Abstract
BackgroundInsulin-producing cell clusters (IPCCs) have recently been generated in vitro from adipose tissue-derived stem cells (ASCs) to circumvent islet shortage. However, it is unknown how long they can survive upon transplantation, whether they are eventually rejected by recipients, and how their long-term survival can be induced to permanently cure type 1 diabetes. IPCC graft survival is critical for their clinical application and this issue must be systematically addressed prior to their in-depth clinical trials.Methodology/Principal FindingsHere we found that IPCC grafts that differentiated from murine ASCs in vitro, unlike their freshly isolated islet counterparts, did not survive long-term in syngeneic mice, suggesting that ASC-derived IPCCs have intrinsic survival disadvantage over freshly isolated islets. Indeed, β cells retrieved from IPCC syngrafts underwent faster apoptosis than their islet counterparts. However, blocking both Fas and TNF receptor death pathways inhibited their apoptosis and restored their long-term survival in syngeneic recipients. Furthermore, blocking CD40-CD154 costimulation and Fas/TNF signaling induced long-term IPCC allograft survival in overwhelming majority of recipients. Importantly, Fas-deficient IPCC allografts exhibited certain immune privilege and enjoyed long-term survival in diabetic NOD mice in the presence of CD28/CD40 joint blockade while their islet counterparts failed to do so.Conclusions/SignificanceLong-term survival of ASC-derived IPCC syngeneic grafts requires blocking Fas and TNF death pathways, whereas blocking both death pathways and CD28/CD40 costimulation is needed for long-term IPCC allograft survival in diabetic NOD mice. Our studies have important clinical implications for treating type 1 diabetes via ASC-derived IPCC transplantation.
Highlights
Pancreatic islet transplantation holds much promise for the cure of type 1 diabetes as transplantation of cadaveric islets is already conducted in the clinic to treat patients with type 1 diabetes
Several elegant studies have shown that Insulin-producing cell clusters (IPCCs) are generated in vitro from both human and murine adipose tissue-derived stem cells (ASCs) [14,15,16,17], suggesting that ASC-derived IPCCs may circumvent worldwide shortage of donor islets and eventually provide a cure for human type 1 diabetes
We found that ASCderived IPCCs have the intrinsic survival disadvantage over freshly isolated islets in syngeneic recipients
Summary
Pancreatic islet transplantation holds much promise for the cure of type 1 diabetes as transplantation of cadaveric islets is already conducted in the clinic to treat patients with type 1 diabetes. Previous studies have shown that insulin-secreting cells are generated from embryonic stem cells [1,2,3,4,5,6,7] Their application in translational medicine could be limited because of ethical and legal concerns. Insulin-producing cell clusters (IPCCs) have recently been generated in vitro from adipose tissue-derived stem cells (ASCs) to circumvent islet shortage. It is unknown how long they can survive upon transplantation, whether they are eventually rejected by recipients, and how their long-term survival can be induced to permanently cure type 1 diabetes. IPCC graft survival is critical for their clinical application and this issue must be systematically addressed prior to their in-depth clinical trials
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