Pharmacological induction of pancreatic islet cell transdifferentiation: relevance to type I diabetes

Type I diabetes (T1D) is an autoimmune disease in which an immune response to pancreatic β-cells results in their loss over time. Although the conventional view is that this loss is due to autoimmune destruction, we present evidence of an additional phenomenon in which autoimmunity promotes islet endocrine cell transdifferentiation. The end result is a large excess of δ-cells, resulting from α- to β- to δ-cell transdifferentiation. Intermediates in the process of transdifferentiation were present in murine and human T1D. Here, we report that the peptide caerulein was sufficient in the context of severe β-cell deficiency to induce efficient induction of α- to β- to δ-cell transdifferentiation in a manner very similar to what occurred in T1D. This was demonstrated by genetic lineage tracing and time course analysis. Islet transdifferentiation proceeded in an islet autonomous manner, indicating the existence of a sensing mechanism that controls the transdifferentiation process within each islet. The finding of evidence for islet cell transdifferentiation in rodent and human T1D and its induction by a single peptide in a model of T1D has important implications for the development of β-cell regeneration therapies for diabetes.The response of a tissue to stress/injury can involve cell death and proliferation. However, it has become increasingly recognized that changes in cellular differentiation state can have an important role.¹ In type I diabetes (T1D), the established view has been that the primary pathophysiological event is β-cell apoptosis due to a β-cell specific autoimmune response,² leading to profound β-cell deficiency. Thus, there has been great interest in inducing β-cell neogenesis, but there has been controversy over how and even whether β-cell regeneration occurs.³Activation of dedicated stem/progenitor cells within the pancreas and transdifferentiation of other differentiated cell types to β-cells are two potential mechanisms. In the past, the prevailing paradigm has been that neogenesis proceeds by the activation of facultative β-cell stem/progenitors within pancreatic ducts.^{4, 5, 6, 7} However, more recent studies have not found evidence of robust β-cell neogenesis from ducts.^{8, 9, 10, 11}β-cell neogenesis from other cell types within the pancreas, including acinar¹² and centroacinar¹³ cells has also been reported.Recently, we demonstrated robust β-cell neogenesis by transdifferentiation from preexisting α-cells in a model of T1D where severe β-cell deficiency was induced by high-dose alloxan.^{14, 15} In this model, β-cell neogenesis from α-cells was stimulated by pancreatic duct ligation (PDL).^{9, 15} Surgical reversal of PDL led to the recovery of β-cell mass and function by a combination of β-cell replication and β-cell neogenesis, demonstrating that β-cell regeneration by α- to β-cell neogenesis could be a robust approach to diabetes therapy,¹⁶ but PDL, which involves major surgery, is not a practical approach to therapy. Importantly, the relevance of α- to β-cell transdifferentiation to human biology remained unclear, as previous studies were performed in rodents.Here, we report the occurrence of efficient islet cell transdifferentiation using an entirely pharmacologically based approach where the peptide caerulein,^{17, 18} substituting for PDL, stimulated β-cell transdifferentiation from α-cells in mice rendered severely β-cell deficient by alloxan. Following caerulein plus alloxan, many of the neogenic β-cells went on to form δ-cells. In murine and human T1D, a similar process appeared to occur, where α-cells transdifferentiated into β-cells, which went on to form δ-cells. This led to a marked δ-cell excess in both murine and human T1D.The finding of endocrine cell transdifferentiation in T1D supports a new paradigm where β-cells, in addition to undergoing destruction by inflammatory mediators, undergo a dynamic process of neogenesis from α-cells and transdifferentiation to δ-cells. Controlling the neogenic process could lead to a new approach to diabetes therapy.