Samsung Advanced Institute for Health Science and Technology,SungKyunKwan University. Transplantation Research Center, Samsung Medical Center, Seoul, Korea
Enhanced effect of shTNFRI and hHO-1 gene expressing hMSC on porcine islet transplantation in humanized mice
Du Yeon Shin1,2, Han Sin Lee1, Geun Soo Kim1, Hwajung Kim1, Kyo Won Lee1,3, Hyojun Park1,3, Jae Berm Park1,3, Jaeseok Yang4,5, Curie Anh4,5,6, Sung Joo Kim1,3.
1Transplantation Research Center, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; 2Department of Health Sciences & Technology, Samsung Advanced Institute for Health Sciences & Technology, Graduate School,Sungkyunkwan University, Seoul, Korea; 3Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Transplantation Research Institute, Seoul National University, Seoul, Korea; 5Transplantation Center, Seoul National University Hospital, Seoul, Korea; 6Division of Nephrology, Seoul National University College of Medicine, Seoul, Korea
Background: Porcine islet xeno-transplantation is considered an attractive alternative treatment for Type 1 diabetes mellitus. However it is largely limited by Initial rejection such as IBMIR, oxidative stress and inflammatory response. Recently some factors, heme oxygenase(HO)-1 and short hairpin-tumor necrosis factor receptor I (shTNFRI), are known to improve viability and functionality of islet after transplantation. In this study, we evaluate the effect of porcine islet transplantation with genetically modified human mesenchymal stem cell expressing shTNFRI and HO-1 (hMSC-shTNFRI-hHO1) by use of adenoviral system in humanized mice.
Materials and methods: Humanized mice (NSG background) were constructed with umbilical cord blood (UCB)-derived CD34+ cells and porcine islets (PWG miniature Pig) were freshly isolated by modified Ricordi's methods. Also shTNFRI and HO-1 gene expressing hMSCs were constructed using adenoviral system. Gene expression level, porcine islet viability and function were confirmed by in-vitro test such as GSIS, AO/PI, ADP/ATP ratio. Subsequently, isolated porcine islets (5000 IEQ) were transplanted underneath the kidney capsule of streptozotocin-induced diabetic humanized mice with or without shTNFRI and HO-1 gene expressing human MSCs (each of 6) and porcine islet only (n=3). After transplantation, we have measured Blood glucose levels and performed intraperitoneal glucose tolerance tests. Graft morphology and function were evaluated by immunohistochemistry.
Results: At 6weeks post-transplantation, six of 6 in co-transplantation with ShTNFRI and HO-1 gene expressing hMSCs maintained, 2 of 6 in co-transplantation with hMSC, and none of 3 in porcine islet only. The mean blood glucose levels of shTNFRI and HO-1 gene expressing MSCs co-transplanted group are low throughout the monitoring period. Moreover the result of Intra-peritoneal glucose tolerance test (IPGTT) was showed that shTNFRI and HO-1 expressing hMSCs co-transplanted group was significantly faster re-cruit normal glycaemia than in other groups. In IHC At 6weeks post-transplantation, porcine islet under kidney capsule was well preserved in co-transplantation group with shTNFRI and HO-1 gene expressing hMSCs.
Conclusions: shTNFRI and HO-1 gene expressing hMSCs enhance co-transplanted porcine islet survival and the capacity of islets to reverse hyperglycaemia in humanized mice.
17:30 - 18:30
|Joint Poster Session||Anti-thymocyte globulin (ATG)-induced T-cell depletion in cynomolgus monkey - For the ATG use in non-human primate organ transplant model||Main Foyer 1 & 2|
11:00 - 12:30
|Alternative Sources of Beta Cells: Xenoislet, Stem Cells, Tissue Engineering||Enhanced effect of shTNFRI and hHO-1 gene expressing hMSC on porcine islet transplantation in humanized mice||Room 110|
17:30 - 18:30
|Joint Poster Session||Partial Pancreatectomy Induces Beta Cell Regeneration in Cynomolgus Monkey||Main Foyer 1 & 2|