantology and Artificial Organs. 2025;27(2):139-147. (In Russ.) https://doi.org/10.15825/1995-1191-2025-2-139-147