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β Cell transplantation and immunosuppression: can’t live with it, can’t live without it
Klaus H. Kaestner
Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Address correspondence to: Klaus H. Kaestner, Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, 560A CRB/6140, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-8759; Fax: (215) 573-5892; E-mail: kaestner@mail.med.upenn.edu.
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Published September 4, 2007 - More info
J Clin Invest. 2007;117(9):2380–2382. https://doi.org/10.1172/JCI33375.
© 2007 The American Society for Clinical Investigation
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Abstract
The mechanisms that regulate pancreatic β cell mass are poorly understood. While autoimmune and pharmacological destruction of insulin-producing β cells is often irreversible, adult β cell mass does fluctuate in response to physiological cues including pregnancy and insulin resistance. This plasticity points to the possibility of harnessing the regenerative capacity of the β cell to treat diabetes. We developed a transgenic mouse model to study the dynamics of β cell regeneration from a diabetic state. Following doxycycline administration, transgenic mice expressed diphtheria toxin in β cells, resulting in apoptosis of 70%–80% of β cells, destruction of islet architecture, and diabetes. Withdrawal of doxycycline resulted in a spontaneous normalization of blood glucose levels and islet architecture and a significant regeneration of β cell mass with no apparent toxicity of transient hyperglycemia. Lineage tracing analysis indicated that enhanced proliferation of surviving β cells played the major role in regeneration. Surprisingly, treatment with Sirolimus and Tacrolimus, immunosuppressants used in the Edmonton protocol for human islet transplantation, inhibited β cell regeneration and prevented the normalization of glucose homeostasis. These results suggest that regenerative therapy for type 1 diabetes may be achieved if autoimmunity is halted using regeneration-compatible drugs.
Authors
Tomer Nir, Douglas A. Melton, Yuval Dor
Although insulin therapy for diabetes has come a long way since the hormone’s discovery in the 1920s, insulin therapy cannot cure the disease and prevent its devastating complications in the long term. Beginning in the 1970s, whole-organ pancreas transplantation showed that replenishment of the β cell complement could fully normalize glucose homeostasis in patients. Transplantation of cadaveric islets into the liver via the portal vein was not successful until 2000, when a glucocorticoid-free immunosuppressive regimen was used and shown to result in insulin independence even in formerly brittle (that is, metabolically unstable) diabetic recipients (1). This advance increased the hopes for diabetics all over the world for a healthy life and led to dramatic policy changes in biomedical research funding. Because available organ donors would never be sufficient for the treatment of the millions of type 1 diabetics in the world, the NIH and private foundations funded major initiatives to develop new sources of β cells for transplantation, for instance through the National Institute of Diabetes and Digestive and Kidney Diseases–funded Beta Cell Biology Consortium (BCBC; http://www.betacell.org).
Multiple sources of cells have been considered as substrates for the development of this cell-based therapy. Among these are embryonic stem cells, hepatocytes, and putative resident endocrine stem cells within the pancreas; yet the success of these efforts has been limited thus far (2). Recent work has refocused the attention of diabetes researchers onto the mature β cell itself, because it was shown using genetic lineage tracing that under normal circumstances in healthy rodents, new β cells are mostly derived from existing β cells (3). Additional support for this concept came from successive labeling of proliferating cells using two thymidine analogs, which showed that adult pancreatic islets do not contain specialized progenitors that turn over rapidly, but rather that most or all β cells have the potential to proliferate (4). What these models had not established is whether β cell proliferation can also occur in the diabetic setting.
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A mouse model for β cell regeneration in the diabetic state
To address this question, Nir and colleagues developed, and describe in this issue of the JCI, a new model for the conditional and controlled ablation of pancreatic β cells (5) (Figure 1). Using an elegant genetic trick, they were able to express diphtheria toxin specifically in β cells at a time of their choosing, which resulted in the elimination of β cells through apoptosis. The treated mice were severely diabetic, consistent with an 80% reduction in their β cell mass and pancreatic insulin content. Unlike commonly used chemical agents employed for the killing of β cells such as streptozotocin, there was no bystander effect of the diphtheria toxin, and the degree of β cell ablation was reproducible. The beauty of the new system is that it allowed the investigators to record the spontaneous recovery of β cell function after ablation by simply removing the inducing agent. Remarkably, within a few weeks after diphtheria toxin expression ceased, β cell mass and glucose homeostasis were normalized. This was accompanied by a dramatically increased rate of β cell proliferation. The fact that β cell mass staged a near-full recovery even in the face of severe hyperglycemia (greater than 500 mg/dl) contradicts the widely held notion that glucotoxicity is a major impediment to β cell proliferation or survival (6, 7).
Figure 1Immunosuppressants inhibit β cell recovery after targeted ablation. (A) Normal β cell mass and glucose homeostasis in transgenic mice before application of doxycycline, the inducer of β cell death, in the transgenic animal model used by Nir et al. in this issue of the JCI (5). DTA, diphtheria toxin A. (B) Doxycycline treatment activates the expression of diphtheria toxin A specifically in the β cells of the pancreas, reducing β cell mass by 80% and causing hyperglycemia. (C) Regeneration of β cell mass through β cell proliferation and normalization of glucose homeostasis after doxycycline withdrawal. In the presence of Sirolimus and Tacrolimus, the immunosuppressants used in human islet transplantation, the regenerative response of the β cells is inhibited, and hyperglycemia persists.
Next, Nir and colleagues (5) addressed the question: What is the origin of the β cells that reappear even in a diabetic setting? The new β cells most likely did not arise from a reactivation of the fetal developmental program, as the neurogenin 3 gene, a marker of fetal endocrine precursors, was not reactivated in their model. Next the authors used genetic pulse-labeling of differentiated β cells, followed by labeling of those cells that had reentered the cell cycle, in order to assess the origin of the new cells. These data showed that the cells that rebuild the destroyed islets are largely if not exclusively derived from existing β cells, and not from neogenesis or from expansion of non–β cell precursors. As the authors point out, it is of course possible that in a setting of even more severe injury to the endocrine pancreas, other cells, including pancreatic duct or acinar cells or even hematopoietic progenitors, are being recruited to the β cell lineage. In this regard, the endocrine pancreas might be similar to the liver, in which hepatocytes are able to repopulate the organ under conditions of mild or medium injury, but activation of oval cells or even hematopoietic stems cells can contribute to the recovery when hepatocyte proliferation is blocked.
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