A new scaffold containing small intestinal submucosa and mesenchymal stem cells improves pancreatic islet function and survival in vitro and in vivo

Wang,Dan; Ding,Xiaoming; Xue,Wujun; Zheng,Jin; Tian,Xiaohui; Li,Yang; Wang,Xiaohong; Song,Huanjin; Liu,Hua; Luo,Xiaohui

doi:10.3892/ijmm.2016.2814

A new scaffold containing small intestinal submucosa and mesenchymal stem cells improves pancreatic islet function and survival in vitro and in vivo

Authors:
- Dan Wang
- Xiaoming Ding
- Wujun Xue
- Jin Zheng
- Xiaohui Tian
- Yang Li
- Xiaohong Wang
- Huanjin Song
- Hua Liu
- Xiaohui Luo
View Affiliations

Affiliations: Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: November 29, 2016 https://doi.org/10.3892/ijmm.2016.2814
Pages: 167-173
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

It is unknown whether a scaffold containing both small intestinal submucosa (SIS) and mesenchymal stem cells (MSCs) for transplantation may improve pancreatic islet function and survival. In this study, we examined the effects of a SIS-MSC scaffold on islet function and survival in vitro and in vivo. MSCs and pancreatic islets were isolated from Sprague-Dawley rats, and SIS was isolated from Bamei pigs. The islets were apportioned among 3 experimental groups as follows: SIS-islets, SIS-MSC-islets and control-islets. In vitro, islet function was measured by a glucose-stimulated insulin secretion test; cytokines in cultured supernatants were assessed by enzyme-linked immunosorbent assay; and gene expression was analyzed by reverse transcription-quantitative PCR. In vivo, islet transplantation was performed in rats, and graft function and survival were monitored by measuring the blood glucose levels. In vitro, the SIS-MSC scaffold was associated with improved islet viability and enhanced insulin secretion compared with the controls, as well as with the increased the expression of insulin 1 (Ins1), pancreatic and duodenal homeobox 1 (Pdx1), platelet endothelial cell adhesion molecule 1 [Pecam1; also known as cluster of differentiation 31 (CD31)] and vascular endothelial growth factor A (Vegfa) in the islets, increased growth factor secretion, and decreased tumor necrosis factor (TNF) secretion. In vivo, the SIS-MSC scaffold was associated with improved islet function and graft survival compared with the SIS and control groups. On the whole, our findings demonstrate that the SIS-MSC scaffold significantly improved pancreatic islet function and survival in vitro and in vivo. This improvement may be associated with the upregulation of insulin expression, the improvement of islet microcirculation and the secretion of cytokines.

