Human beta-cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies.
BACKGROUND
Islet transplantation is limited by the need for chronic immunosuppression and the paucity of donor tissue. As new sources of human beta-cells are developed (e.g., stem cell-derived tissue), transplanting them in a durable device could obviate the need for immunosuppression, while also protecting the patient from any risk of tumorigenicity. Here, we studied (1) the survival and function of encapsulated human beta-cells and their progenitors and (2) the engraftment of encapsulated murine beta-cells in allo- and autoimmune settings.


METHODS
Human islets and human fetal pancreatic islet-like cell clusters were encapsulated in polytetrafluorethylene devices (TheraCyte) and transplanted into immunodeficient mice. Graft survival and function was measured by immunohistochemistry, circulating human C-peptide levels, and blood glucose levels. Bioluminescent imaging was used to monitor encapsulated neonatal murine islets.


RESULTS
Encapsulated human islet-like cell clusters survived, replicated, and acquired a level of glucose responsive insulin secretion sufficient to ameliorate hyperglycemia in diabetic mice. Bioluminescent imaging of encapsulated murine neonatal islets revealed a dynamic process of cell death followed by regrowth, resulting in robust long-term allograft survival. Further, in the non-obese diabetic (NOD) mouse model of type I diabetes, encapsulated primary beta-cells ameliorated diabetes without stimulating a detectable T-cell response.


CONCLUSIONS
We demonstrate for the first time that human beta-cells function is compatible with encapsulation in a durable, immunoprotective device. Moreover, our study suggests that encapsulation of beta-cells before terminal differentiation will be a successful approach for new cell-based therapies for diabetes, such as those derived from stem cells.
Development and Aging Program, Burnham Institute for Medical Research, La Jolla, CA, USA.
Seung-Hee
SH
Lee
Ergeng
E
Hao
Alexei Y
AY
Savinov
Ifat
I
Geron
Alex Y
AY
Strongin
Pamela
P
Itkin-Ansari
D000818:Animals; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D005622:Friend murine leukemia virus / Q000235:genetics; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology / Q000502:physiology* / Q000637:transplantation*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D014183:Transplantation, Heterologous
D007328:Insulin; D008156:Luciferases; D005947:Glucose