Type 1 diabetes is a syndrome defined by high blood glucose levels caused by reduction in number of insulin producing cells, thus a cure for diabetes should entail replacement of -cells. There is a genetic predisposition for autoimmune susceptibility regarding macrophage phenotype in NOD mice and human T1D-patients, which contributes to persistence of inflammation, and -cell destruction. Here, we provide evidence that macrophages are important elements of pancreatic regeneration in general, and -cell generation in particular. Furthermore, we demonstrate that macrophages isolated from the NOD strain have an inherent inability to induce -cell generation. In this proposal, we will test the central hypothesis that Type1 diabetes is the combined effect of autoimmunity and the inability of macrophages to generate a cellular phenotype important for -cell regeneration. The experimental models described in this proposal will allow us to further study the macrophage-dependent -cell proliferation in mice (specific aims 1), to evaluate the ability of human-derived macrophages to induce - cell replication (specific aims 2), and to identify putative factors released by macrophages that are necessary for human -cell generation (specific aims 3). Immune therapy significantly reduces the autoimmune-associated -cell proliferation. Thus, additional therapeutic approaches that would stimulate -cell regeneration in the absence of autoimmune destruction may be needed for recovery of -cell mass. As a potential cell therapeutic approach, macrophages generated from patient's monocytes could be reprogrammed to promote -cell regeneration. This work is a high priority area as it is directly applicable to our full understanding and potential treatment of T1D.
The failure of numerous promising anti-CD3 trials to meet their endpoints indicates that immune therapy alone, as important and crucial as it is to prevent further destruction of -cells in type 1 diabetes, is not sufficient for restoring the -cell mas. We propose that Type1 diabetes results from the combined effect of autoimmunity and the inability of macrophages to mediate appropriate regenerative signals required for -cell regeneration. The experiments described in current proposal have been designed to test this hypothesis. We will take in vitro and in vivo approaches using mouse and human derived macrophages and islets to study the macrophage-dependent -cell generation. The principal goals of this proposal are to first, identify the factors that are normally released by the macrophages that promote -cell generation. Secondly, to determine whether these factors are differentially expressed in T1D-derived macrophages. The long-range objectives would be to define the potential role of the putative factor(s) in islet -cell proliferation and repair in normal and autoimmune settings.
| Schofield, Heather K; Tandon, Manuj; Park, Min-Jung et al. (2018) Pancreatic HIF2? Stabilization Leads to Chronic Pancreatitis and Predisposes to Mucinous Cystic Neoplasm. Cell Mol Gastroenterol Hepatol 5:169-185.e2 |
| Socorro, Mairobys; Criscimanna, Angela; Riva, Patricia et al. (2017) Identification of Newly Committed Pancreatic Cells in the Adult Mouse Pancreas. Sci Rep 7:17539 |
