Bone marrow mesenchymal stromal cells induce nitric oxide synthase-dependent differentiation of CD11b ⁺ cells that expedite hematopoietic recovery

Abstract

Bone marrow microenvironment is fundamental for hematopoietic homeostasis. Numerous efforts have been made to reproduce or manipulate its activity to facilitate engraftment after hematopoietic stem cell transplantation but clinical results remain unconvincing. This probably reflects the complexity of the hematopoietic niche. Recent data have demonstrated the fundamental role of stromal and myeloid cells in regulating hematopoietic stem cell self-renewal and mobilization in the bone marrow. In this study we unveil a novel interaction by which bone marrow mesenchymal stromal cells induce the rapid differentiation of CD11b+ myeloid cells from bone marrow progenitors. Such an activity requires the expression of nitric oxide synthase-2. Importantly, the administration of these mesenchymal stromal cell-educated CD11b+ cells accelerates hematopoietic reconstitution in bone marrow transplant recipients. We conclude that the liaison between mesenchymal stromal cells and myeloid cells is fundamental in hematopoietic homeostasis and suggests that it can be harnessed in clinical transplantation.

The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling

“…Supporting the intrinsic role of PERK in UPR-primed MDSCs, excision of Eif2ak3 abolished the amplified T cell-inhibitory effect found in BM-MDSCs treated with Thaps without altering the regulatory potential of vehicletreated BM-MDSCs (Figure 3F). Furthermore, elimination of PERK did not affect the frequency of common myeloid progenitors (CMPs) or granulocyte-macrophage progenitors (GMPs) (Trento et al, 2017) in the BM of tumor-bearing mice, nor did it affect MDSC development from hematopoietic precursors (Figures S3L and S3M). Because of the role of MDSCs in T cell dysfunction, we studied the effect of T cells in the anti-tumor responses observed in conditional Eif2ak3 À/À mice.…”

Mesenchymal Stromal Cells for Graft Versus Host Disease: Mechanism-Based Biomarkers

“…Likewise, bone marrow progenitors are induced to differentiate into a population of CD11b+ myeloid cells with potent suppressive activity in the presence of MSCs. Such differentiation is mediated by nitric oxide synthase-2 and these MSC-educated CD11b+ cells accelerate hematopoietic reconstitution in bone marrow transplant recipients (55).…”

Manufacturing Mesenchymal Stromal Cells for the Treatment of Graft-versus-Host Disease: A Survey among Centers Affiliated with the European Society for Blood and Marrow Transplantation

“…By reprogramming the inflammatory microenvironment [8], MSC prime tissue repair, thus making them a therapeutic tool not only to control immune-mediated ailments but also in the context of regenerative medicine 9., 10., 11.. Therefore, it is not surprising that MSC therapeutics have met a huge interest in hematopoietic stem cell transplantation (HSCT) whereby they have been exploited to treat challenging conditions such as impaired HSC engraftment 12., 13., 14. and steroid-resistant acute graft-versus-host disease (aGvHD) 15., 16., 17., 18..…”