Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA; Mechanical Engineering, Stanford University School of Medicine, Stanford, CA, USA.
Biomaterials. 2021 Aug;275:120972. doi: 10.1016/j.biomaterials.2021.120972. Epub 2021 Jun 21.
Cell-based therapy for augmentation of core decompression (CD) using mesenchymal stromal cells (MSCs) is a promising treatment for early stage osteonecrosis of the femoral head (ONFH). Recently, the therapeutic potential for immunomodulation of osteogenesis using preconditioned (with pro-inflammatory cytokines) MSCs (pMSCs), or by the timely resolution of inflammation using MSCs that over-express anti-inflammatory cytokines has been described. Here, pMSCs exposed to tumor necrosis factor-alpha and lipopolysaccharide for 3 days accelerated osteogenic differentiation in vitro. Furthermore, injection of pMSCs encapsulated with injectable hydrogels into the bone tunnel facilitated angiogenesis and osteogenesis in the femoral head in vivo, using rabbit bone marrow-derived MSCs and a model of corticosteroid-associated ONFH in rabbits. In contrast, in vitro and in vivo studies demonstrated that genetically-modified MSCs that over-express IL4 (IL4-MSCs), established by using a lentiviral vector carrying the rabbit IL4 gene under the cytomegalovirus promoter, accelerated proliferation of MSCs and decreased the percentage of empty lacunae in the femoral head. Therefore, adjunctive cell-based therapy of CD using pMSCs and IL4-MSCs may hold promise to heal osteonecrotic lesions in the early stage ONFH. These interventions must be applied in a temporally sensitive fashion, without interfering with the mandatory acute inflammatory phase of bone healing.
基于间充质干细胞的细胞疗法通过骨髓间充质干细胞（MSCs）来增强核心减压（CD），是治疗早期股骨头坏死（ONFH）的一种有前途的方法。最近，使用预处理（促炎细胞因子）的 MSCs（pMSCs）进行成骨免疫调节的治疗潜力，或通过及时缓解炎症使用过表达抗炎细胞因子的 MSCs 已被描述。在这里，pMSCs 在肿瘤坏死因子-α和脂多糖中孵育 3 天可加速体外成骨分化。此外，通过将包封有可注射水凝胶的 pMSCs 注入兔骨髓来源的 MSCs 和兔皮质类固醇相关 ONFH 模型的骨隧道中，促进了股骨头内的血管生成和成骨。相反，体外和体内研究表明，通过使用携带巨细胞病毒启动子的兔 IL4 基因的慢病毒载体建立的过表达 IL4（IL4-MSCs）的基因修饰 MSCs 可加速 MSCs 的增殖并减少股骨头中空白腔隙的百分比。因此，通过 pMSCs 和 IL4-MSCs 对 CD 的辅助细胞疗法可能有希望治愈早期 ONFH 的骨坏死病变。这些干预措施必须以时间敏感的方式应用，而不干扰骨愈合的强制性急性炎症期。
