Inducing chondrogenesis in MSC/chondrocyte co-cultures using exogenous TGF-β: a mathematical model
Inducing chondrogenesis in MSC/chondrocyte co-cultures using exogenous TGF-β: a mathematical model
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DOI：
10.1016/j.jtbi.2017.11.024
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发表时间：
2018-02-14
影响因子：
2
通讯作者：
Byrne, Helen M.
中科院分区：
文献类型：
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作者：
Chen, Michael J.;Whiteley, Jonathan P.;Byrne, Helen M.
骨髓间充质干细胞（mesenchymal stem cells，MSCs）向软骨细胞（native cartilage cells，natural cartilage cells）的分化是关节软骨组织工程的关键步骤，MSCs作为种子细胞具有良好的运动性和增殖能力。软骨发生受转化生长因子-β（TGF-β）调节，TGF-β是一种短寿命细胞因子，其作用通过储存在细胞外基质中而延长。组织工程应用需要MSC的初始群体的完全分化，并且用于在体外实现这一点的两种常见策略是（1）将MSC与软骨细胞共培养，其组成性地产生TGF-β;或（2）添加外源性TGF-β。为了研究这些策略，我们开发了TGF-β MSC和软骨细胞之间相互作用的常微分方程模型。在这里，TGF-β的动力学比细胞过程的动力学快得多;这种时间尺度上的差异被用来简化后续的模型分析。使用我们的模型，我们证明，在策略1下，如果软骨细胞的初始比例超过临界值，将诱导完全软骨形成。类似地，在策略2下，我们发现存在临界浓度的外源性TGF-β，高于该临界浓度，所有MSC将最终分化。最后，我们使用该模型来证明采用混合策略的潜在优势，其中将外源性TGF-β 5添加到MSC和软骨细胞的共培养物中，与单独使用策略1或2相比。(C)2017爱思唯尔有限公司版权所有
The differentiation of mesenchymal stem cells (MSCs) into chondrocytes (native cartilage cells), or chondrogenesis, is a key step in the tissue engineering of articular cartilage, where the motility and high proliferation rate of MSCs used as seed cells are exploited. Chondrogenesis is regulated by transforming growth factor-beta (TGF-beta), a short-lived cytokine whose effect is prolonged by storage in the extracellular matrix. Tissue engineering applications require the complete differentiation of an initial population of MSCs, and two common strategies used to achieve this in vitro are (1) co-culture the MSCs with chondrocytes, which constitutively produce TGF-beta; or (2) add exogenous TGF-beta To investigate these strategies we develop an ordinary differential equation model of the interactions between TGF-beta MSCs and chondrocyte. Here the dynamics of TGF-beta are much faster than those of the cell processes; this difference in time-scales is exploited to simplify subsequent model analysis. Using our model we demonstrate that under strategy 1 complete chondrogenesis will be induced if the initial proportion of chondrocytes exceeds a critical value. Similarly, under strategy 2 we find that there is a critical concentration of exogenous TGF-beta above which all MSCs will ultimately differentiate. Finally, we use the model to demonstrate the potential advantages of adopting a hybrid strategy where exogenous TGF-beta 5 is added to a co-culture of MSCs and chondrocytes, as compared to using either strategy 1 or 2 in isolation. (C) 2017 Elsevier Ltd. All rights reserved.