RT Journal Article
SR Electronic
T1 Highly Angiogenic, Nonthrombogenic Bone Marrow Mononuclear Cell–Derived Spheroids in Intraportal Islet Transplantation
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 473
OP 485
DO 10.2337/db17-0705
VO 67
IS 3
A1 Oh, Bae Jun
A1 Jin, Sang-Man
A1 Hwang, Yoonha
A1 Choi, Jin Myung
A1 Lee, Han-Sin
A1 Kim, Gyuri
A1 Kim, Geunsoo
A1 Park, Hyo Jun
A1 Kim, Pilhan
A1 Kim, Sung Joo
A1 Kim, Jae Hyeon
YR 2018
UL http://diabetes.diabetesjournals.org/content/67/3/473.abstract
AB Highly angiogenic bone marrow mononuclear cell–derived spheroids (BM-spheroids), formed by selective proliferation of the CD31+CD14+CD34+ monocyte subset via three-dimensional (3D) culture, have had robust angiogenetic capacity in rodent syngeneic renal subcapsular islet transplantation. We wondered whether the efficacy of BM-spheroids could be demonstrated in clinically relevant intraportal islet transplantation models without increasing the risk of portal thrombosis. The thrombogenic potential of intraportally infused BM-spheroids was compared with that of mesenchymal stem cells (MSCs) and MSC-derived spheroids (MSC-spheroids). The angiogenic efficacy and persistence in portal sinusoids of BM-spheroids were examined in rodent syngeneic and primate allogeneic intraportal islet transplantation models. In contrast to MSCs and MSC-spheroids, intraportal infusion of BM-spheroids did not evoke portal thrombosis. BM-spheroids had robust angiogenetic capacity in both the rodent and primate intraportal islet transplantation models and improved posttransplant glycemic outcomes. MRI and intravital microscopy findings revealed the persistence of intraportally infused BM-spheroids in portal sinusoids. Intraportal cotransplantation of allogeneic islets with autologous BM-spheroids in nonhuman primates further confirmed the clinical feasibility of this approach. In conclusion, cotransplantation of BM-spheroids enhances intraportal islet transplantation outcome without portal thrombosis in mice and nonhuman primates. Generating BM-spheroids by 3D culture prevented the rapid migration and disappearance of intraportally infused therapeutic cells.