bims-ecemfi 2025-01-12 papers

PLoS Comput Biol. 2025 Jan;21(1): e1012664

Fast yet force-effective mode of supracellular collective cell migration due to extracellular force transmission.

Amrit Bagchi, Bapi Sarker, Jialiang Zhang, Marcus Foston, Amit Pathak.

Cell collectives, like other motile entities, generate and use forces to move forward. Here, we ask whether environmental configurations alter this proportional force-speed relationship, since aligned extracellular matrix fibers are known to cause directed migration. We show that aligned fibers serve as active conduits for spatial propagation of cellular mechanotransduction through matrix exoskeleton, leading to efficient directed collective cell migration. Epithelial (MCF10A) cell clusters adhered to soft substrates with aligned collagen fibers (AF) migrate faster with much lesser traction forces, compared to random fibers (RF). Fiber alignment causes higher motility waves and transmission of normal stresses deeper into cell monolayer while minimizing shear stresses and increased cell-division based fluidization. By contrast, fiber randomization induces cellular jamming due to breakage in motility waves, disrupted transmission of normal stresses, and heightened shear driven flow. Using a novel motor-clutch model, we explain that such 'force-effective' fast migration phenotype occurs due to rapid stabilization of contractile forces at the migrating front, enabled by higher frictional forces arising from simultaneous compressive loading of parallel fiber-substrate connections. We also model 'haptotaxis' to show that increasing ligand connectivity (but not continuity) increases migration efficiency. According to our model, increased rate of front stabilization via higher resistance to substrate deformation is sufficient to capture 'durotaxis'. Thus, our findings reveal a new paradigm wherein the rate of leading-edge stabilization determines the efficiency of supracellular collective cell migration.

DOI: https://doi.org/10.1371/journal.pcbi.1012664

Int J Biol Macromol. 2025 Jan 07. pii: S0141-8130(25)00124-2. [Epub ahead of print] 139575

Cellulose-mediated mechanical property tuning in small intestinal submucosal matrix to enhance stem cell osteogenic differentiation.

Boqi Li, Yufeng Gao, Xiaohu Luo, Chuanzhi Hu, Mingyu Deng, Jinghua Chen, Gao Min.

Natural extracellular matrices (ECM) provide a more accurate simulation of the cellular growth environment, making them excellent substrate materials for in vitro cell culture. The porcine small intestinal submucosa (SIS) is one of the most widely used natural ECM that display superior bioactivity. However, decellularization operations often result in fiber breakage and failure to recover mechanical strength in the SIS. In the current study, 2,3-dialdehyde cellulose (DAC) was synthesized and cross-linked with SIS gel to form hydrogels. The introduction of DAC into the SIS matrix resulted in a tunable increase in stiffness, which was instrumental in promoting stem cell adhesion and spreading, crucial factors for osteogenic differentiation. The cytotoxicity assessment confirmed the biocompatibility of the SIS-DAC hydrogels indicating their suitability for prolonged cell culture. Moreover, the degradation rate of the hydrogel could be effectively controlled by adjusting the DAC content, addressing the rapid degradation issue associated with SIS gels. This work confirmed the feasibility of using cellulose derivatives to modulate the mechanical properties of matrix gels and influence cell differentiation which offers a valuable experimental foundation for the development of advanced matrix gels tailored for cell culture and regenerative medicine applications.

Keywords: Dialdehyde cellulose; Stem cell differentiation; Stiffness regulation

DOI: https://doi.org/10.1016/j.ijbiomac.2025.139575

J Mater Chem B. 2025 Jan 10.

Improving the bioactivity and mechanical properties of poly(ethylene glycol)-based hydrogels through a supramolecular support network.

Yuzhu Liu, Md Shariful Islam, Anna Bakker, Zihao Li, Alaa Ajam, Jamie J Kruzic, Kristopher A Kilian.

Most synthetic hydrogels are formed through radical polymerization to yield a homogenous covalent meshwork. In contrast, natural hydrogels form through mechanisms involving both covalent assembly and supramolecular interactions. In this communication, we expand the capabilities of covalent poly(ethylene glycol) (PEG) networks through co-assembly of supramolecular peptide nanofibers. Using a peptide hydrogelator derived from the tryptophan zipper (Trpzip) motif, we demonstrate how in situ formation of nanofiber networks can tune the stiffness of PEG-based hydrogels, while also imparting shear thinning, stress relaxation, and self-healing properties. The hybrid networks show enhanced toughness and durability under tension, providing scope for use in load bearing applications. A small quantity of Trpzip peptide renders the non-adhesive PEG network adhesive, supporting adipose derived stromal cell adhesion, elongation, and growth. The integration of supramolecular networks into covalent meshworks expands the versatility of these materials, opening up new avenues for applications in biotechnology and medicine.

