Mesenchymal stromal cells for treatment of radiation-induced xerostomia

间充质基质细胞用于治疗辐射引起的口干症

• 批准号: 10649465
• 负责人: Cristina Paz
• 金额: $ 3.72万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649465
• 关键词: Acute; Address; Adipose tissue; Adverse effects; Affect; Anatomy; Architecture; Bone Marrow; Cell Therapy; Cell physiology; Cells; Chronic; Clinical; Clinical Research; Cryopreservation; Data; Development; Esthesia; Functional disorder; Future; Goals; Growth and Development function; Head and Neck Cancer; Head and neck structure; In Vitro; Injections; Interferon Type II; Knowledge; Licensing; Long-Term Effects; Marrow; Mentors; Modality; Modeling; Mus; Organ; Organoids; Paracrine Communication; Patients; Perception; Phase; Pilocarpine; Production; Property; Quality of life; Radiation; Radiation exposure; Radiation induced damage; Radiation therapy; Radiosurgery; Regenerative capacity; Reporting; Research Personnel; Role; Saliva; Salivary; Salivary Gland Tissue; Salivary Glands; Source; Submandibular gland; Therapeutic; Time; Tissues; Translating; Work; Xerostomia; cancer type; career development; design; educational atmosphere; effective therapy; epithelial stem cell; exosome; first-in-human; functional improvement; head and neck cancer patient; healing; immunoregulation; improved; in vivo; ineffective therapies; insight; mesenchymal stromal cell; morphogens; mouse model; novel therapeutics; palliation; palliative; paracrine; phase 1 study; prevent; radiation delivery; radiation effect; side effect; stem cell biology; therapeutic development; training opportunity; treatment optimization

PROJECT SUMMARY/ABSTRACT Radiation-induced xerostomia (RIX) is a condition of subjective dry mouth caused by radiation therapy to the head and neck and manifested as hyposalivation and altered sialochemistry. RIX is the most common chronic side effect observed in HNC patients receiving radiation therapy and despite improvements in radiation delivery remains a critical issue for patients. Currently available treatments provide temporary palliation and in some cases (e.g. pilocarpine) can be accompanied by side effects that are as bad or worse than xerostomia. There is a critical need for a treatment that will safely and effectively alleviate RIX without compromising patient quality of life. A small phase I study suggested that MSC therapy could improve the perception of dry mouth and salivary gland function in patients with RIX. However, the mechanisms by which MSCs elicit this effect remain unknown and none of the successful studies investigated to use of cryopreserved MSCs. We aim to fill this important knowledge gap by identifying an optimal source of MSCs for treatment and understanding how MSCs improve salivary function to optimize treatment to maximize patient benefit. This proposal intends to fill this knowledge gap which will potentially lead to the development of novel and effective therapies for RIX. We hypothesize that MSCs provide a reparative effect to the salivary gland through paracrine signaling. We will investigate the short-term and long-term functions of MSCs following injection into the submandibular gland and identify whether there is an ideal potential tissue source for MSCs in terms of cryo-recovery and RIX treatment. We seek to address three questions critical to understand and treat RIX: 1) identify an ideal tissue source for MSC to treat RIX; 2) investigate the effects of MSC treatment on the salivary gland in acute and late-phase radiation damage; and 3) determine if MSC-based products elicit the same effects as MSCs alone. In Aim 1, we will evaluate the ability of MSCs derived from marrow, adipose, and submandibular gland tissue to recover after cryopreservation following IFN-ɣ pre-licensing and evaluate the effects of these MSCs on salivary tissue in vivo and in vitro. We will characterize the secretome of MSCs from different tissue origins alone and investigate bi-directional effects of salivary gland tissue on this secretome using a salivary organoid model. Finally, we will confirm in vivo, differences in reparative effects based on MSC source. In Aim 2, we will define the effects of IFN-ɣ pre-licensed, cryopreserved MSCs in RIX by studying both acute and long-term effects on saliva production and salivary gland architecture in-vivo. We will also investigate the effects of MSC- based products like MSC conditioned media and MSC-derived exosomes on salivary function in vivo and in vitro. Together this work will provide an improved understanding of how MSCs ameliorate radiation damage, support the development of novel therapeutics for the treatment of RIX, and provide an outstanding training opportunity for the PI.

项目总结/摘要 放射性口腔干燥症（Radiation-Induced Xerostomia，RIX）是一种由放射治疗引起的主观性口腔干燥 表现为唾液分泌减少和唾液化学改变RIX是最常见的 在接受放射治疗的HNC患者中观察到慢性副作用，尽管放射治疗改善 分娩对于患者来说仍然是一个关键问题。目前可用的治疗提供暂时的缓解， 某些情况下（例如毛果芸香碱）可能伴随着与口干症一样糟糕或更糟糕的副作用。 目前迫切需要一种治疗方法，可以安全有效地缓解RIX，而不会损害 患者的生活质量。一项小型I期研究表明，MSC治疗可以改善干燥的感觉， RIX患者的口腔和唾液腺功能。然而，MSC引起这种作用的机制 效果仍然未知，并且没有成功的研究调查使用冷冻保存的MSC。我们的目标 通过确定用于治疗和理解的MSC的最佳来源来填补这一重要的知识空白 MSC如何改善唾液功能，以优化治疗，使患者受益最大化。该提案旨在 填补这一知识空白，这将可能导致新的和有效的治疗RIX的发展。 我们假设间充质干细胞通过旁分泌信号对唾液腺提供修复作用。 我们将研究骨髓间充质干细胞注射到下颌下的短期和长期功能 腺，并确定是否有一个理想的潜在组织来源的骨髓间充质干细胞的冷冻复苏和RIX方面 治疗我们试图解决理解和治疗RIX的三个关键问题：1）确定理想的组织 2）研究MSC治疗对急性和慢性RIX患者唾液腺的影响， 晚期辐射损伤;和3）确定基于MSC的产品是否引起与单独MSC相同的效果。 在目标1中，我们将评估来自骨髓、脂肪和下颌下腺组织的MSC的能力， 为了在冷冻保存后在IFN-γ预许可后恢复，并评估这些MSC对 在体内和体外的唾液组织中。我们将表征来自不同组织来源的MSC的分泌组 单独使用，并使用唾液类器官研究唾液腺组织对该分泌组的双向影响 模型最后，我们将在体内确认基于MSC来源的修复效果的差异。在目标2中，我们将 通过研究急性和长期，确定IFN-γ预许可，冷冻保存的MSC在RIX中的作用 对体内唾液产生和唾液腺结构的影响。我们还将研究MSC- 基于MSC的产品，如MSC条件培养基和MSC衍生的外泌体，对体内唾液功能的影响， 体外总之，这项工作将提供一个更好的理解如何骨髓间充质干细胞改善辐射损伤， 支持开发治疗RIX的新疗法，并提供出色的培训 PI的机会。