Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation. Pancreatic islets released abundant CXCR1/2 ligands (CXCL1 and CXCL8). Accordingly, intrahepatic CXCL1 and circulating CXCL1 and CXCL8 were strongly induced shortly after islet infusion. Genetic and pharmacological blockade of the CXCL1-CXCR1/2 axis in mice improved intrahepatic islet engraftment and reduced intrahepatic recruitment of polymorphonuclear leukocytes and NKT cells after islet infusion. In humans, the CXCR1/2 allosteric inhibitor reparixin improved outcome in a phase 2 randomized, open-label pilot study with a single infusion of allogeneic islets. These findings indicate that the CXCR1/2-mediated pathway is a regulator of islet damage and should be a target for intervention to improve the efficacy of transplantation.

The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor acts as a natural physical barrier, impairing drug penetration. Consequently, all of the approaches combining stroma-targeting and anticancer therapy constitute an appealing option for improving drug penetration. Several strategies have been adopted in order to target the PDAC stroma, such as the depletion of ECM components and the targeting of cancer-associated fibroblasts (CAFs), which are responsible for the increased matrix deposition in cancer. Additionally, the leaky and collapsing blood vessels characterizing the tumor might be normalized, thus restoring blood perfusion and allowing drug penetration. Even though many stroma-targeting strategies have reported disappointing results in clinical trials, the ECM offers a wide range of potential therapeutic targets that are now being investigated. The dense ECM might be bypassed by implementing nanoparticle-based systems or by using mesenchymal stem cells as drug carriers. The present review aims to provide an overview of the principal mechanisms involved in the ECM remodeling and of new promising therapeutic strategies for PDAC.

Objectives: Our study aims at producing acellular extracellular matrix scaffolds from the human pancreas (hpaECMs) as a first critical step toward the production of a new-generation, fully human-derived bioartificial endocrine pancreas. In this bioartificial endocrine pancreas, the hardware will be represented by hpaECMs, whereas the software will consist in the cellular compartment generated from patient's own cells. Background: Extracellular matrix (ECM)-based scaffolds obtained through the decellularization of native organs have become the favored platform in the field of complex organ bioengineering. However, the paradigm is now switching from the porcine to the human model. Methods: To achieve our goal, human pancreata were decellularized with Triton-based solution and thoroughly characterized. Primary endpoints were complete cell and DNA clearance, preservation of ECM components, growth factors and stiffness, ability to induce angiogenesis, conservation of the framework of the innate vasculature, and immunogenicity. Secondary endpoint was hpaECMs’ ability to sustain growth and function of human islet and human primary pancreatic endothelial cells. Results: Results show that hpaECMs can be successfully and consistently produced from human pancreata and maintain their innate molecular and spatial framework and stiffness, and vital growth factors. Importantly, hpaECMs inhibit human naïve CD4⁺ T-cell expansion in response to polyclonal stimuli by inducing their apoptosis and promoting their conversion into regulatory T cells. hpaECMs are cytocompatible and supportive of representative pancreatic cell types. Discussion: We, therefore, conclude that hpaECMs has the potential to become an ideal platform for investigations aiming at the manufacturing of a regenerative medicine-inspired bioartificial endocrine pancreas.

Chemokines and their receptors have been associated with or implicated in the pathogenesis of type 1 diabetes (T1D), but the identification of a single specific chemokine/receptor pathway that may constitute a suitable target for the development of therapeutic interventions is still lacking. Here, we used the multiple low doses (MLD)-streptozotocin (STZ) injection and the NOD mouse models to investigate the potency of CXCR1/2 inhibition to prevent inflammatory- and autoimmunity-mediated damage of pancreatic islets. Reparixin and ladarixin, non-competitive allosteric inhibitors, were used to obtain the pharmacologic blockade of CXCR1/2. Transient blockade of said receptors was effective in preventing inflammatory-mediated damage in MLD-STZ and in preventing and reverting diabetes in NOD mice. Blockade of CXCR1/2 was associated with insulitis inhibition and modification of leucocytes distribution in blood, spleen, bone marrow and lymph nodes. Among leucocytes, CXCR2⁺ myeloid cells were the most decreased subpopulations. All together these results propose CXCR1/2 chemokine receptors as “master regulators” of diabetes pathogenesis. The demonstration that this strategy may be successful in preserving the residual β-cells holds the potential to make a significant change in the approach to management of human T1D.