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Volume expansion and TRPV4 activation regulate stem cell fate in three-dimensional microenvironments.

ABSTRACT: For mesenchymal stem cells (MSCs) cultured in three dimensional matrices, matrix remodeling is associated with enhanced osteogenic differentiation. However, the mechanism linking matrix remodeling in 3D to osteogenesis of MSCs remains unclear. Here, we find that MSCs in viscoelastic hydrogels exhibit volume expansion during cell spreading, and greater volume expansion is associated with enhanced osteogenesis. Restriction of expansion by either hydrogels with slow stress relaxation or increased osmotic pressure diminishes osteogenesis, independent of cell morphology. Conversely, induced expansion by hypoosmotic pressure accelerates osteogenesis. Volume expansion is mediated by activation of TRPV4 ion channels, and reciprocal feedback between TRPV4 activation and volume expansion controls nuclear localization of RUNX2, but not YAP, to promote osteogenesis. This work demonstrates the role of cell volume in regulating cell fate in 3D culture, and identifies TRPV4 as a molecular sensor of matrix viscoelasticity that regulates osteogenic differentiation.

SUBMITTER: Lee HP

PROVIDER: S-EPMC6355972 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Volume expansion and TRPV4 activation regulate stem cell fate in three-dimensional microenvironments.

Lee Hong-Pyo HP Stowers Ryan R Chaudhuri Ovijit O

Nature communications 20190131 1

For mesenchymal stem cells (MSCs) cultured in three dimensional matrices, matrix remodeling is associated with enhanced osteogenic differentiation. However, the mechanism linking matrix remodeling in 3D to osteogenesis of MSCs remains unclear. Here, we find that MSCs in viscoelastic hydrogels exhibit volume expansion during cell spreading, and greater volume expansion is associated with enhanced osteogenesis. Restriction of expansion by either hydrogels with slow stress relaxation or increased o ...[more]

PMID: 30705265

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Project description:Epithelial ovarian cancers are among the most aggressive forms of gynecological malignancies. Despite the advent of poly adenosine diphosphate-ribose polymerase (PARP) and checkpoint inhibitors, improvement to patient survival has been modest. Limited in part by clinical translation, beneficial therapeutic strategies remain elusive in ovarian cancers. Although elevated levels of extracellular proteins, including collagens, proteoglycans, and glycoproteins, have been linked to chemoresistance, they are often missing from the processes of drug- development and screening. Biophysical and biochemical signaling from the extracellular matrix (ECM) determine cellular phenotype and affect both tumor progression and therapeutic response. However, many state-of-the-art tumor models fail to mimic the complexities of the tumor microenvironment (TME) and omit key signaling components. In this article, two interpenetrating network (IPN) hydrogel scaffold platforms, comprising of alginate-collagen or agarose-collagen, have been characterized for use as 3D in vitro models of epithelial ovarian cancer ECM. These highly tunable, injection mold compatible, and inexpensive IPNs replicate the critical governing physical and chemical signaling present within the ovarian TME. Additionally, an effective and cell-friendly live-cell retrieval method has been established to recover cells post-encapsulation. Lastly, functional mechanotransduction in ovarian cancers was demonstrated by increasing scaffold stiffness within the 3D in vitro ECM models. With these features, the agarose-collagen and alginate-collagen hydrogels provide a robust TME for the study of mechanobiology in epithelial cancers. STATEMENT OF SIGNIFICANCE: Ovarian cancer is the most lethal gynecologic cancer afflicting women today. Here we present the development, characterization, and validation of 3D interpenetrating platforms to shift the paradigm in standard in vitro modeling. These models help elucidate the roles of biophysical and biochemical cues in ovarian cancer progression. The agarose-collagen and alginate-collagen interpenetrating network (IPN) hydrogels are simple to fabricate, inexpensive, and can be modified to create custom mechanical stiffnesses and concentrations of bio-adhesive motifs. Given that investigations into the roles of biophysical characteristics in ovarian cancers have provided incongruent results, we believe that the IPN platforms will be critically important to uncovering molecular drivers. We also expect these platforms to be broadly applicable to studies involving mechanobiology in solid tumors.

Dataset Information

Volume expansion and TRPV4 activation regulate stem cell fate in three-dimensional microenvironments.

Publications

Volume expansion and TRPV4 activation regulate stem cell fate in three-dimensional microenvironments.

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