Molecular mechanism and signaling pathway during adipogenic differentiation of adipose-derived stem cells

doi:10.3969/j.issn.2095-4344.2017.01.027

Abstract

Abstract:

BACKGROUND: Research on adipogenic differentiation of adipose-derived stem cells (ADSCs) cannot only help us to explore the process and mechanism of obesity, but also to construct tissue-engineered adipose tissue which providing a new method for soft tissue reconstruction.
OBJECTIVE: By summarizing the process, molecular mechanism and signaling pathway, to conclude the effect of miRNA on ADSCs adipogenic differentiation, and to discuss the relation between adipogenic and osteogenic differentiations of ADSCs.
METHODS: Relevant articles were searched in PubMed and SinoMed using the following keywords of “adipose stem cell, adipose-derived stem cell, adipose-derived mesenchymal stem cell, differentiation” in English and Chinese, respectively. Finally, 27 representative articles were included.
RESULTS AND CONCLUSION: PPARγ/MAPK, PI3K/Akt, Wnt/β-Catenin, cAMP, and Notch signal pathways play important roles in adipogenic differentiation of ADSCs; however the relevant genes, proteins, signaling pathways and underlying molecular mechanisms are not well understood. miRNAs have great influence on adipogenic differentiation of ADSCs. For example, miR-24, miR-148a and miR-302 can promote and miR-22, miR-27 can inhibit the adipogenic differentiation of ADSCs. The osteogenic and adipogenic differentiations of ADSCs are closely related. Some growth factors and hormone facilitate the adipogenic but inhibit the osteogenic differentiation of ADSCs simultaneously, whereas others have opposite effects. The future investigation may concentrate on comprehensively utilizing various growth factors and scaffolds to mimic in vivo microenvironment and to improve proliferation and adipogenic differentiation of ADSCs for construction of tissue-engineered adipose tissue.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

Key words: Stem Cells, Adipogenesis, Tissue Engineering

CLC Number:

R318

Chen You-bai, Hao Yong-hong, Wang Lan, Zhang Qi-xu, Han Yan. Molecular mechanism and signaling pathway during adipogenic differentiation of adipose-derived stem cells[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(1): 154-158.

Figures/Tables 2

2.1 脂肪干细胞成脂分化的过程、关键因子和信号通路 2.1.1 脂肪干细胞成脂分化的过程体内的脂肪干细胞位于微血管周围，处于静止状态，在受到刺激后开始分裂和分化。脂肪干细胞的成脂分化，包括从脂肪干细胞分化为脂肪前体细胞和脂肪前体细胞分化为成熟的脂肪细胞2个阶段[4]。在体外诱导脂肪干细胞成脂1 h后，脂肪干细胞开始表达c-fos、c-jun、c-myc基因。Krox20诱导CCAAT/增强子结合蛋白β(CCAAT/enhancer binding protein β，C/EBPβ)的表达，并与cAMP反应元件结合蛋白(cAMP-response element binding protein，CREB)调节C/EBPβ的表达。C/EBPβ和C/EBPδ激活Kruppel样因子5，然后共同诱导过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor γ，PPARγ)的转录，PPARγ与C/EBPβ和C/EBPδ激活C/EBPα，构成了经典的C/EBPβ+δ-PPAR-C/EBPα通路[5]。有研究显示，C/EBPα在PPARγ缺失的情况下不能单独诱导成脂分化，而PPARγ则可在没有C/EBPα的条件下独立启动脂肪分化过程[6]。诱导2-6 h后，c-fos、c-jun、c-myc的表达消失。诱导24 h后，有丝分裂开始，细胞体积变大，由长梭形变为不规则的多角形或类圆形。48 h后有丝分裂完成，脂肪干细胞进入DNA合成前期，即生长抑制期，之后细胞立即重返细胞周期，进入无性扩增阶段。这一阶段C/EBPs激活组蛋白活性，调控C/EBPα、PPARγ和脂肪细胞决定分化因子1/固醇调节元件结合蛋白1c等转录因子与脂肪分化相关基因结合，启动脂肪基因的表达[7]。3-7 d后，PPARγ、FABP4等脂肪分化基因的表达增加，PPARγ的表达增加3倍，细胞质内有透亮的脂滴出现，脂滴逐渐增多增大并聚集融合，细胞体积增大[8]。14-21 d时分化完成，可见大量脂滴，细胞核由细胞中央被挤到边缘，呈现脂肪细胞典型的戒指样形态[9]，并表达包括脂蛋白脂肪酶(lipoprotein lipase, LPL)、脂肪酸结合蛋白4(fatty acid binding protein 4，FABP4)、激活蛋白2(activator protein 2，AP2)、葡萄糖转运蛋白4(Glut4)、瘦素等脂肪细胞基因或蛋白[10](图1)。"

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