Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice
Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice
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DOI：
10.1172/jci33102
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发表时间：
2008-02-01
影响因子：
15.9
通讯作者：
Scadden, David T.
中科院分区：
文献类型：
--
作者：
Mukherjee, Siddhartha;Raje, Noopur;Scadden, David T.
靶向成体干细胞的药物已被提出作为再生医学的策略，但很少有药物已知靶向体内干细胞群。间充质干/祖细胞（MSC）是一种多能细胞群，可以以特定的方式分化为肌肉，骨骼，脂肪和其他细胞类型。硼替佐米（Bzb）是一种临床上可用的蛋白酶体抑制剂，用于治疗多发性骨髓瘤。在这里，我们表明，Bzb诱导骨髓间充质干细胞优先进行成骨细胞分化，部分是通过调节骨特异性转录因子Runx-2（Runx-2）在小鼠。当受体接受低剂量的Bzb时，植入MSCs的小鼠显示异位小骨和骨形成增加。此外，这种治疗增加了骨质疏松症小鼠模型中的骨形成并挽救了骨丢失。因此，我们表明，在体内的组织驻留的成体干细胞群体可以被修饰，以促进成年动物的再生功能。
Drug targeting of adult stem cells has been proposed as a strategy for regenerative medicine, but very few drugs are known to target stem cell populations in vivo. Mesenchymal stem/progenitor cells (MSCs) are a multipotent population of cells that can differentiate into muscle, bone, fat, and other cell types in context-specific manners. Bortezomib (Bzb) is a clinically available proteasome inhibitor used in the treatment of multiple myeloma. Here, we show that Bzb induces MSCs to preferentially undergo osteoblastic differentiation, in part by modulation of the bone-specifying transcription factor runt-related transcription factor 2 (Runx-2) in mice. Mice implanted with MSCs showed increased ectopic ossicle and bone formation when recipients received low doses of Bzb. Furthermore, this treatment increased bone formation and rescued bone loss in a mouse model of osteoporosis. Thus, we show that a tissue-resident adult stem cell population in vivo can be pharmacologically modified to promote a regenerative function in adult animals.