Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 13, Issue 37, Pages 44108-44123Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.1c13630
Keywords
3D cell-derived matrices; extracellular microenvironment; microcarriers; adipose mesenchymal stem cells; macromolecular crowders; cytotoxicity assay
Funding
- Leica Microsystems
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The study introduced a novel method to produce mesenchymal cell-derived matrices (CDMs) aimed at mimicking the fibrotic tumor microenvironment, showing that they closely mimic the composition, structure, and mechanical properties of human fibrotic ECM. CDMs have highly reproducible composition and tunable mechanical properties, and exhibit increased doxorubicin resistance in cancer cells following chemotherapeutic treatment in comparison to 3D culture in collagen hydrogels.
Most morphogenetic and pathological processes are driven by cells responding to the surrounding matrix, such as its composition, architecture, and mechanical properties. Despite increasing evidence for the role of extracellular matrix (ECM) in tissue and disease development, many in vitro substitutes still fail to effectively mimic the native microenvironment. We established a novel method to produce macroscale (>1 cm) mesenchymal cell-derived matrices (CDMs) aimed to mimic the fibrotic tumor microenvironment surrounding epithelial cancer cells. CDMs are produced by human adipose mesenchymal stem cells cultured in sacrificial 3D scaffold templates of fibronectin-coated poly-lactic acid microcarriers (MCs) in the presence of macromolecular crowders. We showed that decellularized CDMs closely mimic the fibrillar protein composition, architecture, and mechanical properties of human fibrotic ECM from cancer masses. CDMs had highly reproducible composition made of collagen types I and III and fibronectin ECM with tunable mechanical properties. Moreover, decellularized and MC-free CDMs were successfully repopulated with cancer cells throughout their 3D structure, and following chemotherapeutic treatment, cancer cells showed greater doxorubicin resistance compared to 3D culture in collagen hydrogels. Collectively, these results support the use of CDMs as a reproducible and tunable tool for developing 3D in vitro cancer models.
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