The design of 3D scaffolds is a crucial step in the field of regenerative medicine. Scaffolds should be degradable and bioresorbable as well as display good porosity, interconnecting pores, and topographic features; these properties favour tissue integration and vascularization. These requirements could be fulfilled by hybrid hydrogels using a combination of natural and synthetic components. Here, the mechanical and biological properties of a polyethylene glycol-fibrinogen hydrogel (PFHy) are improved in order to favour the proliferation and differentiation of human Sca-1(pos) cardiac progenitor cells (hCPCs). PFHys are modified by embedding air- or perfluorohexane-filled bovine serum albumin microbubbles (MBs) and characterized. Changes in cell morphology are observed in MBs-PFHys, suggesting that MBs could enhance the formation of bundles of cells and influence the direction of the spindle growth. The properties of MBs as carriers of active macromolecules are also exploited. For the first time, enzyme-coated MBs have been used as systems for the production of hydrogen sulfide (H2 S)-releasing scaffolds. Novel H2 S-releasing PFHys are produced, which are able to improve the growth of hCPCs. This novel 3D cell-scaffold system will allow the assessment of the effects of H2 S on the cardiac muscle regeneration with its potential applications in tissue repair.
The microenvironment plays a crucial role in the behavior of stem and progenitor cells. In the heart, cardiac progenitor cells (CPCs) reside in specific niches, characterized by key components that are altered in response to a myocardial infarction. To date, there is a lack of knowledge on these niches and on the CPC interplay with the niche components. Insight into these complex interactions and into the influence of microenvironmental factors on CPCs can be used to promote the regenerative potential of these cells. In this review, we discuss cardiac resident progenitor cells and their regenerative potential and provide an overview of the interactions of CPCs with the key elements of their niche. We focus on the interaction between CPCs and supporting cells, extracellular matrix, mechanical stimuli, and soluble factors. Finally, we describe novel approaches to modulate the CPC niche that can represent the next step in recreating an optimal CPC microenvironment and thereby improve their regeneration capacity.
For emerging cardiac regeneration strategies, it is essential to know if and how cardiac stem cells sense and respond to the mechanical stimuli provided by their environment in the beating heart. Here, we study the response to cyclic strain of undifferentiated and predifferentiated human cardiomyocyte progenitor cells (CMPCs), as well as the formation and activation of the cellular structures involved in mechanosensing, that we termed 'mechanosome'. Once verified that the applied uniaxial cyclic strain (10%, 0.5 Hz) did not alter the cardiac lineage commitment and differentiation state of CMPCs, the cellular mechanoresponse to the applied strain was quantified by cellular orientation. While undifferentiated cells maintained their original (random) orientation, upon early cardiomyogenic differentiation (predifferentiated) CMPCs exhibited a distinct strain avoidance response after 48 h of cyclic straining. Interestingly, the mechanosome development and the activation of the mechanotransduction pathways also occurred with early cardiac differentiation of the CMPCs, regardless of the substrate or the applied cyclic strain. These results indicate that the mechanoresponse of CMPCs depends on the presence of a developed mechanosome, which only develops during early cardiomyogenic differentiation Our findings provide the first understanding of mechanotransduction in human CMPCs and as such can contribute to the improvement of cardiac regeneration strategies.
There is a need to further explore the convergence of mechanobiology and dimensionality with systematic investigations of cellular response to matrix mechanics in 2D and 3D cultures. Here, a semisynthetic hydrogel capable of supporting both 2D and 3D cell culture is applied to investigate cell response to matrix modulus and ligand density. The culture materials are fabricated from adducts of polyethylene glycol (PEG) or PluronicF127 and fibrinogen fragments, formed into hydrogels by free‐radical polymerization, and characterized by shear rheology. Control over the modulus of the materials is accomplished by changing the concentration of synthetic PEG‐diacrylate crosslinker (0.5% w/v), and by altering the molecular length of the PEG (10 and 20 kDa). Control over ligand density is accomplished by changing fibrinogen concentrations from 3 to 12 mg mL−1. In 2D culture, cell motility parameters, including cell speed and persistence time are significantly increased with increasing modulus. In both 2D and 3D culture, cells express vinculin and there is evidence of focal adhesion formation in the high stiffness materials. The modulus‐ and ligand‐dependent morphogenesis response from the cells in 2D culture is contradictory to the same measured response in 3D culture. In 2D culture, anchorage‐dependent cells become more elongated and significantly increase their size with increasing ligand density and matrix modulus. In 3D culture, the same anchorage‐dependent cells become less spindled and significantly reduce their size in response to increasing ligand density and matrix modulus. These differences arise from dimensionality constraints, most notably the encapsulation of cells in a non‐porous hydrogel matrix. These insights underscore the importance of mechanical properties in regulating cell morphogenesis in a 3D culture milieu. The versatility of the hydrogel culture environment further highlights the significance of a modular approach when developing materials that aim to optimize the cell culture environment.
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