Paper of the field n°3

Click to find how targeting the bone marrow niche could improve gene therapy outcome!

Abstract for General public

Sickle cell disease (SCD) is characterized by hemolytic anemia, that generates multiple stress signals in the bone marrow (BM), ultimately resulting in impaired function of cellular components. Recent findings in SCD murine models revealed that oxidative stress reduces the engraftment of hematopoietic stem cells (HSCs) after transplantation and the inflammatory milieu alters the function of BM stromal cells, that regulate HSCs. In gene therapy protocols for SCD, HSCs are first collected from patients, then they are genetically modified in order to correct the pathology and finally they are transplanted back into patients. Therefore, impaired HSC function and altered crosstalk between HSCs and BM cells could compromise the clinical outcome. In this study, Tang et al. explore the role of BM mesenchymal stromal cells (MSCs) in regulating HSC function in SCD mouse model.  MSCs, which provide physical and functional support to HSCs secreting important growth factors, are reduced in number with increased oxidative stress and impaired ability to maintain HSC number. As a result, HSCs show decreased frequency and they fail to normally reconstitute the BM after transplantation. The authors demonstrate that the accumulation of free heme, secondary to hemolysis, is the cause of defective crosstalk between MSCs and HSCs and more importantly these defects are reversible by blood transfusions. This work paves the way for a deeper characterization of BM cellular components and their interactions with HSCs aimed to provide novel therapeutic targets to ameliorate the quality of patient-derived HSCs for gene therapy and favour their engraftment. The journey has just begun.

Abstract written by Silvia Sighinolfi from Ospedale San Raffaele (Italy)

Tang, Alice, et al. « Murine Bone Marrow Mesenchymal Stromal Cells Have Reduced Hematopoietic Maintenance Ability in Sickle Cell Disease ». Blood, vol. 138, no 24, décembre 2021, p. 2570‑82.

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