Fiber density and matrix stiffness modulate distinct cell migration modes in a 3D stroma mimetic composite hydrogel.

Autor: Hiraki HL; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States., Matera DL; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States., Wang WY; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States., Prabhu ES; Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States., Zhang Z; Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, 481095, United States., Midekssa F; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States., Argento AE; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States., Buschhaus JM; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Radiology, University of Michigan, Ann Arbor, MI, 48109, United States., Humphries BA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Radiology, University of Michigan, Ann Arbor, MI, 48109, United States., Luker GD; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Radiology, University of Michigan, Ann Arbor, MI, 48109, United States., Pena-Francesch A; Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, 481095, United States., Baker BM; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States. Electronic address: bambren@umich.edu.
Jazyk: angličtina
Zdroj: Acta biomaterialia [Acta Biomater] 2023 Jun; Vol. 163, pp. 378-391. Date of Electronic Publication: 2022 Sep 28.
DOI: 10.1016/j.actbio.2022.09.043
Abstrakt: The peritumoral stroma is a complex 3D tissue that provides cells with myriad biophysical and biochemical cues. Histologic observations suggest that during metastatic spread of carcinomas, these cues influence transformed epithelial cells, prompting a diversity of migration modes spanning single cell and multicellular phenotypes. Purported consequences of these variations in tumor escape strategies include differential metastatic capability and therapy resistance. Therefore, understanding how cues from the peritumoral stromal microenvironment regulate migration mode has both prognostic and therapeutic value. Here, we utilize a synthetic stromal mimetic in which matrix fiber density and bulk hydrogel mechanics can be orthogonally tuned to investigate the contribution of these two key matrix attributes on MCF10A migration mode phenotypes, epithelial-mesenchymal transition (EMT), and invasive potential. We develop an automated computational image analysis framework to extract migratory phenotypes from fluorescent images and determine 3D migration metrics relevant to metastatic spread. Using this analysis, we find that matrix fiber density and bulk hydrogel mechanics distinctly contribute to a variety of MCF10A migration modes including amoeboid, single mesenchymal, clusters, and strands. We identify combinations of physical and soluble cues that induce a variety of migration modes originating from the same MCF10A spheroid and use these settings to examine a functional consequence of migration mode -resistance to apoptosis. We find that cells migrating as strands are more resistant to staurosporine-induced apoptosis than either disconnected clusters or individual invading cells. Improved models of the peritumoral stromal microenvironment and understanding of the relationships between matrix attributes and cell migration mode can aid ongoing efforts to identify effective cancer therapeutics that address cell plasticity-based therapy resistances. STATEMENT OF SIGNIFICANCE: Stromal extracellular matrix structure dictates both cell homeostasis and activation towards migratory phenotypes. However decoupling the effects of myriad biophysical cues has been difficult to achieve. Here, we encapsulate electrospun fiber segments within an amorphous hydrogel to create a fiber-reinforced hydrogel composite in which fiber density and hydrogel stiffness can be orthogonally tuned. Quantification of 3D cell migration reveal these two parameters uniquely contribute to a diversity of migration phenotypes spanning amoeboid, single mesenchymal, multicellular cluster, and collective strand. By tuning biophysical and biochemical cues to elicit heterogeneous migration phenotypes, we find that collective strands best resist apoptosis. This work establishes a composite approach to modulate fibrous topography and bulk hydrogel mechanics and identified biomaterial parameters to direct distinct 3D cell migration phenotypes.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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