Heparin improves BMSC cell therapy: Anticoagulant treatment by heparin improves the safety and therapeutic effect of bone marrow-derived mesenchymal stem cell cytotherapy.
Heparin improves BMSC cell therapy: Anticoagulant treatment by heparin improves the safety and therapeutic effect of bone marrow-derived mesenchymal stem cell cytotherapy.
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肝素改善骨髓间充质干细胞治疗：肝素抗凝治疗提高骨髓间充质干细胞治疗的安全性和治疗效果
作者：
Liao L;Shi B;Chang H;Su X;Zhang L;Bi C;Shuai Y;Du X;Deng Z;Jin Y
骨髓间充质干细胞（BMSCs）的系统输注已成为疾病治疗和组织再生的一种有前途的策略。提高骨髓间充质干细胞治疗效率是促进其临床应用的关键。在这里，我们旨在通过抑制BMSC诱导的凝血反应来改善BMSC细胞治疗。将梯度BMSCs静脉注射到小鼠体内，结果显示BMSCs与血液并不完全相容。大剂量骨髓间充质干细胞诱导了一系列呼吸衰竭和心力衰竭的症状。组织学和稳态分析证实，大剂量BMSCs诱导弥散性血管内血栓形成，血小板和凝血因子耗竭，凝血酶原时间（PT）和活化部分凝血活酶时间（APTT）延长。与小鼠BMSCs相似，山羊和人BMSCs在体外和体内也诱导凝血反应。组织因子主要诱导骨髓间充质干细胞的凝血功能，组织因子的过表达可增强骨髓间充质干细胞体外培养过程中的促凝血活性。值得注意的是，细胞治疗中临床剂量的BMSC也诱导轻度和可逆的凝血，这增加了BMSC肺栓塞和清除。肝素抗凝治疗（400 U/kg）可有效预防BMSCs诱导的凝血和大剂量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BMSC向细胞治疗中靶器官的迁移和维持。基于实验性结肠炎模型，我们证实肝素治疗有效地增强了BMSC治疗的效果，以降低死亡率，防止体重减轻，抑制炎症反应和减轻组织损伤。结论：骨髓间充质干细胞具有促凝血活性，可诱导受者弥散性凝血和血栓形成。肝素抗凝治疗是提高骨髓间充质干细胞治疗安全性和疗效的有效策略。
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 in vitro and in vivo. The coagulation was induced mostly by tissue factor, the overexpression of which enhanced the procoagulant activity of BMSCs during in vitro 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.
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影响因子：
6.7
作者：
Naito, Y;Takagi, T;Yoshikawa, T
通讯作者：
Yoshikawa, T
影响因子：
23.9
作者：
Caplan AI;Correa D
通讯作者：
Correa D
影响因子：
13.6
作者：
Ankrum J;Karp JM
通讯作者：
Karp JM
影响因子：
24
作者：
Hare, Joshua M.;Traverse, Jay H.;Henry, Timothy D.;Dib, Nabil;Strumpf, Robert K.;Schulman, Steven P.;Gerstenblith, Gary;DeMaria, Anthony N.;Denktas, Ali E.;Gammon, Roger S.;Hermiller, James B., Jr.;Reisman, Mark A.;Schaer, Gary L.;Sherman, Warren
通讯作者：
Sherman, Warren
DOI：
10.1073/pnas.0608249103
发表时间：
2006-11-14
影响因子：
11.1
作者：
Lee, Ryang Hwa;Seo, Min Jeong;Prockop, Darwin J.
通讯作者：
Prockop, Darwin J.