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

Abstract

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.

Role of prostaglandin E2 in tissue repair and regeneration

“…PGE2 regulates hematopoietic stem/progenitor cell (HSC/HSPC) homeostasis 147 , 148 and modulates hematopoietic potential 149 . It's known that PGE2 enhances HSC homing, engraftment, survival, and expansion 148 , 150 , 151 . Researchers also reported that EP4 is a key receptor involving PGE2-mediated positive regulation of HSC/HSPC 152 , 153 .…”

Regimen-dependent synergism and antagonism of treprostinil and vildagliptin in hematopoietic cell transplantation

“…Apart from CXCR4 [26], it is the modulation of PD-L1 expression, which represents an attractive target for enhancing immunoregulation by HSPCs [24,25]. Interestingly, PGE2-analogs increase the expression of CXCR4 and PD-L1 [27]. Hence, it is attractive to explore, if treprostinil can be repurposed to facilitate AHSCT.…”

Hematopoietic Stem Cells in Type 1 Diabetes

“…With regard to patients with T1D, the use of AHSCT obtained significant insulin independence and a well-preserved glycometabolic control in the short and mid-term follow-up (Figure 1A and Table 1) (17,31,34,35). Also, an increase in Cpeptide levels and C-peptide area under the curve (AUC) measurement were detectable in AHSCT-treated T1D patients as compared to baseline, and only minor adverse events were registered in the mid-term (25,36). A reduction of the T-helper-1 and T-helper-17 subsets was also observed in the short-term (37).…”

“…The use of ADAM3100, which antagonizes the CXCL12 receptor SDF-1, was associated with increased mobilization of HSCs and T cells, and delayed onset of experimental autoimmune diabetes in NOD mice (24). Recently, a defect in PDL-1 expression has been demonstrated in HSCs of NOD mice, which was associated with a reduced immunomodulatory function (9,25). Genetic and pharmacological modulation of PDL-1 on HSCs restored the HSCs immunomodulatory properties, reset the immune balance and prevented the onset of T1D.…”