View Figures

View References

1	Shi Y and Hu FB: The global implications of diabetes and cancer. Lancet. 383:1947–1948. 2014. View Article : Google Scholar : PubMed/NCBI
2	Inverardi L, Kenyon NS and Ricordi C: Islet transplantation: Immunological perspectives. Curr Opin Immunol. 15:507–511. 2003. View Article : Google Scholar : PubMed/NCBI
3	Olabisi RM: Cell microencapsulation with synthetic polymers. J Biomed Mater Res A. 103:846–859. 2015. View Article : Google Scholar :
4	Shim JB, Ankeny RF, Kim H, Nerem RM and Khang G: A study of a three-dimensional PLGA sponge containing natural polymers co-cultured with endothelial and mesenchymal stem cells as a tissue engineering scaffold. Biomed Mater. 9:0450152014. View Article : Google Scholar : PubMed/NCBI
5	O'Sullivan ES, Vegas A, Anderson DG and Weir GC: Islets transplanted in immunoisolation devices: A review of the progress and the challenges that remain. Endocr Rev. 32:827–844. 2011. View Article : Google Scholar : PubMed/NCBI
6	Su J, Hu BH, Lowe WL Jr, Kaufman DB and Messersmith PB: Anti-inflammatory peptide-functionalized hydrogels for insulin-secreting cell encapsulation. Biomaterials. 31:308–314. 2010. View Article : Google Scholar
7	Calafiore R, Basta G, Luca G, Boselli C, Bufalari A, Giustozzi GM, Moggi L and Brunetti P: Alginate/polyaminoacidic coherent microcapsules for pancreatic islet graft immunoisolation in diabetic recipients. Ann NY Acad Sci. 831:313–322. 1997. View Article : Google Scholar
8	Qi M, Gu Y, Sakata N, Kim D, Shirouzu Y, Yamamoto C, Hiura A, Sumi S and Inoue K: PVA hydrogel sheet macroencapsulation for the bioartificial pancreas. Biomaterials. 25:5885–5892. 2004. View Article : Google Scholar : PubMed/NCBI
9	Lamb M, Storrs R, Li S, Liang O, Laugenour K, Dorian R, Chapman D, Ichii H, Imagawa D, Foster C III, et al: Function and viability of human islets encapsulated in alginate sheets: In vitro and in vivo culture. Transplant Proc. 43:3265–3266. 2011. View Article : Google Scholar : PubMed/NCBI
10	Davis NE, Beenken-Rothkopf LN, Mirsoian A, Kojic N, Kaplan DL, Barron AE and Fontaine MJ: Enhanced function of pancreatic islets co-encapsulated with ECM proteins and mesenchymal stromal cells in a silk hydrogel. Biomaterials. 33:6691–6697. 2012. View Article : Google Scholar : PubMed/NCBI
11	Qureshi KM, Lee J, Paget MB, Bailey CJ, Curnow SJ, Murray HE and Downing R: Low gravity rotational culture and the integration of immunomodulatory stem cells reduce human islet allo-reactivity. Clin Transplant. 29:90–98. 2015. View Article : Google Scholar
12	McPherson TB and Badylak SF: Characterization of fibronectin derived from porcine small intestinal submucosa. Tissue Eng. 4:75–83. 1998. View Article : Google Scholar
13	Prevel CD, Eppley BL, Summerlin DJ, Sidner R, Jackson JR, McCarty M and Badylak SF: Small intestinal submucosa: Utilization as a wound dressing in full-thickness rodent wounds. Ann Plast Surg. 35:381–388. 1995. View Article : Google Scholar : PubMed/NCBI
14	D'Eredità R: Porcine small intestinal submucosa (SIS) myringoplasty in children: A randomized controlled study. Int J Pediatr Otorhinolaryngol. 79:1085–1089. 2015. View Article : Google Scholar : PubMed/NCBI
15	Ferrand BK, Kokini K, Badylak SF, Geddes LA, Hiles MC and Morff RJ: Directional porosity of porcine small-intestinal submucosa. J Biomed Mater Res. 27:1235–1241. 1993. View Article : Google Scholar : PubMed/NCBI
16	Badylak S, Liang A, Record R, Tullius R and Hodde J: Endothelial cell adherence to small intestinal submucosa: An acellular bioscaffold. Biomaterials. 20:2257–2263. 1999. View Article : Google Scholar : PubMed/NCBI
17	Woods EJ, Walsh CM, Sidner RA, Zieger MA, Mullin S, Lakey JR, Ricordi C and Critser JK: Enhanced recovery of cryopreserved islets using SIS. Transplant Proc. 36:1139–1142. 2004. View Article : Google Scholar : PubMed/NCBI
18	Xiaohui T, Wujun X, Xiaoming D, Xinlu P, Yan T, Puxun T and Xinshun F: Small intestinal submucosa improves islet survival and function in vitro culture. Transplant Proc. 38:1552–1558. 2006. View Article : Google Scholar : PubMed/NCBI
19	Lakey JRT, Troendle J, Zieger MAJ, Geary WA, Voytek S and Critser JK: Improved islet survival and in vitro function using small intestinal submucosa. Transplant Proc. 30:383. 1998. View Article : Google Scholar : PubMed/NCBI
20	Zaher W, Harkness L, Jafari A and Kassem M: An update of human mesenchymal stem cell biology and their clinical uses. Arch Toxicol. 88:1069–1082. 2014. View Article : Google Scholar : PubMed/NCBI
21	Secunda R, Vennila R, Mohanashankar AM, Rajasundari M, Jeswanth S and Surendran R: Isolation, expansion and characterisation of mesenchymal stem cells from human bone marrow, adipose tissue, umbilical cord blood and matrix: A comparative study. Cytotechnology. 67:793–807. 2015. View Article : Google Scholar :
22	Nagamura-Inoue T and Mukai T: Umbilical cord is a rich source of mesenchymal stromal cells for cell therapy. Curr Stem Cell Res Ther. Oct 26–2015.Epub ahead of print. PubMed/NCBI
