IGF-1R选择性诱导敲除对Nestin~+骨髓间充质干细胞迁移和分化的影响
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摘要
研究背景及目的：骨重建的过程包括骨吸收和骨形成两个过程。IGF-1与骨量的获得密切相关,血清IGF-1主要影响皮质骨的生长,而基质IGF-1则与小梁骨的获得密切相关。目前IGF-1在体内环境下对骨髓间充质干细胞的增殖、分化和凋亡的影响机制仍未阐明,因此本实验通过诱导选择性基因敲除小鼠建立间充质干细胞追踪系来研究IGF-1对骨髓间充质干细胞的影响。
研究方法：本实验首先建立Nes-CreER::ROSA26-EYFPflox/+报告基因小鼠模型验证Nes-CreER重组酶的作用。我们同时建立Nestin-CreER::Igflrflox/flox诱导性基因敲除小鼠系,在3-7周龄期间注射他莫西芬(0.1mg/Kg.q3d)诱导敲除骨髓间充质干细胞的IGF-1R。在此期间定期测量小鼠体重、身长,并于第7周末对下肢股骨进行MicroCT分析。最后我们取小鼠下肢行H&E染色及免疫组化染色观察骨表面成骨祖细胞和成熟成骨细胞数量的变化。
实验结果：Nes-CreER::ROSA26-EYFPflox/+报告基因小鼠股骨免疫荧光染色发现大量表达过Nestin的细胞(YFP+)分布于骨髓腔及骨表面。诱导选择性基因敲除小鼠体重、身长、股骨长度与对照组相比无明显差异,而MicroCT则发现雌性小鼠股骨远端次级骨松质的体积骨分数(BV/TV)和骨小梁厚度(Tb.Th)与对照组相比明显减少(P<0.05)。通过免疫组化进一步发现,单位骨表面Osterix+成骨祖细胞数量(14.80±2.36)和对照组(14.22±1.39)相比无明显差异(P=0.726),而Osteocalcin+成熟成骨细胞(8.774±0.36)与对照组(14.88±0.66)相比明显减少(P<0.001)。
实验结论：在体内环境下Nestin+骨髓间充质干细胞主要向成骨细胞和成纤维细胞方向分化。诱导选择性敲除Nestin+骨髓间充质干细胞IGF-1R并不影响小鼠正常生长,但会导致小梁骨量减少。同时,在体内环境下IGF-1主要作用为促进成骨祖细胞向成骨细胞的分化,而不影响骨髓间充质干细胞的迁移。
Background:Bone remodeling is a process consisting of bone resorption and bone formation. Insulin-life growth factor1(IGF-1) is important for bone formation. While serum IGF-1tends to target cortical bone, matrix IGF-1is a critical coupling factor for maintenance of trabecular bone. The cell signaling mechanisms for proliferation, differentiation and apoptosis of the mesenchymal stem cells (MSCs) in vivo have yet to be elucidated. This experiment clarified the role of IGF-1signaling on bone marrow MSCs using an inducible gene knockout mouse model.
Methods:We first established a reporter mouse, Nestin-CreER::ROSA26-EYFPflox/+to confirm previous findings that Nestin expression represents a subset of bone marrow MSCs. We then used the same Nestin-CreER mouse crossed with an Igflrflox/flox mouse, to delete the IGF-1type1receptor (Igflr) in the bone marrow mesenchymal stem cells (MSCs) from3-7weeks of age after the injection of Tamoxifen (0.1mg/kg-Body weight.q3d). We measured the weight, nasoanal length and the femoral length of the mice, and analyzed the secondary spongiosa of the femur using microcomputed tomography at the end of week7. Femur were processed for H&E staining and immunhistochemical staining for Osterix and Osteocalcin to localize and quantify osteoprogenitor cells as well as mature osteoblasts, respectively.
Results:YFP staining of the femur in the reporter mice showed that the majority of Nestin-daughter cells were located either in the bone marrow or on the bone surface by immunoflorecent staining, confirming that Nestin-daughter cells differentiate into the osteoblast lineage. In the Nestin-CreER::Igflrflox/flox mice, the size of the knockout mouse was not affected as wild type littermates had similar body weights and nasoanal and femoral lengths. However, bone volume and trabecular bone thickness were decreased in the secondary spongiosa of female knockout mice relative to wild type littermates (P<0.05). Immunohistochemical analysis revealed that a similar number of Osterix+osteoprogenitors were on the bone perimeter (P=0.726), while Osteocalcin+mature osteoblasts on the bone perimeter were significantly decreased in the secondary spongiosa in knockout mice versus wild type littermates (P<0.001).
Conclusion:Nestin+bone marrow MSCs predominantly differentiate into osteoblast lineage in vivo postnatally. Deletion of Igflr in MSCs results in impaired bone formation during bone remodeling secondary to impaired osteoblast differentiation, while MSC recruitment is not affected.
