Heparin improves BMSC cell therapy: Anticoagulant treatment by heparin improves the safety and therapeutic effect of bone marrow-derived mesenchymal stem cell cytotherapy

被引：114

作者：

Liao, Li ^{[1
,2
,3
,4
]}

Shi, Bingzheng ^{[1
,2
,3
,5
]}

Chang, Heran ^{[1
,2
,3
,5
]}

Su, Xiaoxia ^{[6
]}

Zhang, Lichao ^{[1
,2
,3
,5
]}

Bi, Chunsheng ^{[1
,2
,3
]}

Shuai, Yi ^{[1
,2
,3
,4
]}

Du, Xiaoyan ^{[7
]}

Deng, Zhihong ^{[8
]}

Jin, Yan ^{[1
,2
,3
,4
]}

机构：

[1] Fourth Mil Med Univ, State Key Lab Mil Stomatol, Sch Stomatol, Ctr Tissue Engn, Xian 710032, Shaanxi, Peoples R China

[2] Fourth Mil Med Univ, Natl Clin Res Ctr Oral Dis, Ctr Tissue Engn, Sch Stomatol, Xian 710032, Shaanxi, Peoples R China

[3] Fourth Mil Med Univ, Shaanxi Int Joint Res Ctr Oral Dis, Ctr Tissue Engn, Sch Stomatol, Xian 710032, Shaanxi, Peoples R China

[4] Fourth Mil Med Univ, Res & Dev Ctr Tissue Engn, Xian 710032, Shaanxi, Peoples R China

[5] Jia Mu Si Univ, Stomatol Hosp, Jiamusi 154007, Heilongjiang, Peoples R China

[6] Xi An Jiao Tong Univ, Dept Orthodont, Coll Med, Stomatol Hosp, Xian 710032, Shaanxi, Peoples R China

[7] Chinese Assoc Plast & Aesthet, Beijing 100039, Peoples R China

[8] Fourth Mil Med Univ, Xijing Hosp, Dept Otolaryngol, Xian 710032, Shaanxi, Peoples R China

来源：

THERANOSTICS | 2017年 / 7卷 / 01期

关键词：

Anticoagulant; Cell therapy; Coagulation; Heparin; Mesenchymal stem cell; VERSUS-HOST-DISEASE; STROMAL CELLS; INFARCTED HEARTS; TISSUE FACTOR; INJECTION; MICE; TRANSPLANTATION; OSTEOPOROSIS; DELIVERY; COLITIS;

D O I：

10.7150/thno.16911

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：106 / 116

页数：11