脂肪干细胞成骨分化的研究进展

doi:10.3877/cma.j.issn.1673-9450.2016.02.011

中华损伤与修复杂志(电子版) ›› 2016, Vol. 11 ›› Issue (02) : 126 -134. doi: 10.3877/cma.j.issn.1673-9450.2016.02.011

所属专题：文献；

综述

脂肪干细胞成骨分化的研究进展

陈犹白¹, 陈聪慧², Qixu Zhang³, 韩岩⁴^,^†(

)

^1. 100853　北京，解放军总医院整形修复科；77030　休斯敦，美国德克萨斯大学MD安德森肿瘤中心整形外科
^2. 100020　北京，美莱医疗美容医院口腔美容中心
^3. 77030　休斯敦，美国德克萨斯大学MD安德森肿瘤中心整形外科
^4. 100853　北京，解放军总医院整形修复科

收稿日期:2016-02-01 出版日期:2016-04-01
通信作者: 韩岩

Research progress on osteogenic differentiation of adipose-derived stem cell

Youbai Chen¹, Conghui Chen², Qixu Zhang³, Yan Han⁴^,^†()

^1. Department of Plastic and Reconstructive Surgery, People′s Liberation Army General Hospital, Beijing 100853, China; Department of Plastic Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
^2. Dental Cosmetic Center, Mylike Aesthetic and Plastic Surgery Hospital, Beijing 100020, China
^3. Department of Plastic Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
^4. Department of Plastic and Reconstructive Surgery, People′s Liberation Army General Hospital, Beijing 100853, China

Received:2016-02-01 Published:2016-04-01
Corresponding author: Yan Han
About author:
Corresponding: Han Yan, Email: 13720086335@163.com

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引用本文：

陈犹白, 陈聪慧, Qixu Zhang, 韩岩. 脂肪干细胞成骨分化的研究进展[J/OL]. 中华损伤与修复杂志(电子版), 2016, 11(02): 126-134.

Youbai Chen, Conghui Chen, Qixu Zhang, Yan Han. Research progress on osteogenic differentiation of adipose-derived stem cell[J/OL]. Chinese Journal of Injury Repair and Wound Healing(Electronic Edition), 2016, 11(02): 126-134.

创伤或肿瘤导致的骨缺损是骨科、整形修复科、口腔颌面外科等科室的常见疾病，现有的治疗手段均有一定局限性。脂肪干细胞(ASC)是来自脂肪组织的多能干细胞，基于ASC的干细胞疗法和骨组织工程，为骨缺损的修复和再生提供了新的思路。ASC成骨分化是多种基因、蛋白和信号通路相互作用的复杂过程，其中Runx2和Osterix、Wnt、骨形成蛋白、Notch、成纤维细胞生长因子、环磷腺苷/蛋白激酶A、Hedgehog、丝裂原活化蛋白激酶等均扮演了重要角色。体外化学诱导ASC的成骨分化已经非常成熟，利用细胞共培养和各种支架也可诱导ASC的成骨分化。验证ASC分化成骨的方法包括茜素红染色和相关基因与蛋白的检测。影响ASC成骨分化的因素包括供体种属、年龄、脂肪获取部位等供体因素，培养液糖浓度、ASC的代数、冻存等实验因素，血管内皮细胞生长因子、生长分化因子、胰岛素样生长因子、转化生长因子β、尼尔样1型分子、LIM矿化蛋白1、低氧诱导因子1、肿瘤坏死因子α、干扰素γ、IL-6等生长因子，糖皮质激素、雌激素、胰岛素、褪黑素、瘦素等激素，一氧化氮、组蛋白H1、白藜芦醇、曲古抑菌素A、小檗碱、硼替佐米、阿司匹林、辛伐他汀等化学因子及药物，电磁场和超声波等物理因素，拉伸力和剪切力等生物力学因素，钙、锌、锂、锶、硒等金属或非金属离子，微小RNA以及富血小板血清和富血小板纤维蛋白、降钙素基因相关肽、中药和咖啡因等其他因素。本文总结了ASC成骨分化的过程，分析了相关基因和信号通路，回顾了诱导和验证方法，讨论了主要影响因素及其机制，并展望了未来研究方向。

