In human heart failure and in murine hearts with left ventricular pressure overload (LVPO), increases in fibrosis are associated with increases in stiffness. Secreted Protein Acidic and Rich in Cysteine (SPARC) is necessary for both cardiac fibrosis and increases in myocardial stiffness in response to LVPO, however cellular sources of cardiac SPARC are incompletely defined. Irradiation and bone marrow transfer were undertaken to test the hypothesis that SPARC expression by bone marrow-derived cells is an important mediator of fibrosis in LVPO. In recipient SPARC-null mice transplanted with donor wild-type (WT) bone marrow and subjected to LVPO, levels of fibrosis similar to that of WT hearts were found despite the lack of SPARC expression by resident cells. In recipient WT mice with donor SPARC-null bone marrow, significantly less fibrosis versus that of WT was found despite the expression of SPARC by resident cells. Increases in myocardial stiffness followed a similar pattern to that of collagen deposition. Myocardial macrophages were significantly reduced in SPARC-null mice with LVPO versus that of WT hearts. Recipient SPARC-null mice transplanted with donor WT bone marrow exhibited an increase in cardiac macrophages versus that of SPARC-null LVPO and donor WT mice with recipient SPARC-null bone marrow. Expression of Vascular Cellular Adhesion Molecule (VCAM) was found to be in increased in all groups with LVPO with the exception of WT mice. In conclusion, SPARC expression by bone marrow-derived cells was critical for fibrotic deposition of collagen and influenced the expansion of myocardial macrophages in response to LVPO.

中文翻译：

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骨髓来源细胞产生的 SPARC 导致压力超负荷时心肌纤维化


在人类心力衰竭和左心室压力超负荷（LVPO）的小鼠心脏中，纤维化的增加与硬度的增加相关。富含半胱氨酸的酸性分泌蛋白 (SPARC) 对于心脏纤维化和 LVPO 引起的心肌僵硬度增加都是必需的，但心脏 SPARC 的细胞来源尚不完全确定。采用辐射和骨髓移植来检验骨髓来源细胞的 SPARC 表达是 LVPO 纤维化的重要介质的假设。在移植了供体野生型 (WT) 骨髓并进行 LVPO 的 SPARC 缺失受体小鼠中，尽管驻留细胞缺乏 SPARC 表达，但发现纤维化水平与 WT 心脏相似。在具有 SPARC 缺失骨髓的供体 WT 小鼠中，尽管常驻细胞表达 SPARC，但与 WT 相比，纤维化明显减少。心肌硬度的增加遵循与胶原沉积类似的模式。与 WT 心脏相比，LVPO 的 SPARC 缺失小鼠的心肌巨噬细胞显着减少。与 SPARC 无效 LVPO 小鼠和移植 SPARC 无效骨髓的供体 WT 小鼠相比，移植了供体 WT 骨髓的 SPARC 无效受体小鼠的心脏巨噬细胞有所增加。发现除 WT 小鼠外，所有 LVPO 组的血管细胞粘附分子 (VCAM) 表达均增加。总之，骨髓源性细胞的 SPARC 表达对于胶原纤维化沉积至关重要，并影响心肌巨噬细胞响应 LVPO 的扩张。