Murine bone marrow mesenchymal stromal cells have reduced hematopoietic maintenance ability in sickle cell disease

Abstract

Sickle Cell Disease (SCD) is characterized by hemolytic anemia, which can trigger oxidative stress, inflammation, and tissue injury that contributes to disease complications. Bone marrow mesenchymal stromal cells (MSCs) tightly regulate hematopoietic stem cell (HSC) homeostasis in health and disease but their functionality in SCD remains unclear. We identified for the first time murine SCD MSCs to have altered gene signatures, reduced stem cell properties, and increased oxidative stress, due in part to hemolysis. Murine SCD MSCs had lower HSC maintenance ability in vitro and in vivo as manifested by increased HSC mobilization and decreased HSC engraftment following transplant. Activation of TLR4 through p65 in MSCs further contributed to MSC dysfunction. Transfusions led to improved MSC and HSC oxidative state in SCD mice. Improving the regulation between MSCs and HSCs has vital implications for enhancing clinical HSC transplantation and gene therapy outcomes and for identification of new molecular targets for alleviating SCD complications.

Targeting the Hematopoietic Stem Cell Niche in β-Thalassemia and Sickle Cell Disease

“…Alterations in SCD HSCs were reported by Tang et al, who showed a decrease in HSC frequency, increased DNA damage, and an accumulation of ROS in HSCs from SCD mice, associated with the reduced hematopoietic supportive ability of MSCs [ 115 ].…”

“…The status of HSCs and BM niche, indeed, should be considered in the context of allogeneic HSCT to ensure a sustained engraftment of donor cells and especially in recent autologous gene therapy settings, to develop optimized protocols for increasing the efficacy and safety of ex-vivo genetic manipulation [ 44 ]. The reduced number of HSCs available for collection and the impaired engraftment potential of HSCs in BThal and SCD mouse models [ 114 , 115 ] highlighted the need for a better characterization of the primitive HSC compartment and BM niche features to develop targeting strategies for improving the outcome of allogeneic and autologous HSCT.…”

“…Human MSCs derived from SCD BM were found to have altered expression of SCF and CXCL12, but showed normal in vitro functionality [ 135 ]. However, recent work by Tang et al reported a reduced frequency of MSCs in the BM of SCD mice, ROS accumulation, and a decreased adipogenic and osteogenic differentiation potential, also suggesting impaired MSC functional properties [ 115 ]. Gene expression profiling revealed a decreased transcription of key niche molecules, such as Opn , as well as vascular cell adhesion to protein 1 ( Vcam1 ) , Angpt1 , Scf , and Cxcl12 , associated with an impaired ability to maintain HSCs in vitro and in vivo.…”

“…Park et al demonstrated that a 6-week transfusion regimen completely reversed the abnormal SCD BM vasculature by reducing proangiogenic mediators, such as VEGF-A, ANG1, and ANG2, as well as markers of inflammatory vascular activation [ 71 ]. Transfusions were demonstrated to also alleviate SCD MSC disfunction [ 115 ]. Upon transfusion, SCD MSCs showed decreased ROS content and enhanced expression of Scf and Cxcl12 , correlating with increased HSC frequency.…”

“…Upon transfusion, SCD MSCs showed decreased ROS content and enhanced expression of Scf and Cxcl12 , correlating with increased HSC frequency. Similarly, NAC antioxidant treatment improved SCD MSC ability to maintain HSCs [ 115 ].…”