Acute damage to the heart, as in the case of myocardial infarction (MI), triggers a robust inflammatory response to the sterile injury that is part of a complex and highly organized wound healing process. Cortical bone stem cell (CBSC) therapy after MI has been shown to reduce adverse structural and functional remodeling of the heart after MI in both mouse and swine models. The basis for these CBSC treatment effects on wound healing are unknown. The present experiments show that CBSCs secrete paracrine factors known to have immunomodulatory properties, most notably Macrophage Colony Stimulating Factor (M-CSF) and Transforming Growth Factor-b, but not IL-4. CBSC therapy increased the number of Galectin-3+ macrophages, CD4+ T-cells, and fibroblasts in the heart while decreasing apoptosis in an in vivo swine model of MI. Macrophages treated with CBSC medium in vitro polarized to a pro-reparative phenotype characterized by increased CD206 expression, increased efferocytic ability, increased IL-10, TGF-b, and IL-1RA secretion, and increased mitochondrial respiration. Next generation sequencing revealed a transcriptome significantly different from M2a or M2c macrophage phenotypes. Paracrine factors from CBSC-treated macrophages increased proliferation, decreased a-Smooth Muscle Actin expression, and decreased contraction by fibroblasts in vitro. These data support the idea that CBSCs are modulating the immune response to MI to favor cardiac repair through a unique macrophage polarization that ultimately reduces cell death and alters fibroblast populations that may result in smaller scar size and preserved cardiac geometry and function.

中文翻译：

---

皮质骨干细胞通过诱导新的巨噬细胞表型改变心肌梗塞后的心脏炎症

心脏的急性损伤，如心肌梗塞 (MI)，会引发对无菌损伤的强烈炎症反应，这是复杂且高度组织化的伤口愈合过程的一部分。在小鼠和猪模型中，MI 后皮质骨干细胞 (CBSC) 治疗已被证明可减少 MI 后心脏的不良结构和功能重塑。这些 CBSC 治疗对伤口愈合影响的基础尚不清楚。本实验表明，CBSC 分泌已知具有免疫调节特性的旁分泌因子，最显着的是巨噬细胞集落刺激因子 (M-CSF) 和转化生长因子-b，但不分泌 IL-4。CBSC 治疗增加了心脏中 Galectin-3+ 巨噬细胞、CD4+ T 细胞和成纤维细胞的数量，同时减少了 MI 猪体内模型中的细胞凋亡。体外用 CBSC 培养基处理的巨噬细胞极化为促修复表型，其特征是 CD206 表达增加、细胞增殖能力增加、IL-10、TGF-b 和 IL-1RA 分泌增加，以及线粒体呼吸增加。下一代测序揭示了与 M2a 或 M2c 巨噬细胞表型显着不同的转录组。来自 CBSC 处理的巨噬细胞的旁分泌因子增加了增殖，降低了α-平滑肌肌动蛋白的表达，并减少了体外成纤维细胞的收缩。这些数据支持这样一种观点，即 CBSC 正在调节对 MI 的免疫反应，通过独特的巨噬细胞极化来促进心脏修复，最终减少细胞死亡并改变成纤维细胞群，这可能导致更小的疤痕尺寸和保留的心脏几何形状和功能。