Natesh Naveen R, Mogha Pankaj, Chen Alan, Antonia Scott J, Varghese Shyni
Department of Biomedical Engineering, Duke University, 203 Research Drive, MSRB1 Room No. 381, Durham, North Carolina 27710, USA.
Department of Orthopaedic Surgery, Duke University, 200 Trent Drive, Durham, North Carolina 27710, USA.
APL Bioeng. 2024 Mar 19;8(1):016120. doi: 10.1063/5.0188238. eCollection 2024 Mar.
Perfusable microvascular networks offer promising three-dimensional models to study normal and compromised vascular tissues as well as phenomena such as cancer cell metastasis. Engineering of these microvascular networks generally involves the use of endothelial cells stabilized by fibroblasts to generate robust and stable vasculature. However, fibroblasts are highly heterogenous and may contribute variably to the microvascular structure. Here, we study the effect of normal and cancer-associated lung fibroblasts on the formation and function of perfusable microvascular networks. We examine the influence of cancer-associated fibroblasts on microvascular networks when cultured in direct (juxtacrine) and indirect (paracrine) contacts with endothelial cells, discovering a generative inhibition of microvasculature in juxtacrine co-cultures and a functional inhibition in paracrine co-cultures. Furthermore, we probed the secreted factors differential between cancer-associated fibroblasts and normal human lung fibroblasts, identifying several cytokines putatively influencing the resulting microvasculature morphology and functionality. These findings suggest the potential contribution of cancer-associated fibroblasts in aberrant microvasculature associated with tumors and the plausible application of such platforms in identifying new therapeutic targets and/or agents that can prevent formation of aberrant vascular structures.
可灌注微血管网络为研究正常和受损血管组织以及癌细胞转移等现象提供了有前景的三维模型。这些微血管网络的构建通常涉及利用成纤维细胞稳定的内皮细胞来生成强大且稳定的脉管系统。然而，成纤维细胞具有高度异质性，可能对微血管结构产生不同的影响。在此，我们研究正常和癌症相关的肺成纤维细胞对可灌注微血管网络形成和功能的影响。我们考察了癌症相关成纤维细胞在与内皮细胞直接（旁分泌）和间接（自分泌）接触培养时对微血管网络的影响，发现在旁分泌共培养中微血管生成受到抑制，而在自分泌共培养中微血管功能受到抑制。此外，我们探究了癌症相关成纤维细胞与正常人肺成纤维细胞之间分泌因子的差异，鉴定出几种可能影响最终微血管形态和功能的细胞因子。这些发现表明癌症相关成纤维细胞在与肿瘤相关的异常微血管形成中可能发挥作用，并且这种平台在识别可预防异常血管结构形成的新治疗靶点和/或药物方面具有潜在应用价值。