23	Ding Y, Xu D, Feng G, Bushell A, Muschel RJ and Wood KJ: Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metal-loproteinase-2 and -9. Diabetes. 58:1797–1806. 2009. View Article : Google Scholar : PubMed/NCBI
24	Itakura S, Asari S, Rawson J, Ito T, Todorov I, Liu CP, Sasaki N, Kandeel F and Mullen Y: Mesenchymal stem cells facilitate the induction of mixed hematopoietic chimerism and islet allograft tolerance without GVHD in the rat. Am J Transplant. 7:336–346. 2007. View Article : Google Scholar : PubMed/NCBI
25	Shin JY, Jeong JH, Han J, Bhang SH, Jeong GJ, Haque MR, Al-Hilal TA, Noh M, Byun Y and Kim BS: Transplantation of heterospheroids of islet cells and mesenchymal stem cells for effective angiogenesis and antiapoptosis. Tissue Eng Part A. 21:1024–1035. 2015. View Article : Google Scholar :
26	Yoshimatsu G, Sakata N, Tsuchiya H, Minowa T, Takemura T, Morita H, Hata T, Fukase M, Aoki T, Ishida M, et al: The co-transplantation of bone marrow derived mesenchymal stem cells reduced inflammation in intramuscular islet transplantation. PLoS One. 10:e01175612015. View Article : Google Scholar : PubMed/NCBI
27	Borg DJ, Weigelt M, Wilhelm C, Gerlach M, Bickle M, Speier S, Bonifacio E and Hommel A: Mesenchymal stromal cells improve transplanted islet survival and islet function in a syngeneic mouse model. Diabetologia. 57:522–531. 2014. View Article : Google Scholar
28	Gao X, Song L, Shen K, Wang H, Qian M, Niu W and Qin X: Bone marrow mesenchymal stem cells promote the repair of islets from diabetic mice through paracrine actions. Mol Cell Endocrinol. 388:41–50. 2014. View Article : Google Scholar : PubMed/NCBI
29	Badylak SF, Lantz GC, Coffey A and Geddes LA: Small intestinal submucosa as a large diameter vascular graft in the dog. J Surg Res. 47:74–80. 1989. View Article : Google Scholar : PubMed/NCBI
30	Rackham CL, Chagastelles PC, Nardi NB, Hauge-Evans AC, Jones PM and King AJ: Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice. Diabetologia. 54:1127–1135. 2011. View Article : Google Scholar : PubMed/NCBI
31	Li W, Zhao R, Liu J, Tian M, Lu Y, He T, Cheng M, Liang K, Li X, Wang X, et al: Small islets transplantation superiority to large ones: Implications from islet microcirculation and revascularization. J Diabetes Res. 2014:1920932014. View Article : Google Scholar : PubMed/NCBI
32	Carlsson PO, Schwarcz E, Korsgren O and Le Blanc K: Preserved β-cell function in type 1 diabetes by mesenchymal stromal cells. Diabetes. 64:587–592. 2015. View Article : Google Scholar
33	Franchi F, Peterson KM, Xu R, Miller B, Psaltis PJ, Harris PC, Lerman LO and Rodriguez-Porcel M: Mesenchymal Stromal Cells Improve Renovascular Function in Polycystic Kidney Disease. Cell Transplant. 24:1687–1698. 2015. View Article : Google Scholar :
34	Sumi S and Yanai G: Fusion of mesenchymal stem cells and islet cells for cell therapy. Methods Mol Biol. 1313:107–113. 2015. View Article : Google Scholar : PubMed/NCBI
35	Rackham CL, Vargas AE, Hawkes RG, Amisten S, Persaud SJ, Austin ALF, King AJF and Jones PM: Annexin A1 is a key modulator of Mesenchymal Stromal Cell mediated improvements in islet function. Diabetes. 65:129–139. 2016.
36	Costa RG, Lontra MB, Scalco P, Cavazzola LT and Gurski RR: Polylactic acid film versus acellular porcine small intestinal submucosa mesh in peritoneal adhesion formation in rats. Acta Cir Bras. 24:128–135. 2009. View Article : Google Scholar : PubMed/NCBI
37	Schaschkow A, Mura C, Bietiger W, Peronet C, Langlois A, Bodin F, Dissaux C, Bruant-Rodier C, Pinget M, Jeandidier N, et al: Impact of an autologous oxygenating matrix culture system on rat islet transplantation outcome. Biomaterials. 52:180–188. 2015. View Article : Google Scholar : PubMed/NCBI
38	Lin P, Li W, Yao Z, Sun Y, Wang L, Li S and Chen L: Oral administration of PDX1 confers protection against insulitis in the non-obese diabetic (NOD) mice. Biochem Biophys Res Commun. 466:656–663. 2015. View Article : Google Scholar : PubMed/NCBI
39	Yuan H, Liu H, Tian R, Li J and Zhao Z: Regulation of mesenchymal stem cell differentiation and insulin secretion by differential expression of Pdx-1. Mol Biol Rep. 39:7777–7783. 2012. View Article : Google Scholar : PubMed/NCBI
40	Boumaza I, Srinivasan S, Witt WT, Feghali-Bostwick C, Dai Y, Garcia-Ocana A and Feili-Hariri M: Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia. J Autoimmun. 32:33–42. 2009. View Article : Google Scholar
41	Zanone MM, Favaro E and Camussi G: From endothelial to beta cells: Insights into pancreatic islet microendothelium. Curr Diabetes Rev. 4:1–9. 2008. View Article : Google Scholar : PubMed/NCBI
42	Lai M, Cai K, Hu Y, Zhang Y, Li L, Luo Z, Hou Y, Li J, Ding X and Chen X: Construction of microenvironment onto titanium substrates to regulate the osteoblastic differentiation of bone marrow stromal cells in vitro and osteogenesis in vivo. J Biomed Mater Res A. 101:653–666. 2013. View Article : Google Scholar
43	SoRelle JA, Itoh T, Peng H, Kanak MA, Sugimoto K, Matsumoto S, Levy MF, Lawrence MC and Naziruddin B: Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation. Diabetologia. 56:814–824. 2013. View Article : Google Scholar : PubMed/NCBI