Liao Li, Shi Bingzheng, Chang Heran, Su Xiaoxia, Zhang Lichao, Bi Chunsheng, Shuai Yi, Du Xiaoyan, Deng Zhihong, Jin Yan
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China;; Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Xi'an, Shaanxi 710032, China.
State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China;; Stomatological Hospital Affiliated to Jia Mu Si University, JiaMuSi, Heilongjiang 154007, China.
Theranostics. 2017 Jan 1;7(1):106-116. doi: 10.7150/thno.16911. eCollection 2017.
Systemic infusion of bone marrow-derived mesenchymal stem cells (BMSCs) has become a promising strategy for disease treatment and tissue regeneration. Strategies to enhance the efficiency of BMSC cell therapy are crucial to promote its clinical application. Here, we aimed to improve BMSC cell therapy by inhibiting the BMSC-induced coagulation reaction. Intravenous injection of gradient BMSCs into mice showed that BMSCs were not fully compatible with blood. Large doses of BMSCs induced a series of symptoms of respiratory failure and heart failure. Histological and homeostasis analysis confirmed that large doses of BMSCs induced disseminated intravascular thrombosis, exhaustion of platelets and coagulation factors, and prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT). Similar to mouse BMSCs, goat and human BMSCs also induced coagulation reactions and . The coagulation was induced mostly by tissue factor, the overexpression of which enhanced the procoagulant activity of BMSCs during culture. Notably, clinical doses of BMSCs in cell therapy also induced mild and reversible coagulation, which increased BMSC lung embolism and clearance. Anticoagulation treatment by heparin (400 U/kg) prevented BMSC-induced coagulation and the acute adverse effects of large-dose BMSCs infusion efficiently. Importantly, heparin treatment led to decreased BMSC lung embolism and enhanced migration and maintenance of BMSCs to target organs in cell therapy. Based on an experimental colitis model, we confirmed that heparin treatment enhanced the effect of BMSC therapy efficiently to reduce mortality, prevent weight loss, suppress inflammation reaction and alleviate tissue injury. In conclusion, BMSCs possess procoagulant activity that could induce disseminated coagulation and thrombosis in recipients. Anticoagulation treatment by heparin is a practical strategy to improve both the safety and therapeutic effect of BMSC therapy.
全身输注骨髓间充质干细胞（BMSCs）已成为一种有前景的疾病治疗和组织再生策略。提高BMSC细胞治疗效率的策略对于促进其临床应用至关重要。在此，我们旨在通过抑制BMSC诱导的凝血反应来改善BMSC细胞治疗。向小鼠静脉注射梯度BMSCs表明，BMSCs与血液不完全相容。大剂量的BMSCs会引发一系列呼吸衰竭和心力衰竭症状。组织学和内环境稳定分析证实，大剂量的BMSCs会导致弥散性血管内血栓形成、血小板和凝血因子耗竭，以及凝血酶原时间（PT）延长和活化部分凝血活酶时间（APTT）延长。与小鼠BMSCs类似，山羊和人BMSCs也会诱导凝血反应。这种凝血主要由组织因子诱导，其过度表达增强了培养过程中BMSCs的促凝活性。值得注意的是，细胞治疗中临床剂量的BMSCs也会诱导轻度且可逆的凝血，这增加了BMSC肺栓塞和清除率。肝素（400 U/kg）抗凝治疗有效预防了BMSC诱导的凝血以及大剂量BMSCs输注的急性不良反应。重要的是，肝素治疗导致BMSC肺栓塞减少，并增强了细胞治疗中BMSCs向靶器官的迁移和留存。基于实验性结肠炎模型，我们证实肝素治疗有效增强了BMSC治疗的效果，以降低死亡率、防止体重减轻、抑制炎症反应并减轻组织损伤。总之，BMSCs具有促凝活性，可在受体中诱导弥散性凝血和血栓形成。肝素抗凝治疗是一种提高BMSC治疗安全性和治疗效果的实用策略。
