Division of Rheumatology, Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Daigaku-Machi 2-7, Takatsuki, Osaka, Japan.
Department of Legal Medicine, Osaka Medical and Pharmaceutical University, Daigaku-Machi 2-7, Takatsuki, Osaka, Japan.
Arthritis Res Ther. 2022 Oct 7;24(1):228. doi: 10.1186/s13075-022-02915-6.
Adipose-derived mesenchymal stem cells (ASCs) have gained attention as a new treatment for systemic sclerosis (SSc). Low-molecular-weight heparin (LMWH) enhances cell function and stimulates the production of hepatocyte growth factor (HGF) in a variety of cells. This study investigated the effects of LMWH on the functions of mouse ASCs (mASCs), and the therapeutic effects of mASCs activated with LMWH (hep-mASCs) in mouse models of SSc.
The cellular functions of mASCs cultured with different concentrations of LMWH were determined. Mice were divided into four groups: bleomycin (BLM)-induced SSc (BLM-alone), BLM-induced SSc administered with mASCs (BLM-mASC), and BLM-induced SSc administered with mASCs activated with 10 or 100 μg/mL LMWH (BLM-hep-mASC); there were 9 mice per group (n = 9). Skin inflammation and fibrosis were evaluated using histological and biochemical examinations and gene expression levels.
In vitro assays showed that migration ability and HGF production were significantly higher in hep-mASCs than in mASCs alone. The mRNA expression levels of cell migration factors were significantly upregulated in hep-mASCs compared to those in mASCs alone. The hep-mASCs accumulated in the skin tissues more than mASCs alone. The thickness of skin and hydroxyproline content in BLM-hep-mASC groups were significantly decreased, and the skin mRNA expression levels of interleukin-2, α-smooth muscle actin, transforming growth factor β1, collagen type 1 alpha 1, and tissue inhibitor of metalloproteinase 2 were significantly downregulated compared to those in the BLM-alone group.
hep-mASCs showed higher anti-inflammatory and anti-fibrotic effects than mASCs alone and may be a promising candidate for SSc treatment.
脂肪间充质干细胞（ASCs）作为一种治疗系统性硬化症（SSc）的新方法受到关注。低分子肝素（LMWH）可增强多种细胞的细胞功能并刺激肝细胞生长因子（HGF）的产生。本研究探讨了 LMWH 对小鼠 ASCs（mASCs）功能的影响，以及 LMWH 激活的 mASCs（hep-mASCs）在 SSc 小鼠模型中的治疗效果。
用不同浓度 LMWH 培养 mASCs，测定其细胞功能。将小鼠分为四组：博来霉素（BLM）诱导的 SSc（BLM-alone）、BLM 诱导的 SSc 给予 mASCs（BLM-mASC）、BLM 诱导的 SSc 给予 10 或 100μg/ml LMWH 激活的 mASCs（BLM-hep-mASC）；每组 9 只小鼠（n=9）。通过组织学和生化检查以及基因表达水平评估皮肤炎症和纤维化。
体外试验显示，与 mASCs 相比，hep-mASCs 的迁移能力和 HGF 产量显著提高。与 mASCs 相比，hep-mASCs 中细胞迁移因子的 mRNA 表达水平显著上调。hep-mASCs 在皮肤组织中的积累量明显多于 mASCs。与 BLM-alone 组相比，BLM-hep-mASC 组皮肤厚度和羟脯氨酸含量明显降低，皮肤组织中白细胞介素-2、α-平滑肌肌动蛋白、转化生长因子-β1、胶原 I 型α1 和基质金属蛋白酶 2 组织抑制剂的 mRNA 表达水平明显下调。
与 mASCs 相比，hep-mASCs 具有更高的抗炎和抗纤维化作用，可能是治疗 SSc 的有前途的候选药物。
