Chansaenroj Ajjima, Yodmuang Supansa, Ferreira João N
Exocrine Gland Biology and Regeneration Research Group, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Tissue Eng Part B Rev. 2021 Apr;27(2):155-165. doi: 10.1089/ten.TEB.2020.0149. Epub 2020 Aug 26.
Xerostomia or dry mouth are commonly diagnosed in head and neck cancer patients due to salivary gland (SG) epithelial injury after radiotherapy. Regenerative medicine has fetched the opportunity to replace or regenerate the SG epithelia and restore its secretory function. Early adult stem cell transplantation strategies in rodents have recently shown to improve clinical outcomes in radiotherapy-induced xerostomia in Phase 1/2 human trials. Mesenchymal stem cells from adipose tissue are the most promising, although the ones from the labial mucosa, bone marrow, or dental pulp have an attractive therapeutic value after successful findings in and mouse models of SG injury. Emerging approaches using cell-free therapy with cell "extracts", "soups" or secretome components also exhibit favorable outcomes in the same rodent models. When compared to cell-based approaches, extracellular vesicles (EV) from the secretome (i.e., exosomes) can be easily extracted, quantified, and are more stable for long-term storage and use in SG tissue engineering. Additive manufacturing and three-dimensional bioprinting or bioassembly have an important role on generating spheroids or organoids for cell transplantation to ameliorate SG injury. Moreover, organoids can secrete EV, which may have a therapeutic potential worth to explore in future studies. In this review, we will describe the technological advancements and challenges of these different cell-based and cell-free strategies in SG tissue engineering and regeneration. Impact statement Salivary gland (SG)-like innervated epithelial organoids and the secretome produced from stem cells may constitute feasible therapeutic alternatives to regenerate the SG due to their user-friendly, short-lived, consistent, and scalable additive manufacturing processes. Bioprinting such human SG organoids toward drug discovery may further reduce the incorporation of animal-derived components to the tissue constructs and minimize the use of animal experimentation in SG regeneration. Despite such advancements, transplantation with human adipose-derived mesenchymal stem cells is the only tissue engineering strategy that has reached Phase 1/2 clinical trials and shown to enlarge the serous SG epithelium and improve salivary flow.
头颈部癌症患者常因放疗后涎腺（SG）上皮损伤而被诊断为口干症或口腔干燥。再生医学为替换或再生SG上皮并恢复其分泌功能带来了契机。近期在啮齿动物中的早期成体干细胞移植策略已在1/2期人体试验中显示出可改善放疗引起的口干症的临床结果。脂肪组织来源的间充质干细胞最具前景，不过在SG损伤的小鼠模型中取得成功发现后，唇黏膜、骨髓或牙髓来源的间充质干细胞也具有诱人的治疗价值。使用细胞“提取物”“培养液”或分泌组成分进行无细胞治疗的新兴方法在相同的啮齿动物模型中也显示出良好结果。与基于细胞的方法相比，分泌组中的细胞外囊泡（EV，即外泌体）易于提取、定量，并且在长期储存和用于SG组织工程时更稳定。增材制造以及三维生物打印或生物组装在生成用于细胞移植以改善SG损伤的球体或类器官方面具有重要作用。此外，类器官可以分泌EV，其治疗潜力值得在未来研究中探索。在本综述中，我们将描述这些不同的基于细胞和无细胞策略在SG组织工程和再生中的技术进步与挑战。影响声明 类似涎腺（SG）的神经支配上皮类器官以及干细胞产生的分泌组可能因其用户友好、寿命短、一致性和可扩展的增材制造过程而成为再生SG的可行治疗选择。将此类人类SG类器官用于药物发现的生物打印可能会进一步减少动物源性成分在组织构建物中的掺入，并最大限度减少SG再生中动物实验的使用。尽管有这些进展，但人脂肪来源的间充质干细胞移植是唯一已进入1/2期临床试验并显示可扩大浆液性SG上皮并改善唾液分泌的组织工程策略。
