Paradiso Francesca, Quintela Marcos, Lenna Stefania, Serpelloni Stefano, James David, Caserta Sergio, Conlan Steve, Francis Lewis, Taraballi Francesca
Center for Musculoskeletal Regeneration, Houston Methodist Academic Institute, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX, 77030, USA.
Reproductive Biology and Gynaecological Oncology Group, Swansea University Medical School, Singleton Park, Swansea, Wales, SA28PP, UK.
Macromol Biosci. 2022 Apr;22(4):e2100450. doi: 10.1002/mabi.202100450. Epub 2022 Jan 20.
Fibrosis and solid tumor progression are closely related, with both involving pathways associated with chronic wound dysregulation. Fibroblasts contribute to extracellular matrix (ECM) remodeling in these processes, a crucial step in scarring, organ failure, and tumor growth, but little is known about the biophysical evolution of remodeling regulation during the development and progression of matrix-related diseases including fibrosis and cancer. A 3D collagen-based scaffold model is employed here to mimic mechanical changes in normal (2 kPa, soft) versus advanced pathological (12 kPa, stiff) tissues. Activated fibroblasts grown on stiff scaffolds show lower migration and increased cell circularity compared to those on soft scaffolds. This is reflected in gene expression profiles, with cells cultured on stiff scaffolds showing upregulated DNA replication, DNA repair, and chromosome organization gene clusters, and a concomitant loss of ability to remodel and deposit ECM. Soft scaffolds can reproduce biophysically meaningful microenvironments to investigate early stage processes in wound healing and tumor niche formation, while stiff scaffolds can mimic advanced fibrotic and cancer stages. These results establish the need for tunable, affordable 3D scaffolds as platforms for aberrant stroma research and reveal the contribution of physiological and pathological microenvironment biomechanics to gene expression changes in the stromal compartment.
纤维化与实体瘤进展密切相关，二者均涉及与慢性伤口调节异常相关的信号通路。在这些过程中，成纤维细胞有助于细胞外基质（ECM）重塑，这是瘢痕形成、器官衰竭和肿瘤生长的关键步骤，但对于包括纤维化和癌症在内的基质相关疾病发生发展过程中重塑调节的生物物理演变，我们知之甚少。本文采用基于三维胶原蛋白的支架模型来模拟正常（2kPa，柔软）与晚期病理（12kPa，坚硬）组织中的力学变化。与在柔软支架上生长的成纤维细胞相比，在坚硬支架上生长的活化成纤维细胞迁移能力较低，细胞圆形度增加。这反映在基因表达谱中，在坚硬支架上培养的细胞显示DNA复制、DNA修复和染色体组织基因簇上调，同时丧失了重塑和沉积ECM的能力。柔软支架可以再现具有生物物理意义的微环境，以研究伤口愈合和肿瘤微环境形成的早期过程，而坚硬支架可以模拟晚期纤维化和癌症阶段。这些结果表明，需要可调谐、经济实惠的三维支架作为异常基质研究的平台，并揭示生理和病理微环境生物力学对基质区室基因表达变化的影响。
