bims-ecemfi 2025-01-19 papers

Acta Biomater. 2025 Jan 09. pii: S1742-7061(25)00017-0. [Epub ahead of print]

Interpenetrating networks of fibrillar and amorphous collagen promote cell spreading and hydrogel stability.

Lucia G Brunel, Chris M Long, Fotis Christakopoulos, Betty Cai, Patrik K Johansson, Diya Singhal, Annika Enejder, David Myung, Sarah C Heilshorn.

Hydrogels composed of collagen, the most abundant protein in the human body, are widely used as scaffolds for tissue engineering due to their ability to support cellular activity. However, collagen hydrogels with encapsulated cells often experience bulk contraction due to cell-generated forces, and conventional strategies to mitigate this undesired deformation often compromise either the fibrillar microstructure or cytocompatibility of the collagen. To support the spreading of encapsulated cells while preserving the structural integrity of the gels, we present an interpenetrating network (IPN) of two distinct collagen networks with different crosslinking mechanisms and microstructures. First, a physically self-assembled collagen network preserves the fibrillar microstructure and enables the spreading of encapsulated human corneal mesenchymal stromal cells. Second, an amorphous collagen network covalently crosslinked with bioorthogonal chemistry fills the voids between fibrils and stabilizes the gel against cell-induced contraction. This collagen IPN balances the biofunctionality of natural collagen with the stability of covalently crosslinked, engineered polymers. Taken together, these data represent a new avenue for maintaining both the fiber-induced spreading of cells and the structural integrity of collagen hydrogels by leveraging an IPN of fibrillar and amorphous collagen networks. STATEMENT OF SIGNIFICANCE: Collagen hydrogels are widely used as scaffolds for tissue engineering due to their support of cellular activity. However, collagen hydrogels often undergo undesired changes in size and shape due to cell-generated forces, and conventional strategies to mitigate this deformation typically compromise either the fibrillar microstructure or cytocompatibility of the collagen. In this study, we introduce an innovative interpenetrating network (IPN) that combines physically self-assembled, fibrillar collagen-ideal for promoting cell adhesion and spreading-with covalently crosslinked, amorphous collagen-ideal for enhancing bulk hydrogel stability. Our IPN design maintains the native fibrillar structure of collagen while significantly improving resistance against cell-induced contraction, providing a promising solution to enhance the performance and reliability of collagen hydrogels for tissue engineering applications.

Keywords: Cell morphology; Collagen; Crosslinking; Hydrogel contraction; Interpenetrating network

DOI: https://doi.org/10.1016/j.actbio.2025.01.009

Chembiochem. 2025 Jan 10. e202400955

Click hydrogels to assess stiffness-induced activation of pancreatic cancer-associated fibroblasts and its impact on cancer cell spreading.

Chun-Yi Chang, Chien-Chi Lin.

Pancreatic ductal adenocarcinoma (PDAC) is marked by significant desmoplastic reactions, or the accumulation of excessive extracellular matrices. PDAC stroma has abnormally high stiffness, which alters cancer cell behaviors and creates a barrier for effective drug delivery. Unfortunately, clinical trials using a combination of chemotherapy and matrix-degrading enzyme have led to disappointing results, as the degradation of stromal tissue likely accelerated the dissemination of cancer cells. High matrix stiffness has been shown to activate cancer-associated fibroblasts (CAFs), increasing their interaction with pancreatic cancer cells (PCCs) through promoting proliferation, migration, and resistance to chemotherapy. With the advance of biomaterials science and engineering, it is now possible to design chemically defined matrices to understand the role of stiffness in activating pancreatic CAFs and how this may alter cancer cell migration. Here, we developed a norbornene-based click hydrogel system with independently tunable stiffness and cell adhesive ligand to evaluate stiffness-induced activation of CAFs and migration of PCCs. Our results show that matrix stiffness did not alter matrix deposition from CAFs but affected nuclear localization of Yes-associated protein (YAP). Our results also verify the role of CAFs on promoting PCC migration and an elevated substrate stiffness further increased PCC motility.

Keywords: Hydrogels; click chemistry; pancreatic cancer; stromal cells, cell-cell interactions

DOI: https://doi.org/10.1002/cbic.202400955

Sci Adv. 2025 Jan 17. 11(3): eadq5011

Programmed shape transformations in cell-laden granular composites.

Nikolas Di Caprio, Alex J Hughes, Jason A Burdick.

