Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Advanced Cell Therapy Centre, Finnish Red Cross Blood Service, Helsinki, Finland.
Cytotherapy. 2019 Feb;21(2):175-188. doi: 10.1016/j.jcyt.2018.11.011. Epub 2019 Jan 2.
Mesenchymal stromal cells (MSCs) are a promising candidate for treatment of inflammatory disorders, but their efficacy in human inflammatory bowel diseases (IBDs) has been inconsistent. Comparing the results from various pre-clinical and clinical IBD studies is also challenging due to a large variation in study designs.
In this comparative pre-clinical study, we compared two administration routes and investigated the safety and feasibility of both fresh and cryopreserved platelet-lysate-expanded human bone marrow-derived MSCs without additional licensing in a dextran sodium sulfate (DSS) colitis mouse model both in the acute and regenerative phases of colitis. Body weight, macroscopic score for inflammation and colonic interleukin (IL)-1β and tumor necrosis factor (TNF)α concentrations were determined in both phases of colitis. Additionally, histopathology was assessed and Il-1β and Agtr1a messenger RNA (mRNA) levels and angiotensin-converting enzyme (ACE) protein levels were measured in the colon in the regenerative phase of colitis.
Intravenously administered MSCs exhibited modest anti-inflammatory capacity in the acute phase of colitis by reducing IL-1β protein levels in the inflamed colon. There were no clear improvements in mice treated with fresh or cryopreserved unlicensed MSCs according to weight monitoring results, histopathology and macroscopic score results. Pro-inflammatory ACE protein expression and shedding were reduced by cryopreserved MSCs in the colon.
In conclusion, we observed a good safety profile for bone marrow-derived platelet lysate-expanded MSCs in a mouse pre-clinical colitis model, but the therapeutic effect of MSCs prepared without additional licensing (i.e. such as MSCs are administered in graft-versus-host disease) was modest in the chosen in vivo model system and limited to biochemical improvements in cytokines without a clear benefit in histopathology or body weight development.
间充质基质细胞（MSCs）是治疗炎症性疾病的有前途的候选物，但它们在人类炎症性肠病（IBD）中的疗效一直不一致。由于研究设计的差异很大，比较各种临床前和临床 IBD 研究的结果也具有挑战性。
在这项比较性临床前研究中，我们比较了两种给药途径，并在葡聚糖硫酸钠（DSS）结肠炎小鼠模型中，在急性和再生阶段的结肠炎中，分别研究了新鲜和冷冻保存的血小板裂解物扩展的人骨髓源性 MSCs 的安全性和可行性，而无需额外的许可。在两个阶段的结肠炎中，我们测定了体重、炎症的宏观评分以及结肠白细胞介素（IL）-1β和肿瘤坏死因子（TNF）α的浓度。此外，在再生阶段的结肠炎中，我们评估了组织病理学，并测定了结肠中 IL-1β和 Agtr1a 信使 RNA（mRNA）水平和血管紧张素转换酶（ACE）蛋白水平。
静脉内给予 MSCs 在急性结肠炎阶段通过降低炎症结肠中的 IL-1β蛋白水平表现出适度的抗炎作用。根据体重监测结果、组织病理学和宏观评分结果，未观察到新鲜或冷冻保存未经许可的 MSC 治疗的小鼠有明显改善。冷冻保存的 MSC 降低了结肠中的促炎 ACE 蛋白表达和脱落。
总之，我们在结肠炎小鼠临床前模型中观察到骨髓源性血小板裂解物扩展的 MSC 具有良好的安全性，但是在所选的体内模型系统中，未经额外许可制备的 MSC（例如在移植物抗宿主病中给予 MSC）的治疗效果适中，仅限于细胞因子的生化改善，而在组织病理学或体重发育方面没有明显益处。
