Survival and biodistribution of xenogenic adipose mesenchymal stem cells is not affected by the degree of inflammation in arthritis.
Survival and biodistribution of xenogenic adipose mesenchymal stem cells is not affected by the degree of inflammation in arthritis.
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DOI：
10.1371/journal.pone.0114962
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Noël D
中科院分区：
文献类型：
--
作者：
Toupet K;Maumus M;Luz-Crawford P;Lombardo E;Lopez-Belmonte J;van Lent P;Garin MI;van den Berg W;Dalemans W;Jorgensen C;Noël D
骨髓间充质干细胞(MSCs)在治疗不同疾病，特别是骨关节疾病中的应用目前正在研究中。我们已经证明了在免疫缺陷小鼠中使用人类脂肪组织来源的基质干细胞(HASCs)是安全的。在本研究中，我们研究了在两种关节炎炎症模型中，MSC的持久性是否受到炎症程度的影响，并与治疗效果有关。我们用C57BL/6或DBA/1小鼠分别建立胶原酶诱导的骨关节炎(CIOA)和胶原诱导的关节炎(CIA)模型。正常和患病小鼠膝关节注射2.5×105个hASCs，尾静脉注射106个hASCs。对于CIA，临床评分是在疾病的时间进程中监测的，而对于CIOA，OA评分是在安乐死时通过组织学评估的。在不同时间点采集13个组织，进行实时荧光定量聚合酶链式反应和Alu序列检测。在实施安乐死时进行免疫学分析。静注后第1天，正常小鼠和CIA小鼠肺中hASCs的百分率没有显著差异，而在第10天，考虑到检测的敏感性，没有检测到细胞，这表明高水平的炎症不影响细胞的持久性。在CIOA小鼠中，我们报道了当关节中没有检测到hASCs时，hASCs在第42天降低OA临床评分的疗效。然而，在植入后第1天和第10天，骨关节炎小鼠和正常小鼠的hASCs的百分比和分布相似，表明中度炎症不会改变HASC在体内的持久性。虽然炎症信号是MSCs免疫抑制功能所必需的，但它们并不能增强其在体内的存活能力，正如在两个关节炎的异种炎症临床前模型中所评估的那样。
Application of mesenchymal stem/stromal cells (MSCs) in treating different disorders, in particular osteo-articular diseases, is currently under investigation. We have already documented the safety of administrating human adipose tissue-derived stromal MSCs (hASCs) in immunodeficient mice. In the present study, we investigated whether the persistence of MSC is affected by the degree of inflammation and related to the therapeutic effect in two inflammatory models of arthritis. We used C57BL/6 or DBA/1 mice to develop collagenase-induced osteoarthritis (CIOA) or collagen-induced arthritis (CIA), respectively. Normal and diseased mice were administered 2.5×105 hASCs in the knee joints (IA) or 106 in the tail vein (IV). For CIA, clinical scores were monitored during the time course of the disease while for CIOA, OA scores were assessed by histology at euthanasia. Thirteen tissues were recovered at different time points and processed for real-time PCR and Alu sequence detection. Immunological analyses were performed at euthanasia. After IV infusion, no significant difference in the percentage of hASCs was quantified in the lungs of normal and CIA mice at day 1 while no cell was detected at day 10 taking into account the sensitivity of the assay, indicating that a high level of inflammation did not affect the persistence of cells. In CIOA mice, we reported the therapeutic efficacy of hASCs at reducing OA clinical scores at day 42 when hASCs were not detected in the joints. However, the percentage and distribution of hASCs were similar in osteoarthritic and normal mice at day 1 and 10 after implantation indicating that moderate inflammation does not alter hASC persistence in vivo. While inflammatory signals are required for the immunosuppressive function of MSCs, they do not enhance their capacity to survive in vivo, as evaluated in two xenogeneic inflammatory pre-clinical models of arthritis.
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