骨关节炎软骨细胞分泌的形态发生素可诱导人间充质干细胞的软骨分化。
Osteoarthritic chondrocyte-secreted morphogens induce chondrogenic differentiation of human mesenchymal stem cells.
作者信息
Aung Aereas, Gupta Gunjan, Majid Ghassemian, Varghese Shyni
机构信息
Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
出版信息
Arthritis Rheum. 2011 Jan;63(1):148-158. doi: 10.1002/art.30086.
OBJECTIVE
The potential of stem cells to repair compromised cartilage tissue, such as in osteoarthritis (OA), depends strongly on how transplanted cells respond to factors secreted from the residing OA chondrocytes. This study was undertaken to determine the effect of morphogenetic signals from OA chondrocytes on chondrogenic differentiation of human mesenchymal stem cells (MSCs).
METHODS
The effect of OA chondrocyte-secreted morphogens on chondrogenic differentiation of human MSCs was evaluated using a coculture system involving both primary and passaged OA chondrocytes. The findings were compared against findings for human MSCs cultured in OA chondrocyte-conditioned medium. Gene expression analysis, biochemical assays, and immunofluorescence staining were used to characterize the chondrogenic differentiation of human MSCs. Mass spectrometry analysis was used to identify the soluble factors. Numerical analysis was carried out to model the concentration profile of soluble factors within the human MSC-laden hydrogels.
RESULTS
The human MSCs cocultured with primary OA chondrocytes underwent chondrogenic differentiation even in the absence of growth factors; however, the same effect could not be mimicked using OA chondrocyte-conditioned medium or expanded cells. Additionally, the cocultured environment down-regulated hypertrophic differentiation of human MSCs. Mass spectrometry analysis demonstrated cell-cell communication and chondrocyte phenotype-dependent effects on cell-secreted morphogens.
CONCLUSION
The experimental findings, along with the results of the numerical analysis, suggest a crucial role of soluble morphogens and their local concentrations in the differentiation pattern of human MSCs in a 3-dimensional environment. The concept of using a small number of chondrocytes to promote chondrogenic differentiation of human MSCs while preventing their hypertrophic differentiation could be of great importance in formulating effective stem cell-based cartilage repair.
目的
干细胞修复受损软骨组织（如骨关节炎（OA）中的软骨组织）的潜力在很大程度上取决于移植细胞对驻留的OA软骨细胞分泌因子的反应。本研究旨在确定OA软骨细胞的形态发生信号对人间充质干细胞（MSCs）软骨分化的影响。
方法
使用包含原代和传代OA软骨细胞的共培养系统，评估OA软骨细胞分泌的形态发生素对人间充质干细胞软骨分化的影响。将研究结果与在OA软骨细胞条件培养基中培养的人间充质干细胞的结果进行比较。采用基因表达分析、生化分析和免疫荧光染色来表征人间充质干细胞的软骨分化。使用质谱分析来鉴定可溶性因子。进行数值分析以模拟载有人间充质干细胞的水凝胶中可溶性因子的浓度分布。
结果
与原代OA软骨细胞共培养的人间充质干细胞即使在没有生长因子的情况下也会发生软骨分化；然而，使用OA软骨细胞条件培养基或扩增细胞无法模拟相同的效果。此外，共培养环境下调了人间充质干细胞的肥大分化。质谱分析证明了细胞间通讯以及软骨细胞表型对细胞分泌的形态发生素的影响。
结论
实验结果以及数值分析结果表明，可溶性形态发生素及其局部浓度在三维环境中人间充质干细胞的分化模式中起着关键作用。利用少量软骨细胞促进人间充质干细胞的软骨分化同时防止其肥大分化的概念，在制定有效的基于干细胞的软骨修复方案中可能具有重要意义。
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