Prostaglandin E2 Stimulates the Expansion of Regulatory Hematopoietic Stem and Progenitor Cells in Type 1 Diabetes

• Main Authors: Moufida Ben Nasr, Francesca D’Addio, Amir Mohammad Malvandi, Silvia Faravelli, Eduardo Castillo-Leon, Vera Usuelli, Francesca Rocchio, Teresa Letizia, Abdel Basset El Essawy, Emma Assi, Chiara Mameli, Elisa Giani, Maddalena Macedoni, Anna Maestroni, Alice Dassano, Cristian Loretelli, Moira Paroni, Giuseppe Cannalire, Giacomo Biasucci, Marco Sala, Alessandra Biffi, Gian Vincenzo Zuccotti, Paolo Fiorina
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2018-06-01
• Series: Frontiers in Immunology
• Subjects: hematopoietic stem and progenitor cells; prostaglandins; autoimmune diseases; PD-L1; CXCR4
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2018.01387/full

Hematopoietic stem and progenitor cells (HSPCs) are multipotent stem cells that have been harnessed as a curative therapy for patients with hematological malignancies. Notably, the discovery that HSPCs are endowed with immunoregulatory properties suggests that HSPC-based therapeutic approaches may be used to treat autoimmune diseases. Indeed, infusion with HSPCs has shown promising results in the treatment of type 1 diabetes (T1D) and remains the only “experimental therapy” that has achieved a satisfactory rate of remission (nearly 60%) in T1D. Patients with newly diagnosed T1D have been successfully reverted to normoglycemia by administration of autologous HSPCs in association with a non-myeloablative immunosuppressive regimen. However, this approach is hampered by a high incidence of adverse effects linked to immunosuppression. Herein, we report that while the use of autologous HSPCs is capable of improving C-peptide production in patients with T1D, ex vivo modulation of HSPCs with prostaglandins (PGs) increases their immunoregulatory properties by upregulating expression of the immune checkpoint-signaling molecule PD-L1. Surprisingly, CXCR4 was upregulated as well, which could enhance HSPC trafficking toward the inflamed pancreatic zone. When tested in murine and human in vitro autoimmune assays, PG-modulated HSPCs were shown to abrogate the autoreactive T cell response. The use of PG-modulated HSPCs may thus provide an attractive and novel treatment of autoimmune diabetes.