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.

项目概要/摘要 放射引起的口干症 (RIX) 是一种由放射治疗引起的主观口干症状 最常见的是头部和颈部，表现为唾液分泌不足和唾液化学改变。 尽管放射治疗有所改善，但在接受放射治疗的 HNC 患者中仍观察到慢性副作用 对于患者来说，分娩仍然是一个关键问题。目前可用的治疗方法只能提供暂时的姑息治疗。 某些情况下（例如毛果芸香碱）可能会伴有与口干一样严重或更严重的副作用。 迫切需要一种能够安全有效地缓解 RIX 且不影响 RIX 的治疗方法 一项小型 I 期研究表明 MSC 治疗可以改善患者对干燥的感觉。 RIX 患者的口腔和唾液腺功能然而，MSC 引发这种情况的机制。 效果仍然未知，并且没有一项成功的研究调查了冷冻间充质干细胞的使用。 通过确定用于治疗和理解的最佳 MSC 来源来填补这一重要的知识空白 间充质干细胞如何改善唾液功能以优化治疗以最大限度地提高患者利益。 填补这一知识空白，这将有可能导致 RIX 新型有效疗法的开发。 我们发现间充质干细胞通过旁分泌信号为唾液腺提供修复作用。 我们将研究 MSC 注射到颌下后的短期和长期功能 腺体并确定 MSCs 在冷冻回收和 RIX 方面是否存在理想的潜在组织来源 我们寻求解决对于理解和治疗 RIX 至关重要的三个问题：1）确定理想的组织。 MSC 治疗 RIX 的来源；2) 研究 MSC 治疗对急性和慢性唾液腺的影响。 晚期辐射损伤；3) 确定基于 MSC 的产品是否能产生与单独 MSC 相同的效果。 在目标 1 中，我们将评估源自骨髓、脂肪和颌下腺组织的 MSC 的能力 在 IFN-ɣ 预许可后冷冻保存后恢复并评估这些 MSC 对 我们将表征来自不同组织来源的 MSC 的分泌组。 单独使用唾液类器官研究唾液腺组织对该分泌组的双向影响 最后，我们将在目标 2 中确认基于 MSC 来源的体内修复效果的差异。 通过研究急性和长期来确定 IFN-ɣ 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- 的影响。 基于 MSC 条件培养基和 MSC 衍生的外泌体等产品对体内和体内唾液功能的影响 这项工作将共同促进人们更好地了解间充质干细胞如何改善辐射损伤， 支持 RIX 治疗新疗法的开发，并提供出色的培训 PI 的机会。