Engraftment and reversal of diabetes after intramuscular transplantation of neonatal porcine islet-like clusters.
BACKGROUND
Intraportal infusion is currently the method of choice for clinical islet cell transplantation but suffers from poor efficacy. As the liver may not represent an optimal transplantation site for Langerhans islets, we examined the potential of neonatal porcine islet-like clusters (NPICCs) to engraft in skeletal muscle as an alternative transplantation site.


METHODS
Neonatal porcine islet-like clusters were isolated from 2- to 5-day-old piglets and either transplanted under the kidney capsule (s.k.) or injected into the lower hindlimb muscle (i.m.) of streptozotocin-diabetic NOD-SCID IL2rγ(-/-) (NSG) mice. Survival, vascularization, maturation, and functional activity were analyzed by intraperitoneal glucose tolerance testing and immunohistochemical analyses.


RESULTS
Intramuscular transplantation of NPICCs resulted in development of normoglycemia and restored glucose homeostasis. Time to reversal of diabetes and glucose tolerance (AUC glucose and AUC insulin) did not significantly differ as compared to s.k. transplantation. Intramuscular grafts exhibited rapid neovascularization and graft composition with cytokeratin-positive ductal cells and beta cells at post-transplant weeks 2 and 8 and after establishment of normoglycemia was comparable in both groups.


CONCLUSIONS
Intramuscular injection represents a minimally invasive but efficient alternative for transplantation of NPICCs and, thus, offers an attractive alternative site for xenotransplantation approaches. These findings may have important implications for improving the outcome and the monitoring of pig islet xenotransplantation.
Medizinische Klinik und Poliklinik IV-Campus Innenstadt, Diabetes Zentrum, Klinikum der Ludwig-Maximilians-Universität, München, Germany.|Transregio Collaborative Research Center 127, Ludwig-Maximilians-Universität, München, Germany.
Lelia
L
Wolf-van Buerck
Medizinische Klinik und Poliklinik IV-Campus Innenstadt, Diabetes Zentrum, Klinikum der Ludwig-Maximilians-Universität, München, Germany.|Transregio Collaborative Research Center 127, Ludwig-Maximilians-Universität, München, Germany.
Marion
M
Schuster
Transregio Collaborative Research Center 127, Ludwig-Maximilians-Universität, München, Germany.|Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität, München, Germany.
Andrea
A
Baehr
Transregio Collaborative Research Center 127, Ludwig-Maximilians-Universität, München, Germany.|Department of Cardiac Surgery, Ludwig-Maximilians-Universität, München, Germany.
Tanja
T
Mayr
Transregio Collaborative Research Center 127, Ludwig-Maximilians-Universität, München, Germany.|Department of Cardiac Surgery, Ludwig-Maximilians-Universität, München, Germany.
Sonja
S
Guethoff
Transregio Collaborative Research Center 127, Ludwig-Maximilians-Universität, München, Germany.|Department of Anesthesiology, Ludwig-Maximilians-Universität, München, Germany.
Jan
J
Abicht
Transregio Collaborative Research Center 127, Ludwig-Maximilians-Universität, München, Germany.
Bruno
B
Reichart
Institute of Pathology, Ludwig-Maximilians-Universität, München, Germany.
Yun-Chung
YC
Nam-Apostolopoulos
Transregio Collaborative Research Center 127, Ludwig-Maximilians-Universität, München, Germany.|Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität, München, Germany.
Nikolai
N
Klymiuk
Transregio Collaborative Research Center 127, Ludwig-Maximilians-Universität, München, Germany.|Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität, München, Germany.
Eckhard
E
Wolf
Medizinische Klinik und Poliklinik IV-Campus Innenstadt, Diabetes Zentrum, Klinikum der Ludwig-Maximilians-Universität, München, Germany.|Transregio Collaborative Research Center 127, Ludwig-Maximilians-Universität, München, Germany.
Jochen
J
Seissler
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D005951:Glucose Tolerance Test / Q000379:methods; D006085:Graft Survival / Q000502:physiology*; D007328:Insulin / Q000097:blood*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology*; D016381:Islets of Langerhans Transplantation / Q000379:methods; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013552:Swine; D013997:Time Factors
D001786:Blood Glucose; D007328:Insulin
intramuscular transplantation; islet xenotransplantation; neonatal porcine islets