The role of Hippo signaling pathway and mechanotransduction in tuning embryoid body formation and differentiation

Abstract

Embryoid bodies (EBs) are the three‐dimensional aggregates of pluripotent stem cells that are used as a model system for the in vitro differentiation. EBs mimic the early stages of embryogenesis and are considered as a potential biomimetic body in tuning the stem cell fate. Although EBs have a spheroid shape, they are not formed accidentally by the agglomeration of cells; they are formed by the deliberate and programmed aggregation of stem cells in a complex topological and biophysical microstructure instead. EBs could be programmed to promisingly differentiate into the desired germ layers with specific cell lineages, in response to intra‐ and extra‐biochemical and biomechanical signals. Hippo signaling and mechanotransduction are the key pathways in controlling the formation and differentiation of EBs. The activity of the Hippo pathway strongly relies on cell–cell junctions, cell polarity, cellular architecture, cellular metabolism, and mechanical cues in the surrounding microenvironment. Although the Hippo pathway was initially thought to limit the size of the organ by inhibiting the proliferation and the promotion of apoptosis, the evidence suggests that this pathway even regulates stem cell self‐renewal and differentiation. Considering the abovementioned explanations, the present study investigated the interplay of the Hippo signaling pathway, mechanotransduction, differentiation, and proliferation pathways to draw the molecular network involved in the control of EBs fate. In addition, this study highlighted several neglected critical parameters regarding EB formation, in the interplay with the Hippo core component involved in the promising differentiation.

Designing robust chitosan-based hydrogels for stem cell nesting under oxidative stress

“…Moreover, ECM plays an important role in regulating the cell function by providing biochemical and biomechanical signals. 2 Evidence supports that the interaction with microenvironment affects the function of the injected stem cells in tissue engineering approaches. 3 Engineered biomaterials provide a suitable platform to best mimic the microenvironment of the MSCs and to improve cell function and viability.…”

Autonomy in the Development of Stem Cell-Derived Embryoids: Sprouting Blastocyst-Like Cysts, and Ethical Implications

“…As has been discussed earlier [14], it seems to be significant for what is going on in cultures of stem cells that the asymmetry signals which probably govern morphogenetic patterning (the development of embryonic axes) in vivo can obviously be replaced by surrogate asymmetries in stem cell cultures, e.g., asymmetries in cell-cell and matrix densities that are always present in cultures and which arise stochastically [14]. Nevertheless, in many of the recent embryoid formation experiments using stem cells, it was found to be helpful to use a degree of "engineering" by providing some type of spatial information, e.g., to combine the various types of cells in an appropriate polar arrangement [23], or to apply physical constraints or specially engineered matrices [37,49,74]. Such experimental details are at least helpful for allowing morphogenesis to regularly reach stages largely resembling oocyte-derived embryos and their extraembryonic membranes [22].…”

“…Such approaches are sometimes addressed as "embryo engineering". Technical details that are found to be critical for permitting complex morphogenesis in these embryo engineering approaches are: specific culturing media supplements that regulate certain steps of lineage differentiation; various intricate manipulations, e.g., to use a defined small number of cells that are aggregated in separate wells to form initial clusters; to keep cell clusters non-attached or attached to specific kinds of substratum; to restrict the use of adhesive surfaces to certain stages of differentiation; or to construct a surrogate for axis pre-information for embryogenesis by combining different types of stem cell clusters in a specific way [18,22,[24][25][26][27][37][38][39][40][41][42][43][44][45][46][47][48][49]; for reviews see [3,5,50,51], and for a discussion of the signaling and gene activation processes involved see [4,52,53].…”

LINCking the Nuclear Envelope to Sperm Architecture

“…One of the kinds of main intracellular mechanosensor signaling generated from mechanical cues and linked to actin stimulation is the Hippo kinase signaling cascade. This evolutionarily conserved pathway, involved in the regulation of cell proliferation and fate, tissue differentiation, and organ size, is triggered downstream from a mechanical force able to induce actin activation [ 73 , 74 , 75 ]. It also includes Yes-associated protein (YAP) and its homologous protein Transcriptional Co-Activator With PDZ-Binding Motif (TAZ), two transcriptional co-activators able to deliver mechanical cues to the transcriptional machinery of the nucleus by shuttling between the cytoplasm and nucleus [ 76 , 77 , 78 ].…”