Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan.
Department of Innovative Medical Science, Tokai University School of Medicine, Kanagawa, Japan; Research Center for Regenerative Medicine, Tokai University School of Medicine, Kanagawa, Japan.
Biochem Biophys Res Commun. 2021 Jun 11;557:180-186. doi: 10.1016/j.bbrc.2021.04.017. Epub 2021 Apr 15.
Bone marrow adipocytes (BMAs) have recently been recognized as a niche component with a suppressive function. Obese individuals with abundant BMAs exhibit impaired hematopoietic regeneration after hematopoietic stem cell transplantation (HSCT). We hypothesized that plasminogen activator inhibitor type-1 (PAI-1), an adipokine that regulates the fibrinolytic system, contributes to impaired hematopoiesis in bone marrow (BM) microenvironment with abundant BMAs. We demonstrated that BMAs differentiated in vitro could secrete PAI-1 and were positive for PAI-1 in vivo. In addition, the abundance of BMAs was associated with high levels of PAI-1 expression. The BMA-rich microenvironment exhibited impaired hematopoietic regeneration after HSCT when compared with a BMA-less microenvironment. The impaired hematopoietic regeneration in BMA-rich microenvironment was significantly alleviated by PAI-1 knockout or PAI-1 inhibitor treatment. Obese mice with abundant BMAs, compared with normal-weight mice, exhibited higher bone marrow PAI-1 concentrations, increased fibrinolytic system suppression, and lower stem cell factor (SCF) concentrations after HSCT. PAI-1 inhibitor administration significantly activated the fibrinolytic system in obese mice, contributing to the higher SCF concentration. Moreover, PAI-1 inhibitor treatment significantly alleviated the impaired hematopoietic regeneration in obese mice both after 5-fluorouracil injection and HSCT. These results indicate that PAI-1 hinders hematopoietic regeneration in BMA-rich microenvironments. The blockade of PAI-1 activity could be a novel therapeutic means of facilitating hematopoietic reconstitution in BMA-rich patients.
骨髓脂肪细胞（BMAs）最近被认为是具有抑制功能的龛位成分。骨髓脂肪细胞丰富的肥胖个体在造血干细胞移植（HSCT）后表现出造血再生受损。我们假设纤溶酶原激活物抑制剂 1（PAI-1），一种调节纤维蛋白溶解系统的脂肪因子，有助于富含 BMAs 的骨髓（BM）微环境中的造血功能受损。我们证明了体外分化的 BMAs 可以分泌 PAI-1 并在体内呈 PAI-1 阳性。此外，BMAs 的丰度与 PAI-1 表达水平升高相关。与 BMAs 较少的微环境相比，HSCT 后富含 BMAs 的微环境表现出造血再生受损。与 PAI-1 敲除或 PAI-1 抑制剂治疗相比，富含 BMAs 的微环境中的造血再生受损明显减轻。与正常体重小鼠相比，富含 BMAs 的肥胖小鼠在 HSCT 后表现出更高的骨髓 PAI-1 浓度、更高的纤维蛋白溶解系统抑制和更低的干细胞因子（SCF）浓度。PAI-1 抑制剂给药可显著激活肥胖小鼠的纤维蛋白溶解系统，导致 SCF 浓度升高。此外，PAI-1 抑制剂治疗可显著缓解肥胖小鼠在氟尿嘧啶注射和 HSCT 后造血再生受损。这些结果表明 PAI-1 阻碍了富含 BMAs 的微环境中的造血再生。PAI-1 活性的阻断可能是促进富含 BMAs 患者造血重建的一种新的治疗手段。
