Spatial Configurations of 3D Extracellular Matrix Collagen Density and Anisotropy Simultaneously Guide Angiogenesis.
Spatial Configurations of 3D Extracellular Matrix Collagen Density and Anisotropy Simultaneously Guide Angiogenesis.
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3D细胞外基质胶原密度和各向异性的空间构型同时引导血管生成。
DOI：
10.1371/journal.pcbi.1011553
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发表时间：
2023-10
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
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细胞外基质（ECM）胶原蛋白密度和原纤维各向异性被认为会影响病理和稳态血管生成过程中新脉管系统的发育。计算模拟正在成为研究矩阵结构配置对细胞引导作用的工具。然而，先前的计算模型仅考虑胶原蛋白的方向作为模型输入。最近的实验证据表明，细胞引导同时受到排列方向和强度（即各向异性程度）以及局部胶原密度的影响。本研究的目的是通过在 AngioFE 和 FEBio 建模框架中进行模拟，探讨 ECM 胶原蛋白各向异性和密度在血管生成过程中的作用。 AngioFE 是 FEBio（生物力学有限元）的插件，可模拟血管生成过程中细胞与基质的相互作用。我们扩展了 AngioFE，将 ECM 胶原蛋白表示为可变形的 3D 椭圆体原纤维分布 (EFD)。微血管生长的速率和方向被修改为同时取决于 ECM 胶原各向异性（各向异性的方向和程度）和密度。调整生长中的新血管对这些刺激的敏感性，以便 AngioFE 可以重现在不同各向异性和密度的胶原凝胶中培养微血管的实验中观察到的生长和引导。然后，我们将使用 EFD 的模拟结果与使用 AngioFE 先前的胶原各向异性矢量场表示的模拟结果进行比较。我们发现，在预测实验观察到的微血管引导方面，EFD 模拟比矢量场模拟更准确。预测模拟证明了各向异性梯度能够招募与伤口愈合相关的短距离和长距离的微血管。此外，模拟预测胶原蛋白排列可以使微血管克服致密的组织界面，例如结缔组织增生和肿瘤间质界面中发现的肿瘤相关胶原结构（TACS）。这种方法可以推广到计算环境中细胞引导现象期间的其他力学生物学关系。基质胶原纤维的各向异性和密度因其在细胞生长和引导中的机械调节作用而得到认可。例如，我们最近证明，在体外血管生成过程中，新血管的生长随着基质胶原蛋白排列程度的增加而增加，并以密度依赖性方式增加。相邻组织之间胶原纤维排列和密度的空间配置被认为影响病理和稳态血管生成过程中新脉管系统的发育。计算模拟正在成为一种工具，用于评估不同基质结构线索的综合效应如何参与组织之间微血管的引导和偏转。因此，本研究的目的是结合我们之前的实验发现，即血管新生血管同时对 ECM 胶原密度和原纤维各向异性（各向异性的方向和程度）敏感。我们发现原纤维的各向异性使新血管有勇气长距离迁移并通过致密的组织界面持续存在。这些发现对伤口愈合过程中的血管生成和癌症肿瘤发生等病理学具有影响。
Extracellular matrix (ECM) collagen density and fibril anisotropy are thought to affect the development of new vasculatures during pathologic and homeostatic angiogenesis. Computational simulation is emerging as a tool to investigate the role of matrix structural configurations on cell guidance. However, prior computational models have only considered the orientation of collagen as a model input. Recent experimental evidence indicates that cell guidance is simultaneously influenced by the direction and intensity of alignment (i.e., degree of anisotropy) as well as the local collagen density. The objective of this study was to explore the role of ECM collagen anisotropy and density during sprouting angiogenesis through simulation in the AngioFE and FEBio modeling frameworks. AngioFE is a plugin for FEBio (Finite Elements for Biomechanics) that simulates cell-matrix interactions during sprouting angiogenesis. We extended AngioFE to represent ECM collagen as deformable 3D ellipsoidal fibril distributions (EFDs). The rate and direction of microvessel growth were modified to depend simultaneously on the ECM collagen anisotropy (orientation and degree of anisotropy) and density. The sensitivity of growing neovessels to these stimuli was adjusted so that AngioFE could reproduce the growth and guidance observed in experiments where microvessels were cultured in collagen gels of varying anisotropy and density. We then compared outcomes from simulations using EFDs to simulations that used AngioFE’s prior vector field representation of collagen anisotropy. We found that EFD simulations were more accurate than vector field simulations in predicting experimentally observed microvessel guidance. Predictive simulations demonstrated the ability of anisotropy gradients to recruit microvessels across short and long distances relevant to wound healing. Further, simulations predicted that collagen alignment could enable microvessels to overcome dense tissue interfaces such as tumor-associated collagen structures (TACS) found in desmoplasia and tumor-stroma interfaces. This approach can be generalized to other mechanobiological relationships during cell guidance phenomena in computational settings. Matrix collagen fibril anisotropy and density are gaining recognition for their mechanoregulatory roles in cellular growth and guidance. For instance, we recently demonstrated that new vessel growth increases with the degree of matrix collagen alignment in a density-dependent manner during in vitro angiogenesis. The spatial configuration of collagen fibril alignment and density between adjacent tissues is thought to affect development of new vasculatures during pathologic and homeostatic angiogenesis. Computational simulation is emerging as a tool to evaluate how the integrated effects of different matrix structural cues are involved in guidance and deflection of microvessels between tissues. Thus, the objective of this study was to incorporate our prior experimental finding that angiogenic neovessels are simultaneously sensitive to ECM collagen density and fibril anisotropy (orientation and degree of anisotropy). We found that fibril anisotropy emboldens neovessels to migrate long distances and persist through dense tissue interfaces. These findings have implications for angiogenesis during wound healing and pathologies such as cancer tumorigenesis.
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DOI：
10.1158/1541-7786.mcr-12-0307
发表时间：
2012-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Karagiannis GS;Poutahidis T;Erdman SE;Kirsch R;Riddell RH;Diamandis EP
通讯作者：
Diamandis EP
DOI：
10.1115/1.2796072
发表时间：
1997-05-01
影响因子：
1.7
作者：
Barocas, VH;Tranquillo, RT
通讯作者：
Tranquillo, RT
影响因子：
3.5
作者：
Checa, Sara;Rausch, Manuel K.;Duda, Georg N.
通讯作者：
Duda, Georg N.
影响因子：
6
作者：
Conklin, Matthew W.;Eickhoff, Jens C.;Keely, Patricia J.
通讯作者：
Keely, Patricia J.
细胞外基质密度调节新血管生长和萌芽血管生成中的分支速率。
影响因子：
3.7
作者：
Edgar LT;Underwood CJ;Guilkey JE;Hoying JB;Weiss JA
通讯作者：
Weiss JA