研究方法：本实验首先建立Nes-CreER::ROSA26-EYFPflox/+报告基因小鼠模型验证Nes-CreER重组酶的作用。我们同时建立Nestin-CreER::Igflrflox/flox诱导性基因敲除小鼠系,在3-7周龄期间注射他莫西芬(0.1mg/Kg.q3d)诱导敲除骨髓间充质干细胞的IGF-1R。在此期间定期测量小鼠体重、身长,并于第7周末对下肢股骨进行MicroCT分析。最后我们取小鼠下肢行H&E染色及免疫组化染色观察骨表面成骨祖细胞和成熟成骨细胞数量的变化。
实验结果：Nes-CreER::ROSA26-EYFPflox/+报告基因小鼠股骨免疫荧光染色发现大量表达过Nestin的细胞(YFP+)分布于骨髓腔及骨表面。诱导选择性基因敲除小鼠体重、身长、股骨长度与对照组相比无明显差异,而MicroCT则发现雌性小鼠股骨远端次级骨松质的体积骨分数(BV/TV)和骨小梁厚度(Tb.Th)与对照组相比明显减少(P<0.05)。通过免疫组化进一步发现,单位骨表面Osterix+成骨祖细胞数量(14.80±2.36)和对照组(14.22±1.39)相比无明显差异(P=0.726),而Osteocalcin+成熟成骨细胞(8.774±0.36)与对照组(14.88±0.66)相比明显减少(P<0.001)。
实验结论：在体内环境下Nestin+骨髓间充质干细胞主要向成骨细胞和成纤维细胞方向分化。诱导选择性敲除Nestin+骨髓间充质干细胞IGF-1R并不影响小鼠正常生长,但会导致小梁骨量减少。同时,在体内环境下IGF-1主要作用为促进成骨祖细胞向成骨细胞的分化,而不影响骨髓间充质干细胞的迁移。
Background:Bone remodeling is a process consisting of bone resorption and bone formation. Insulin-life growth factor1(IGF-1) is important for bone formation. While serum IGF-1tends to target cortical bone, matrix IGF-1is a critical coupling factor for maintenance of trabecular bone. The cell signaling mechanisms for proliferation, differentiation and apoptosis of the mesenchymal stem cells (MSCs) in vivo have yet to be elucidated. This experiment clarified the role of IGF-1signaling on bone marrow MSCs using an inducible gene knockout mouse model.
Methods:We first established a reporter mouse, Nestin-CreER::ROSA26-EYFPflox/+to confirm previous findings that Nestin expression represents a subset of bone marrow MSCs. We then used the same Nestin-CreER mouse crossed with an Igflrflox/flox mouse, to delete the IGF-1type1receptor (Igflr) in the bone marrow mesenchymal stem cells (MSCs) from3-7weeks of age after the injection of Tamoxifen (0.1mg/kg-Body weight.q3d). We measured the weight, nasoanal length and the femoral length of the mice, and analyzed the secondary spongiosa of the femur using microcomputed tomography at the end of week7. Femur were processed for H&E staining and immunhistochemical staining for Osterix and Osteocalcin to localize and quantify osteoprogenitor cells as well as mature osteoblasts, respectively.
Results:YFP staining of the femur in the reporter mice showed that the majority of Nestin-daughter cells were located either in the bone marrow or on the bone surface by immunoflorecent staining, confirming that Nestin-daughter cells differentiate into the osteoblast lineage. In the Nestin-CreER::Igflrflox/flox mice, the size of the knockout mouse was not affected as wild type littermates had similar body weights and nasoanal and femoral lengths. However, bone volume and trabecular bone thickness were decreased in the secondary spongiosa of female knockout mice relative to wild type littermates (P<0.05). Immunohistochemical analysis revealed that a similar number of Osterix+osteoprogenitors were on the bone perimeter (P=0.726), while Osteocalcin+mature osteoblasts on the bone perimeter were significantly decreased in the secondary spongiosa in knockout mice versus wild type littermates (P<0.001).
Conclusion:Nestin+bone marrow MSCs predominantly differentiate into osteoblast lineage in vivo postnatally. Deletion of Igflr in MSCs results in impaired bone formation during bone remodeling secondary to impaired osteoblast differentiation, while MSC recruitment is not affected.
引文
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[4]Wang Y, Nishida S, Sakata T, et al. Insulin-like growth factor-I is essential for embryonic bone development. Endocrinology,2006,147(10):4753-61.
[5]He J, Rosen C J, Adams D J, et al. Postnatal growth and bone mass in mice with IGF-I haploinsufficiency. Bone,2006,38(6):826-35.
[6]Bikle D, Majumdar S, Laib A, et al. The skeletal structure of insulin-like growth factor I-deficient mice. J Bone Miner Res,2001,16(12):2320-9.
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[8]DeMambro V E, Kawai M, Clemens T L, et al. A novel spontaneous mutation of Irsl in mice results in hyperinsulinemia, reduced growth, low bone mass and impaired adipogenesis. J Endocrinol,2010,204(3):241-53.
[9]Silha J V, Gui Y, Modric T, et al. Overexpression of the acid-labile subunit of the IGF ternary complex in transgenic mice. Endocrinology,2001, 142(10):4305-13.
[10]Ben Lagha N, Seurin D, Le Bouc Y, et al. Insulin-like growth factor binding protein (IGFBP-1) involvement in intrauterine growth retardation:study on IGFBP-1 overexpressing transgenic mice. Endocrinology,2006, 147(10):4730-7.
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