关键词: 转录因子, 组织工程, 再生医学, 脂肪干细胞, 成骨分化, 基因, 信号通路

Bone defect due to trauma or tumor resection is the common disease in orthopedics, oral maxillofacial surgery, plastic and reconstructive surgery. Existing methods including artificial bone material filling and bone grafting all have limitations. Adipose-derived stem cell (ASC) is multipotent stem cell isolated from adipose tissue. Stem cell therapy and bone tissue engineering based on the osteogenic differentiation capacity of ASC opens a new era of bone defect repairment and regeneration. The osteogenic differentiation of ASC is a complex procedure associated with interactions of numerous genes, proteins and signal pathways, in which the activation and transcription of Runx2 and Osterix play an important role. Wnt, bone morphogenetic protein, Notch, fibroblast growth factor, cyclic adenosine monophosphate/protein kinase A, Hedgehog and mitogen activated protein kinase are also involed in the regulation of ASC′s osteogenic differentiation. In vitro osteogenic induction of ASC using chemical had been well established. Cell co-culture and various biomaterial scaffold can promote ASC′s osteogenic differentiation. Osteogenic differentiation of ASC can be verified by alizarin staining and detection of osteogenic genes and proteins. Factors that may affect ASC′s osteogenic differentiation include donor factors, experimental factors, growth factors, hormones, medication and chemicals, physical factors, biomechanical factors, micro RNAs, metallic and nonmetallic ions, et al. Although research, clinical trials and applications of ASC osteogenesis are the most focused fields, there are some issues need to be clarified. For example genes, transcription factors, and signal pathways involved in the early stage of ASC′s osteogenic differentiation are still unclear. Interactions between signal pathways are unknown. Factors that may affect ASC′s osteogenic differentiation are lack of summary. Therefore, it is essential to review pathways of ASC′s osteogenic differentiation, to combine growth factors and various scaffold for improvement of ASC′s proliferation and specific differentiation. This review focused on the genes, transcription factors and signal pathways, induction and verification methods, factors and their mechanisms of ASC′s osteogenic differentiation. We also looked forward the future research interest of ASC′s osteogenic differentiation based on current issues.

Key words: Transcription factors, Tissue engineering, Regenerative medicine, Adipose-derived stem cell, Differentiation, Genes, Signal pathway

表1 影响ASC成骨分化的因素

作用方式		影响因素
促进		?
?	信号通路	Runx2、Osterix、Wnt、BMP
?	生长因子	VEGF、GDF-5、IGF-1、LIM矿化蛋白1、HIF-1、Nell-1
?	激素	糖皮质激素、雌激素、瘦素、胰岛素
?	化学因子和药物	一氧化氮、组蛋白H1、曲古抑菌素A、白藜芦醇、小檗碱、硼替佐米、阿司匹林、辛伐他汀
?	物理因素	低强度磁场、低脉冲超声波
?	生物力学	拉伸应力、剪切力
?	微小RNA	miR-218、miR-233、miR-141、miR-200a
?	支架材料	β-磷酸三钙、羟基磷灰石、藻酸钙、透明质酸、胶原、聚乳酸、聚氨酯、聚羟基乙酸、Medpor、石墨烯水凝胶
?	离子	钙、氯化锂、锶、硒、镁黄长石
?	其他	PRP和PRF、CGRP、右归丸
抑制		GSK3、头蛋白、高糖培养基、IGF-2、IFN-γ、褪黑素、miR-204、miR-211、miR-133、miR-125b
无影响		细胞代数、冻存、锌离子
双向		Notch、TGF-β、TNF-α、BDNF、人参皂苷Rbl、咖啡因
尚无定论		Hedgehog、FGF、cAMP/PKA、MAPK、供体种属、年龄、脂肪获取部位

表1 影响ASC成骨分化的因素

作用方式		影响因素
促进		?
?	信号通路	Runx2、Osterix、Wnt、BMP
?	生长因子	VEGF、GDF-5、IGF-1、LIM矿化蛋白1、HIF-1、Nell-1
?	激素	糖皮质激素、雌激素、瘦素、胰岛素
?	化学因子和药物	一氧化氮、组蛋白H1、曲古抑菌素A、白藜芦醇、小檗碱、硼替佐米、阿司匹林、辛伐他汀
?	物理因素	低强度磁场、低脉冲超声波
?	生物力学	拉伸应力、剪切力
?	微小RNA	miR-218、miR-233、miR-141、miR-200a
?	支架材料	β-磷酸三钙、羟基磷灰石、藻酸钙、透明质酸、胶原、聚乳酸、聚氨酯、聚羟基乙酸、Medpor、石墨烯水凝胶
?	离子	钙、氯化锂、锶、硒、镁黄长石
?	其他	PRP和PRF、CGRP、右归丸
抑制		GSK3、头蛋白、高糖培养基、IGF-2、IFN-γ、褪黑素、miR-204、miR-211、miR-133、miR-125b
无影响		细胞代数、冻存、锌离子
双向		Notch、TGF-β、TNF-α、BDNF、人参皂苷Rbl、咖啡因
尚无定论		Hedgehog、FGF、cAMP/PKA、MAPK、供体种属、年龄、脂肪获取部位

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Research progress on osteogenic differentiation of adipose-derived stem cell

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