Vascular smooth muscle cells (VSMCs) play essential roles in regulating blood vessel form and function. Regeneration of functional vascular smooth muscle tissue to repair vascular diseases is an area of intense research in tissue engineering and regenerative medicine. For functional vascular smooth muscle tissue regeneration to become a practical therapy over the next decade, the field will need to have access to VSMC sources that are effective, robust and safe. While pluripotent stem cells hold good future promise to this end, more immediate translation is expected to come from approaches that generate functional VSMCs from adult sources of multipotent adipose-derived and bone marrow-derived mesenchymal stromal cells (ASCs and BMSCs). The research to this end is extensive and is dominated by studies relating to classical biochemical signalling molecules used to induce differentiation of ASCs and BMSCs. However, prolonged use of the biochemical induction factors is costly and can cause potential endotoxin contamination in culture. Over recent years several non-traditional differentiation approaches have been devised to mimic defined aspects of the native micro-environment in which VSMCs reside to contribute to the differentiation of VSMC-like cells from ASCs and BMSCs. In this review, the promises and limitations of several non-traditional culture factors (e.g., co-culture, biomechanical, and biomaterial stimuli) targeting VSMC differentiation are discussed. The extensive crosstalk between the underlying signalling cascades are delineated and put into a translational context. It is expected that this review will not only provide significant insight into VSMC differentiation strategies for vascular smooth muscle tissue engineering applications, but will also highlight the fundamental importance of engineering the cellular microenvironment on multiple scales (with consideration of different combinatorial pathways) in order to direct cell differentiation fate and obtain cells of a desired and stable phenotype. These strategies may ultimately be applied to different sources of stem cells in the future for a range of biomaterial and tissue engineering disciplines.

血管平滑肌细胞（VSMC）在调节血管形式和功能中起着重要作用。功能性血管平滑肌组织的再生以修复血管疾病是组织工程学和再生医学领域的一项广泛研究领域。为了使功能性血管平滑肌组织再生在接下来的十年中成为一种实用疗法，该领域将需要获得有效，稳健和安全的VSMC来源。尽管多能干细胞在这一方面具有良好的未来前景，但有望从能够从多能脂肪来源和骨髓来源的间充质基质细胞（ASC和BMSC）的成人来源产生功能性VSMC的方法中获得更多即时翻译。为此目的的研究是广泛的，并且被与用于诱导ASC和BMSC的分化的经典生化信号分子有关的研究所主导。然而，长时间使用生化诱导因子是昂贵的，并且会在培养物中引起潜在的内毒素污染。近年来，已设计出几种非传统的分化方法来模拟VSMC所驻留的自然微环境的特定方面，以促进从ASC和BMSC分化VSMC样细胞。在这篇综述中，讨论了针对VSMC分化的几种非传统文化因素（例如共培养，生物力学和生物材料刺激）的前景和局限性。描绘了底层信令级联之间的广泛串扰，并将其置于翻译环境中。预计该综述不仅将为血管平滑肌组织工程应用中的VSMC分化策略提供重要见解，还将突显在多个尺度上工程化细胞微环境的根本重要性（考虑到不同的组合途径），以便指导细胞分化命运并获得所需和稳定表型的细胞。这些策略将来可能会在一系列生物材料和组织工程学科中最终应用于不同的干细胞来源。但也将突出显示在多个尺度上工程化细胞微环境（考虑不同的组合途径）以指导细胞分化命运并获得所需和稳定表型的细胞的根本重要性。这些策略将来可能会在一系列生物材料和组织工程学科中最终应用于不同的干细胞来源。但也将突出显示在多个尺度上工程化细胞微环境（考虑不同的组合途径）以指导细胞分化命运并获得所需和稳定表型的细胞的根本重要性。这些策略将来可能会在一系列生物材料和组织工程学科中最终应用于不同的干细胞来源。