Subcutaneous Transplantation of Engineered Islet/adipose-derived Mesenchymal Stem Cell Sheets in Diabetic Pigs with Total Pancreatectomy

Overview

Journal Regen Ther

Date 2021 Feb 1

PMID 33521172

Citations 7

Authors

Mampei Yamashita

Toshiyuki Adachi

Tomohiko Adachi

Shinichiro Ono

Naomi Matsumura

Kyoichiro Maekawa

Yusuke Sakai

Masaaki Hidaka

Kengo Kanetaka

Tamotsu Kuroki

Susumu Eguchi

Affiliations

Soon will be listed here.

Abstract

Introduction: Intraportal islet transplantation is a promising therapeutic approach for patients with type 1 diabetes mellitus (T1DM). However, despite being minimally invasive, the method has some limitations, such as short-term graft loss, portal venous thrombosis, and difficulty in collecting adequate amounts of islets. Subcutaneous islet transplantation on adipose-derived mesenchymal stem cell (ADSC) sheets has been suggested to overcome these limitations, and in this study, we have examined its feasibility in T1DM pigs.

Methods: Inguinal subcutaneous fat was harvested from young pigs and then isolated and cultured adequate ADSCs to prepare sheets. Islets were isolated from the pancreases of mature pigs and seeded on the ADSC sheets. T1DM pigs were generated by total pancreatectomy, and ADSC sheets with transplanted islets were administered subcutaneously to the waist ( = 2). The effects of the islets on the ADSC sheets and on blood glucose levels were evaluated. Insulin secretion was measured by insulin stimulation index.

Results: Islet viability was higher on ADSCs compared to islets alone (91.8 ± 4.3 vs. 81.7 ± 4.1%). The insulin stimulation index revealed higher glucose sensitivity of islets on ADSC sheets compared to islets alone (2.8 ± 2.0 vs. 0.8 ± 0.3). After transplantation, the blood glucose levels of two pigs were within the normal range, and sensitive insulin secretion was confirmed by intravenous glucose tolerance tests. After graftectomy, decreased insulin secretion and hyperglycemia were observed.

Conclusions: Subcutaneous islet transplantation using ADSC sheets can regulate the blood glucose levels of T1DM pigs.

Citing Articles

Strategy for Clinical Setting of Co-transplantation of Mesenchymal Stem Cells and Pancreatic Islets.

Mei L, Yuwei Y, Weiping L, Zhiran X, Bingzheng F, Jibing C Cell Transplant. 2024; 33:9636897241259433.

PMID: 38877672 PMC: 11179456. DOI: 10.1177/09636897241259433.

A first-in-human clinical study of laparoscopic autologous myoblast sheet transplantation to prevent delayed perforation after duodenal endoscopic mucosal dissection.

Kanetaka K, Maruya Y, Higashi M, Yamaguchi S, Matsumoto R, Kobayashi S Stem Cell Res Ther. 2024; 15(1):117.

PMID: 38654373 PMC: 11040870. DOI: 10.1186/s13287-024-03730-3.

A Gelatin Hydrogel Nonwoven Fabric Enhances Subcutaneous Islet Engraftment in Rats.

Saito R, Inagaki A, Nakamura Y, Imura T, Kanai N, Mitsugashira H Cells. 2024; 13(1).

PMID: 38201255 PMC: 10777905. DOI: 10.3390/cells13010051.

Preclinical models for Type 1 Diabetes Mellitus - A practical approach for research.

Peng X, Rao G, Li X, Tong N, Tian Y, Fu X Int J Med Sci. 2023; 20(12):1644-1661.

PMID: 37859703 PMC: 10583179. DOI: 10.7150/ijms.86566.

No Time to Die-How Islets Meet Their Demise in Transplantation.

Kale A, Rogers N Cells. 2023; 12(5).

PMID: 36899932 PMC: 10000424. DOI: 10.3390/cells12050796.

References

Wild S, Roglic G, Green A, Sicree R, King H . Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004; 27(5):1047-53. DOI: 10.2337/diacare.27.5.1047. View

Cao Y, Sun Z, Liao L, Meng Y, Han Q, Zhao R . Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun. 2005; 332(2):370-9. DOI: 10.1016/j.bbrc.2005.04.135. View

Planat-Benard V, Silvestre J, Cousin B, Andre M, Nibbelink M, Tamarat R . Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation. 2004; 109(5):656-63. DOI: 10.1161/01.CIR.0000114522.38265.61. View

Wise M, Gordon C, Johnson R . Intraportal autotransplantation of cryopreserved porcine islets of Langerhans. Cryobiology. 1985; 22(4):359-66. DOI: 10.1016/0011-2240(85)90183-x. View

