Mesenchymal stem cells expressing insulin-like growth factor-I (MSCIGF) promote fracture healing and restore new bone formation in Irs1 knockout mice: analyses of MSCIGF autocrine and paracrine regenerative effects.
Mesenchymal stem cells expressing insulin-like growth factor-I (MSCIGF) promote fracture healing and restore new bone formation in Irs1 knockout mice: analyses of MSCIGF autocrine and paracrine regenerative effects.
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DOI：
10.1002/stem.697
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发表时间：
2011-10
期刊：
影响因子：
5.2
通讯作者：
Spagnoli, Anna
中科院分区：
文献类型：
--
作者：
Granero-Molto, Froilan;Myers, Timothy J.;Weis, Jared A.;Longobardi, Lara;Li, Tieshi;Yan, Yun;Case, Natasha;Rubin, Janet;Spagnoli, Anna
骨折修复失败(不愈合)发生在所有骨折中的10%。间充质干细胞(MSC)在组织再生中的应用似乎是合理、安全和可行的。MSC对修复过程的贡献可以通过自分泌和旁分泌作用来实现。本研究的主要目的是寻找一种新的方法，通过移植表达胰岛素样生长因子-I(MSCIGF)的骨髓来源的MSC的原代培养，促进MSC的种子和土壤作用，以充分发挥其在骨折修复和骨不连中的再生能力。将MSCIGF或可追踪的MSCIGF-Lac-Z移植到胫骨骨折稳定的野生型或胰岛素受体底物敲除(IRS1−/−)小鼠体内。通过生物力学测试、显微计算机断层扫描(µCT)和组织学分析评价愈合情况。我们发现系统移植的MSCIGF通过自分泌和旁分泌作用提高了骨折的机械强度，增加了新骨含量，同时加速了矿化。我们确定IGF-I适应移植的MSCIGF的反应，以促进其向成骨细胞分化。体外和体内研究表明，IGF-I诱导的MSC成骨作用依赖于完整的IRS1-PI3K信号。此外，通过改变胰岛素样生长因子信号，我们使用irs1−/−小鼠作为骨折不愈合模型，我们证明了胰岛素样生长因子-I对骨髓间充质干细胞的自分泌作用恢复了骨折处的新骨形成，并促进了组织良好的骨痂的出现，弥合了缝隙；一个在irs1−/−中基本缺失的骨痂保留了未移植的或移植的骨髓间充质干细胞。我们为移植MSCIGF在骨折修复和潜在治疗骨不连中的作用和机制提供了证据。
Failures of fracture repair (non-unions) occur in 10% of all fractures. The use of mesenchymal stem cells (MSC) in tissue regeneration appears to be rationale, safe and feasible. The contributions of MSC to the reparative process can occur through autocrine as well as paracrine effects. The primary objective of this study is to find a novel mean, by transplanting primary cultures of bone marrow-derived MSC expressing insulin-like growth factor-I (MSCIGF), to promote these seed-and-soil actions of MSC to fully implement their regenerative abilities in fracture repair and non-unions. MSCIGF or traceable MSCIGF-Lac-Z were transplanted into wild-type or insulin-receptor-substrate knock-out (Irs1−/−) mice with a stabilized tibia fracture. Healing was assed using biomechanical testing, micro-computed-tomography (µCT) and histological analyses. We found that systemically transplanted MSCIGF through autocrine and paracrine actions improved the fracture mechanical strength and increased new bone content while accelerating mineralization. We determined that IGF-I adapted the response of transplanted MSCIGF to promote their differentiation into osteoblasts. In vitro and in vivo studies showed that IGF-I-induced induced osteoglastogenesis in MSC was dependent of an intact IRS1-PI3K signaling. Furthermore, using Irs1−/− mice as a non-union fracture model through altered IGF signaling, we demonstrated that the autocrine effect of IGF-I on MSC restored the fracture new bone formation and promoted the occurrence of a well-organized callus that bridged the gap; a callus that basically absent in Irs1−/− left untransplanted or transplanted with MSC. We provided evidence of effects and mechanisms for transplanted MSCIGF in fracture repair and potentially to treat non-unions.
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影响因子：
5.2
作者：
Gandia, Carolina;Arminan, Ana;Sepulveda, Pilar
通讯作者：
Sepulveda, Pilar
DOI：
10.1097/phm.0b013e31818e002d
发表时间：
2009-02-01
影响因子：
3
作者：
Di Monaco, Marco;Vallero, Fulvia;Cavanna, Alberto
通讯作者：
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DOI：
10.1016/j.bbrc.2006.05.034
发表时间：
2006-07-07
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
7.6
作者：
Feng, JQ;Huang, H;Mishina, Y
通讯作者：
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影响因子：
6.2
作者：
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通讯作者：
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