Safety and Efficacy of Mesenchymal Stem Cells in the Treatment of Chronic Pancreatitis and Its Associated Pain

摘要： 慢性胰腺炎（CP）是一种以不可逆的形态学改变（纤维化）为特征的衰弱性疾病 以及胰腺的持续炎症腹痛是主要症状之一， 在高达90%的CP患者中，与阿片类药物的大量使用有关。慢性疼痛会导致阿片类药物 依赖、焦虑、抑郁和生活质量下降。虽然阿片类药物对急性疼痛有效， 作为一种长期治疗策略并不有效。迫切需要更有效、更安全、更安全的方法， 成瘾性治疗选择的人谁遭受慢性疼痛与CP或其他疾病。 间充质基质细胞（MSC）在治疗疼痛中的应用代表了一种有前途的新型干预， 越来越多的证据表明，MSC治疗可以有效地靶向多种损伤途径， 纤维炎性疾病，同时减少疼痛，这是大多数药物干预不能 完成。MSC通过释放促有丝分裂、抗凋亡、抗炎 和免疫调节可溶性因子，以减轻代谢组学和氧化应激失衡。数据从 动物模型和临床试验支持MSC输注在抑制肿瘤生长中的突出和持久的作用， 慢性炎症和与各种疾病相关的神经性疼痛。我们自己的动物研究 结果表明，MSC输注显著减轻疼痛，改善纤维化和胰腺体积， CP小鼠模型。然而，骨髓间充质干细胞的输注是否可以作为一种新的方法，以缓解 慢性疼痛和改善CP患者的胰腺功能尚未得到测试，将是本研究的重点。 study. 基于令人信服的数据，我们的假设是MSC治疗可以减轻慢性疼痛并改善症状 胰腺纤维化和功能通过其靶向多个损伤途径的能力。本研究的目的是 两个方面：（i）准备临床试验（UG 3阶段，第1年），并确定MSC的安全性和有效性 疼痛性CP患者的治疗（UH 3期，2-5年）。临床试验阶段的另一个关键部分将是 通过测量胰腺组织中细胞因子的变化来确定MSC缓解胰腺多发性损伤的机制。 外周血单核细胞（PBMC），尤其是单核细胞亚群和血清促炎细胞因子 治疗患者的特征，目的是确定反应的生化途径和血清生物标志物 MSC疗法这项研究可能有助于开发新的非成瘾性细胞治疗慢性胰腺炎， 痛苦

Abstract: Chronic pancreatitis (CP) is a debilitating disease characterized by irreversible morphological changes (fibrosis) and persistent inflammation in the pancreas. Abdominal pain is one of the predominant symptoms and presents in up to 90% of CP patients and is associated with the heavy use of opioids. Chronic pain can cause opioid dependence, anxiety, depression and reduced quality of life. Although opioids are effective for acute pain, they are not effective as a long-term treatment strategy. There is a critical need for more effective, safer, and non- addictive therapeutic options for people who suffer from chronic pain associated with CP or other diseases. The use of mesenchymal stromal cells (MSCs) in treating pain represents a promising novel intervention as increasing evidence demonstrates that MSC therapy can effectively target several injury pathways in a variety of fibroinflammatory diseases while reducing pain, something that most pharmacological interventions cannot accomplish. MSCs exert protective effects through the release of pro-mitotic, antiapoptotic, anti-inflammatory, and immunomodulatory soluble factors, to mitigate metabolomic and oxidative stress imbalance. Data from animal models and clinical trials support the outstanding and durable effects of MSC infusion in the suppression of chronic inflammation and neurological pain associated with various diseases. Our own animal study demonstrated that MSC infusion significantly reduces pain and improves fibrosis and pancreatic volume in mouse models of CP. However, whether the infusion of MSCs can be used as a novel approach to relieving chronic pain and improve pancreatic function in CP patients has not been tested and will be the focus of this study. Based on compelling data, our hypothesis is that treatment with MSCs reduces chronic pain and improves pancreatic fibrosis and function by their ability to target multiple injury pathways. The objective of this study is two folds: (i) prepare for the clinical trial (UG3 phase, year 1), and determine the safety and efficacy of MSC therapy in patients with painful CP (UH3 phase, year 2-5). Another critical part of the clinical trial phase will be to define the mechanisms by which MSCs relieve multiple injuries in the pancreas by measuring changes of peripheral blood mononuclear cells (PBMCs), especially monocyte subsets and serum proinflammatory cytokine profiles of treated patients, with the goal of identifying biochemical pathways and serum biomarkers of response to MSC therapy. This study may help develop novel non-addictive cellular therapy for chronic pancreatitis and pain.