Coppola A, Tomasello L, Pitrone M, Cillino S, Richiusa P, Pizzolanti G . Human limbal fibroblast-like stem cells induce immune-tolerance in autoreactive T lymphocytes from female patients with Hashimoto's thyroiditis. Stem Cell Res Ther. 2017; 8(1):154. PMC: 5496215. DOI: 10.1186/s13287-017-0611-5. View

Kobayashi K, Kobayashi N, Okitsu T, Yong C, Fukazawa T, Ikeda H . Development of a porcine model of type 1 diabetes by total pancreatectomy and establishment of a glucose tolerance evaluation method. Artif Organs. 2004; 28(11):1035-42. DOI: 10.1111/j.1525-1594.2004.00002.x. View

Ricordi C, Lacy P, FINKE E, Olack B, Scharp D . Automated method for isolation of human pancreatic islets. Diabetes. 1988; 37(4):413-20. DOI: 10.2337/diab.37.4.413. View

Kawamura M, Miyagawa S, Fukushima S, Saito A, Miki K, Ito E . Enhanced survival of transplanted human induced pluripotent stem cell-derived cardiomyocytes by the combination of cell sheets with the pedicled omental flap technique in a porcine heart. Circulation. 2013; 128(11 Suppl 1):S87-94. DOI: 10.1161/CIRCULATIONAHA.112.000366. View

Shapiro E, Tillil H, Miller M, Frank B, GALLOWAY J, Rubenstein A . Insulin secretion and clearance. Comparison after oral and intravenous glucose. Diabetes. 1987; 36(12):1365-71. DOI: 10.2337/diab.36.12.1365. View

10.

Yin Z, Wang S, Li Q, Huang Y, Chen L, Chen G . Gastric submucosa is inferior to the liver as transplant site for autologous islet transplantation in pancreatectomized diabetic Beagles. J Huazhong Univ Sci Technolog Med Sci. 2016; 36(4):529-533. DOI: 10.1007/s11596-016-1620-9. View

11.

Schwarze M, Houser S, Muniappan A, Allan J, Menard M, McMorrow I . Effects of mycophenolate mofetil on cardiac allograft survival and cardiac allograft vasculopathy in miniature swine. Ann Thorac Surg. 2005; 80(5):1787-93. DOI: 10.1016/j.athoracsur.2005.04.054. View

12.

Bruni A, Gala-Lopez B, Pepper A, Abualhassan N, Shapiro A . Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges. Diabetes Metab Syndr Obes. 2014; 7:211-23. PMC: 4075233. DOI: 10.2147/DMSO.S50789. View

13.

Pileggi A, Molano R, Berney T, Cattan P, Vizzardelli C, Oliver R . Heme oxygenase-1 induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation. Diabetes. 2001; 50(9):1983-91. DOI: 10.2337/diabetes.50.9.1983. View

14.

Kanak M, Takita M, Kunnathodi F, Lawrence M, Levy M, Naziruddin B . Inflammatory response in islet transplantation. Int J Endocrinol. 2014; 2014:451035. PMC: 4021753. DOI: 10.1155/2014/451035. View

15.

Choi S, Choi K, Yoon I, Shin J, Kim J, Park W . IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced cell death and functional impairment in vitro and in vivo. Transpl Immunol. 2004; 13(1):43-53. DOI: 10.1016/j.trim.2004.04.001. View

16.

Alessiani M, Spada M, Dionigi P, Arbustini E, Regazzi M, Fossati G . Combined immunosuppressive therapy with tacrolimus and mycophenolate mofetil for small bowel transplantation in pigs. Transplantation. 1996; 62(5):563-7. DOI: 10.1097/00007890-199609150-00004. View

17.

Ryan E, Lakey J, Rajotte R, Korbutt G, Kin T, Imes S . Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes. 2001; 50(4):710-9. DOI: 10.2337/diabetes.50.4.710. View

18.

Movahedi B, Gysemans C, Jacobs-Tulleneers-Thevissen D, Mathieu C, Pipeleers D . Pancreatic duct cells in human islet cell preparations are a source of angiogenic cytokines interleukin-8 and vascular endothelial growth factor. Diabetes. 2008; 57(8):2128-36. PMC: 2494672. DOI: 10.2337/db07-1705. View

19.

Plesner A, Liston P, Tan R, Korneluk R, Verchere C . The X-linked inhibitor of apoptosis protein enhances survival of murine islet allografts. Diabetes. 2005; 54(9):2533-40. DOI: 10.2337/diabetes.54.9.2533. View

20.

Imamura H, Adachi T, Kin T, Ono S, Sakai Y, Adachi T . An engineered cell sheet composed of human islets and human fibroblast, bone marrow-derived mesenchymal stem cells, or adipose-derived mesenchymal stem cells: An in vitro comparison study. Islets. 2018; 10(3):e1445948. PMC: 5989879. DOI: 10.1080/19382014.2018.1445948. View