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Spatio-Temporal Metabolokinetics and Efficacy of Human Placenta-Derived Mesenchymal Stem/Stromal Cells on Mice with Refractory Crohn’s-like Enterocutaneous Fistula
Stem Cell Reviews and Reports ( IF 4.8 ) Pub Date : 2020-10-03 , DOI: 10.1007/s12015-020-10053-2
Huixing Hou 1 , Leisheng Zhang 2, 3, 4 , Liyun Duan 1 , Yuanyuan Liu 1 , Zhongchao Han 3, 4 , Zongjin Li 2 , Xiaocang Cao 1
Affiliation  

Crohn’s disease (CD) with externally fistulizing openings indicates the aggressive and relapsing manifestation and results in undesirable long-term outcomes of patients. MSC-based approach combined with multidisciplinary strategy has mandated a redefinition of the administration and management of numerous recurrent and refractory diseases whereas the spatio-temporal evaluation of the metabolokinetics and efficacy of MSCs on intractable CD with enterocutaneous fistula (EF) are largely inaccessible and dauntingly complex. Herein, we primitively established dual-fluorescence expressing placenta-derived MSCs (DF-MSCs) and explored their multidimensional attributes, including cytomorphology, immunophenotying, multilineage differentiation and long-term proliferation, together with the recognition of bifluorescence intensity (BLI). Then, with the aid of in vivo living imaging, clinicopathological or inflammatory cytokine examinations and in vitro analyses, we systematically and meticulously dissected the metabolokinetics and curative effect of MSCs on mice with refractory Crohn’s-like EF (EF mice), together with revealing the underlying mechanism including reactive oxygen species (ROS) and neovascularization. Strikingly, the DF-MSCs exhibited stabilized BLI and biological properties. The spatio-temporal distribution and therapeutic process of MSCs in EF mice were intuitively delineated. Meanwhile, our data indicated the curative mechanisms of DF-MSCs by simultaneously downregulating ROS and accelerating neovascularization. Collectively, we systematically illuminated the spatio-temporal biofunction and mechanism of DF-MSCs on EF mice. Our findings have supplied new references for safety and effectiveness assessments as well as the establishment of guidelines for optimal administrations of MSC-based cytotherapy in preclinical studies, which collectively indicates the prospect of P-MSC administration in clinical trials during a wide spectrum of disease remodeling including the fistulizing CD.



中文翻译:

人胎盘源性间充质干/基质细胞对难治性克罗恩样肠皮瘘小鼠的时空代谢动力学和疗效

具有外部瘘口的克罗恩病 (CD) 表明具有侵袭性和复发性表现,并导致患者的长期不良结果。基于 MSC 的方法结合多学科策略要求重新定义许多复发性和难治性疾病的管理和管理,而对 MSCs 对难治性 CD 肠皮肤瘘 (EF) 的代谢动力学和疗效的时空评估在很大程度上是难以接近和令人生畏的复杂的。在此,我们初步建立了双荧光表达胎盘来源的间充质干细胞 (DF-MSCs),并探索了它们的多维属性,包括细胞形态学、免疫表型、多向分化和长期增殖,以及双荧光强度 (BLI) 的识别。然后,借助体内活体成像、临床病理或炎症细胞因子检查和体外分析,我们系统细致地剖析了 MSCs 对难治性克罗恩样 EF 小鼠(EF 小鼠)的代谢动力学和疗效,并揭示了其潜在机制包括活性氧 (ROS) 和新血管形成。引人注目的是,DF-MSC 表现出稳定的 BLI 和生物学特性。直观描绘了 EF 小鼠中 MSCs 的时空分布和治疗过程。同时,我们的数据表明了 DF-MSCs 通过同时下调 ROS 和加速新生血管形成的治疗机制。总的来说,我们系统地阐明了 DF-MSCs 对 EF 小鼠的时空生物功能和机制。

更新日期:2020-10-04
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