Microenvironmental determinants of organized iPSC-cardiomyocyte tissues on synthetic fibrous matrices

DePalma, Samuel J.; Davidson, Christopher D.; Stis, Austin; Helms, Adam S.; Baker, Brendon M.

doi:10.1039/d0bm01247e

Cited by 30 publications

(53 citation statements)

References 68 publications

(136 reference statements)

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“…Thus, cells could interact with both structural components without altering expression of integrin subtypes. DexVS fibers can be readily functionalized with other thiolated peptides via Michael-type addition, including GxOGER to model stromal type I collagen and other full-length proteins 38 .…”

Section: Discussionmentioning

confidence: 99%

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

Hiraki

et al. 2021

Preprint

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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 phenotypes has prognostic and therapeutic value. Here, we utilize a synthetic stromal mimetic in which matrix fiber density and bulk hydrogel stiffness 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 developed 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 stiffness distinctly contribute to a variety of MCF10A migration modes including amoeboid, single mesenchymal, multicellular clusters, and collective strands. Taking advantage of the tunability of this material platform, we identify a combination of physical and soluble cues that induces distinct heterogeneous migration modes originating from the same MCF10A spheroid and use this setting to examine a functional consequence of migration mode in apoptotic resistance. We find that cells migrating as part of collective strands are more resistant to staurosporine-induced apoptosis than either disconnected multicellular clusters or individual invading cells. Improved models of the peritumoral stromal microenvironment that help elucidate relationships between matrix attributes and cell migration mode can contribute to ongoing efforts to identify efficacious cancer therapeutics that address migration plasticity-based therapy resistances.

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Section: Discussionmentioning

confidence: 99%

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

Hiraki

et al. 2021

Preprint

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“…These properties are very attractive for tissue engineering. Indeed, in [ 128 ], iPSC-CMs were seeded on electrospun dextran vinyl sulfone (DVS) fibers with varying biochemical, architectural, and mechanical properties, and it was shown that the optimal configuration was fibronectin-functionalized DVS matrices with highly aligned fibers and low stiffness. The tissues generated on these scaffolds even demonstrated better maturation than micropatterned fibronectin lines.…”

Section: Cardiac Organoids To Reproduce the Features Of Human Cardiac Tissuementioning

confidence: 99%

Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

et al. 2021

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Cardiac tissue engineering aims at creating contractile structures that can optimally reproduce the features of human cardiac tissue. These constructs are becoming valuable tools to model some of the cardiac functions, to set preclinical platforms for drug testing, or to alternatively be used as therapies for cardiac repair approaches. Most of the recent developments in cardiac tissue engineering have been made possible by important advances regarding the efficient generation of cardiac cells from pluripotent stem cells and the use of novel biomaterials and microfabrication methods. Different combinations of cells, biomaterials, scaffolds, and geometries are however possible, which results in different types of structures with gradual complexities and abilities to mimic the native cardiac tissue. Here, we intend to cover key aspects of tissue engineering applied to cardiology and the consequent development of cardiac organoids. This review presents various facets of the construction of human cardiac 3D constructs, from the choice of the components to their patterning, the final geometry of generated tissues, and the subsequent readouts and applications to model and treat cardiac diseases.

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“…While RGD was used to enable cell adhesion to fiber segments here, other ECM peptides can be used to model full length proteins such as the GXOGER sequence of type I collagen ( DePalma et al, 2021 ). As DVS fiber segments are not hydrolytically or proteolytically degradable, cell force-mediated reorganization of fibrous architecture could also be investigated.…”

Section: Discussionmentioning

confidence: 99%

Magnetic Alignment of Electrospun Fiber Segments Within a Hydrogel Composite Guides Cell Spreading and Migration Phenotype Switching

Hiraki

Matera

Rose

et al. 2021

Front. Bioeng. Biotechnol.

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Fibrous extracellular matrix (ECM) proteins provide mechanical structure and adhesive scaffolding to resident cells within stromal tissues. Aligned ECM fibers play an important role in directing morphogenetic processes, supporting mechanical loads, and facilitating cell migration. Various methods have been developed to align matrix fibers in purified biopolymer hydrogels, such as type I collagen, including flow-induced alignment, uniaxial tensile deformation, and magnetic particles. However, purified biopolymers have limited orthogonal tunability of biophysical cues including stiffness, fiber density, and fiber alignment. Here, we generate synthetic, cell-adhesive fiber segments of the same length-scale as stromal fibrous proteins through electrospinning. Superparamagnetic iron oxide nanoparticles (SPIONs) embedded in synthetic fiber segments enable magnetic field induced alignment of fibers within an amorphous bulk hydrogel. We find that SPION density and magnetic field strength jointly influence fiber alignment and identify conditions to control the degree of alignment. Tuning fiber length allowed the alignment of dense fibrous hydrogel composites without fiber entanglement or regional variation in the degree of alignment. Functionalization of fiber segments with cell adhesive peptides induced tendon fibroblasts to adopt a uniaxial morphology akin to within native tendon. Furthermore, we demonstrate the utility of this hydrogel composite to direct multicellular migration from MCF10A spheroids and find that fiber alignment prompts invading multicellular strands to separate into disconnected single cells and multicellular clusters. These magnetic fiber segments can be readily incorporated into other natural and synthetic hydrogels and aligned with inexpensive and easily accessible rare earth magnets, without the need for specialized equipment. 3D hydrogel composites where stiffness/crosslinking, fiber density, and fiber alignment can be orthogonally tuned may provide insights into morphogenetic and pathogenic processes that involve matrix fiber alignment and can enable systematic investigation of the individual contribution of each biophysical cue to cell behavior.

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Microenvironmental determinants of organized iPSC-cardiomyocyte tissues on synthetic fibrous matrices

Abstract: This work provides microenvironmental design parameters to optimize iPSC-cardiomyocyte tissues formed on tunable synthetic matrices that mimic myocardial ECM.

Cited by 30 publications

References 68 publications

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

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

Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

Magnetic Alignment of Electrospun Fiber Segments Within a Hydrogel Composite Guides Cell Spreading and Migration Phenotype Switching

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