Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms
Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms
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DOI：
10.1182/blood-2011-12-400085
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发表时间：
2012-08-30
期刊：
影响因子：
20.3
通讯作者：
Horwitz, Edwin M.
中科院分区：
文献类型：
--
作者：
Otsuru, Satoru;Gordon, Patricia L.;Horwitz, Edwin M.
全骨髓（BMT）以及体外扩增的间充质基质细胞（MSC）的移植在儿童成骨障碍（OI）中产生了显着的临床益处;然而，这些细胞疗法的潜在机制尚未阐明。在这里，我们表明，非（塑料）贴壁骨髓细胞（NABMCs）是更有效的骨祖细胞比骨髓间充质干细胞在小鼠。将这些发现转化为临床，给予先前接受过BMT的OI儿童T细胞耗尽的骨髓单核细胞加强（> 99.99%NABMC）导致患者亚组的显著生长加速，明确表明骨髓细胞对这些患者的治疗潜力。然后，在OI的小鼠模型中，我们证明了当供体NABMC分化成成骨细胞时，它们为骨基质提供正常的胶原蛋白。相比之下，MSC基本上不植入骨中，而是分泌间接刺激生长的可溶性介质，这些数据提供了我们先前对患有OI的儿童进行MSC治疗的临床试验的潜在机制。总的来说，我们的数据表明，NABMCs和MSC都构成了OI的有效细胞疗法，但通过不同的互补机制发挥其临床影响。该研究在www.clinicaltrials.gov注册为NCT 00187018。（血。2012;120（9）：1933-1941）
Transplantation of whole bone marrow (BMT) as well as ex vivo-expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non-(plastic)-adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell-depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at www.clinicaltrials.gov as NCT00187018. (Blood. 2012;120(9):1933-1941)