Clinic for Stem Cell Transplantation, Department of Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
PLoS One. 2011 Jan 5;6(1):e14486. doi: 10.1371/journal.pone.0014486.
Successful treatment of acute radiation syndromes relies on immediate supportive care. In patients with limited hematopoietic recovery potential, hematopoietic stem cell (HSC) transplantation is the only curative treatment option. Because of time consuming donor search and uncertain outcome we propose MSC treatment as an alternative treatment for severely radiation-affected individuals.
Mouse mesenchymal stromal cells (mMSCs) were expanded from bone marrow, retrovirally labeled with eGFP (bulk cultures) and cloned. Bulk and five selected clonal mMSCs populations were characterized in vitro for their multilineage differentiation potential and phenotype showing no contamination with hematopoietic cells. Lethally irradiated recipients were i.v. transplanted with bulk or clonal mMSCs. We found a long-term survival of recipients with fast hematopoietic recovery after the transplantation of MSCs exclusively without support by HSCs. Quantitative PCR based chimerism analysis detected eGFP-positive donor cells in peripheral blood immediately after injection and in lungs within 24 hours. However, no donor cells in any investigated tissue remained long-term. Despite the rapidly disappearing donor cells, microarray and quantitative RT-PCR gene expression analysis in the bone marrow of MSC-transplanted animals displayed enhanced regenerative features characterized by (i) decreased proinflammatory, ECM formation and adhesion properties and (ii) boosted anti-inflammation, detoxification, cell cycle and anti-oxidative stress control as compared to HSC-transplanted animals.
Our data revealed that systemically administered MSCs provoke a protective mechanism counteracting the inflammatory events and also supporting detoxification and stress management after radiation exposure. Further our results suggest that MSCs, their release of trophic factors and their HSC-niche modulating activity rescue endogenous hematopoiesis thereby serving as fast and effective first-line treatment to combat radiation-induced hematopoietic failure.
急性辐射综合征的成功治疗依赖于立即的支持性护理。对于造血恢复潜力有限的患者，造血干细胞（HSC）移植是唯一的治愈性治疗选择。由于供体搜索耗时且结果不确定，我们提出将间充质干细胞（MSC）治疗作为治疗严重辐射影响个体的替代方法。
从小鼠骨髓中扩增间充质基质细胞（mMSC），用 eGFP 逆转录病毒标记（批量培养）并克隆。对批量和五个选定的克隆 mMSC 群体进行体外多能性分化潜力和表型特征分析，结果显示无造血细胞污染。致死性辐射的受者通过静脉内移植批量或克隆 mMSC。我们发现，在没有 HSC 支持的情况下，仅通过 MSC 移植即可使受者长期存活并快速恢复造血。基于定量 PCR 的嵌合分析在注射后立即和 24 小时内在肺部检测到 eGFP 阳性供体细胞。然而，在任何研究的组织中都没有长期存在的供体细胞。尽管供体细胞迅速消失，但骨髓中 MSC 移植动物的微阵列和定量 RT-PCR 基因表达分析显示，再生特征增强，表现为（i）促炎、细胞外基质形成和黏附特性降低，以及（ii）抗炎、解毒、细胞周期和抗氧化应激控制增强，与 HSC 移植动物相比。
我们的数据表明，系统给予的 MSC 可引发一种保护性机制，抵消炎症事件，并在辐射暴露后支持解毒和应激管理。此外，我们的结果表明，MSC 及其释放的营养因子和对 HSC 巢位的调节活性可挽救内源性造血，从而作为对抗辐射诱导的造血衰竭的快速有效的一线治疗方法。