Tissues form during development through mechanical compaction of their extracellular matrix (ECM) and shape morphing, processes that result in complex-shaped structures that contribute to tissue function. While observed in vivo, control over these processes in vitro to understand both tissue development and guide tissue formation has remained challenging. Here, we use combinations of mesenchymal stromal cell spheroids and hydrogel microparticles (microgels) with varied hydrolytic stability to fabricate programmable and dynamic granular composites that control compaction and tissue formation over time. Mixed microgel populations of varying stability provide a further handle to alter compaction, and the level of compaction guides the uniformity and level of ECM deposition within tissues. Last, spatially patterned granular composites of varying compaction enable shape transformations (i.e., bending/curvature) that are stable with culture and are predicted by finite element models.

DOI: https://doi.org/10.1126/sciadv.adq5011

Biol Reprod. 2025 Jan 17. pii: ioaf012. [Epub ahead of print]

Collagen turnover during cervical remodeling involves both intracellular and extracellular collagen degradation pathways.

Mariano Colon-Caraballo, Serena R Russell, Kristin M Myers, Mala Mahendroo.

Reproductive success requires accurately timed remodeling of the cervix to orchestrate the maintenance of pregnancy, the process of labor, and birth. Prior work in mice established that a combination of continuous turnover of fibrillar collagen and reduced formation of collagen cross-links allows for the gradual increase in tissue compliance and delivery of the fetus during labor. However, the mechanism for continuous collagen degradation to ensure turnover during cervical remodeling is still unknown. This study demonstrates the functional role of extracellular and intracellular collagen degradative pathways in two different settings of cervical remodeling: physiological term remodeling and inflammation-mediated premature remodeling. Extracellular collagen degradation is achieved by the activity of fibroblast-derived matrix metalloproteases MMP14, MMP2, and fibroblast activation protein (FAP). In parallel, we demonstrate the function of an intracellular collagen degradative pathway in fibroblast cells mediated by the collagen endocytic mannose receptor type-2 (MRC2). These pathways appear to be functionally redundant as loss of MRC2 does not obstruct collagen turnover or cervical function in pregnancy. While both extracellular and intracellular pathways are also utilized in inflammation-mediated premature cervical remodeling, the extracellular collagen degradation pathway uniquely employs fibroblast and immune-cell derived proteases. In sum, these findings identify the dual utilization of two distinct degradative pathways as a failsafe mechanism to achieve continuous collagen turnover in the cervix, thereby allowing dynamic shifts in cervical tissue mechanics and function.

Keywords: Cervical remodeling; Collagen degradation; Fibroblast activation protein; Mannose receptor type-2; Matrix metalloproteases; Pregnancy; Preterm birth

DOI: https://doi.org/10.1093/biolre/ioaf012

J Mater Chem B. 2025 Jan 13.

The effect of microenvironmental viscosity on the emergence of colon cancer cell resistance to doxorubicin.

Tianjiao Zeng, Chengyu Lu, Man Wang, Huajian Chen, Toru Yoshitomi, Naoki Kawazoe, Yingnan Yang, Guoping Chen.

The colon possesses a unique physiological environment among human organs, where there is a highly viscous body fluid layer called the mucus layer above colonic epithelial cells. Dysfunction of the mucus layer not only contributes to the occurrence of colorectal cancer (CRC) but also plays an important role in the development of chemoresistance in CRC. Although viscosity is an essential property of the mucus layer, it remains elusive how viscosity affects chemoresistance in colon cancer cells. In this study, the influence of viscosity on their chemoresistance was elucidated by culturing colon cancer cells in media of different viscosities supplemented with doxorubicin (DOX). The viscosity range was adjusted from 99.4 mPa s to 776.6 mPa s by adding polyethylene glycol of different molecular weights in culture medium. Cell viability in the high viscosity medium was higher than that in the low viscosity medium. Expression of chemoresistance-related genes such as ABCC2 and ABCG2 increased when cells were cultured in the high viscosity medium. Furthermore, cell migration increased while proliferation decreased when cells were cultured in the high viscosity medium. The colon cancer cells cultured in the high viscosity medium exhibited high expression of p21 mRNA. The results suggested that viscosity could affect the resistance of colon cancer cells to DOX by regulating the expression of chemoresistance-related and proliferation-related genes.

DOI: https://doi.org/10.1039/d4tb02334j