DOI: https://doi.org/10.1039/d4tb02002b

Nat Commun. 2025 Jan 08. 16(1): 498

YAP-driven malignant reprogramming of oral epithelial stem cells at single cell resolution.

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells at single cell resolution. Tumor initiating cells displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal invasive gene programs. YAP-mediated tumor initiating cell programs included activation of oncogenic transcriptional networks and mTOR signaling, and recruitment of myeloid cells to the invasive front contributing to tumor infiltration. Tumor initiating cell transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.

DOI: https://doi.org/10.1038/s41467-024-55660-6

STAR Protoc. 2025 Jan 07. pii: S2666-1667(24)00704-4. [Epub ahead of print]6(1): 103539

Protocol for generating a pancreatic cancer organoid associated with heterogeneous tumor microenvironment.

Kenta Takeuchi, Shunsuke Tabe, Yuya Yamamoto, Kenta Takahashi, Megumi Matsuo, Yasuharu Ueno, Masayuki Ohtsuka, Soichiro Morinaga, Yohei Miyagi, Tomoyuki Yamaguchi, Naoki Tanimizu, Hideki Taniguchi.

Pancreatic ductal adenocarcinoma (PDAC) organoids that simulate the tumor microenvironment (TME) are an effective tool to identify how TME affects PDAC malignancy. We present a protocol for generating a fused pancreatic cancer organoid (FPCO) that partly reproduces the TME, including heterogeneous cancer-associated fibroblasts (CAFs), using patient-derived PDAC cells and human-induced pluripotent cell-derived endothelial and mesenchymal cells. We also describe the procedure for analyzing FPCO characteristics. FPCO can provide a platform for establishing a reliable drug screening system. For complete details on the use and execution of this protocol, please refer to Takeuchi et al.1.

Keywords: Cancer; Organoids; Stem Cells

DOI: https://doi.org/10.1016/j.xpro.2024.103539

Int J Mol Sci. 2024 Dec 21. pii: 13691. [Epub ahead of print]25(24):

The Complex Role of Matrix Metalloproteinase-2 (MMP-2) in Health and Disease.

Marta Wolosowicz, Slawomir Prokopiuk, Tomasz W Kaminski.

Matrix metalloproteinase-2 (MMP-2), a zinc-dependent enzyme, plays a critical role in the degradation and remodeling of the extracellular matrix (ECM). As a member of the gelatinase subgroup of matrix metalloproteinases, MMP-2 is involved in a variety of physiological processes, including tissue repair, wound healing, angiogenesis, and embryogenesis. It is primarily responsible for the degradation of type IV and V collagen, fibronectin, laminin, and elastin, which are essential components of the ECM. MMP-2 is secreted as an inactive pro-enzyme (proMMP-2) and activated through proteolytic cleavage, with its activity being precisely regulated by tissue inhibitors of metalloproteinases (TIMPs). Dysregulation of MMP-2 has been linked to a variety of pathological conditions, including cardiovascular diseases, diabetic complications, kidney diseases, and cancer. In cardiovascular diseases, it contributes to vascular remodeling, atherosclerosis, and aneurysms, while in fibrotic diseases, it mediates excessive ECM degradation leading to tissue scarring. In diabetes, elevated MMP-2 activity exacerbates complications such as nephropathy, retinopathy, and cardiovascular disease. In cancer, MMP-2 facilitates tumor invasion and metastasis by degrading ECM components and promoting angiogenesis. Despite its essential roles in both physiological and pathological processes, targeting MMP-2 for therapeutic purposes presents challenges due to its dual functions in tissue remodeling and repair, raising concerns about unplanned consequences such as impaired tissue healing or excessive tissue damage. These challenges underscore the need for future research to focus on developing selective modulators that can precisely balance their activity under specific disease environments. Clinical trials targeting MMP-2 modulation highlight the potential of gelatinase inhibitors, including those targeting MMP-2, to reduce tumor progression in fibrosarcoma, breast, and lung cancers. This paper reviews the structure, function, and regulation of MMP-2, its involvement in disease pathogenesis, and the potential challenges in the therapeutic implications of modulating its activity.

Keywords: ECM; MMP-2; extracellular matrix; matrix metalloproteinase-2; tissue remodeling

DOI: https://doi.org/10.3390/ijms252413691