Role of the extracellular matrix and YAP/TAZ in cell reprogramming
Introduction
Stem cells have the ability to self-renew and differentiate into specific cell types. Stem cell studies have contributed to new research on tissue regeneration and enabled greater understanding of regenerative drugs and physiological processes related to disease and injury. A large number of studies have shown that mechanical signals induce reprogramming of somatic cells into stem cells in vitro, and that these reprogrammed stem cells maintain higher rates of proliferation, greater differentiation potential, less cell heterogeneity (Kishimoto et al., 2018), and improved biological safety than do primitive stem cells (e.g., adipose-derived or bone marrow mesenchymal stem cells) in vitro (Jumabay et al., 2014). As a source of cells for the treatment of many diseases, stem cells reprogrammed by mechanical signals offer unique advantages that can be widely used in the field of regenerative medicine and cell therapy.
In recent years, studies of how mechanical signals are transduced from the microenvironment into cells to affect their behavior have become a focus of research in cell biology. External mechanical forces sensed by cells are an important factor affecting reprogramming of somatic cells into stem cells (Jaalouk and Lammerding, 2009). Mechanical signals usually involve binding of cell surface receptors to ligands in the extracellular matrix (ECM) or on the surfaces of other cells. Research on stem cells suggests that properties of the ECM, mainly stiffness and geometry, can regulate reprogramming of somatic cells into stem cells by affecting the transduction of mechanical signals into cells (d'Angelo et al., 2019). Furthermore, it has been shown that mechanical signal transduction includes not only mechanical and other physical transduction mechanisms but also that it connects with biochemical signal mechanisms (Song et al., 2020). In this review we focus on the mechanical signal-induced reprogramming of somatic cells in vitro based on the focal adhesions-cytoskeleton-LINC (linker of nucleoskeleton and cytoskeleton) complex axis, and an associated biochemical signaling pathway based on YAP/TAZ (Yes-associated protein/transcriptional co-activator with PDZ-binding motif).
Section snippets
Role of the ECM in inducing cell reprogramming in vitro
Mechanical stiffness and shape of biological materials are two important physical characteristics that affect cell reprogramming (d'Angelo et al., 2019). Cell fate is in part determined by elasticity and stiffness of the ECM. Normally, soft cells are found on soft matrices and hard cells are found on hard matrices (Guilak et al., 2009). By adjusting the elasticity of the matrix, Engler et al. showed that human mesenchymal stem cells differentiated into neurogenic cells when cultured on a matrix
YAP/TAZ in regulation of cell reprogramming
The transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), are two highly related transcriptional co-activators that regulate cell proliferation, differentiation, survival, and other cell functions by integrating different cell signaling pathways (Ma et al., 2019b; Panciera et al., 2017; Totaro et al., 2018b). They are believed to be the central sensors of physical and mechanical forces in the cellular microenvironment (Totaro
Role of ENH in mechanical signaling
Studies have shown that mechanical signaling involves both physical and biochemical signals (Song et al., 2020). In terms of physical structure, mechanical signals are sensed at the plasma membrane by integrins in focal adhesion (FA) complexes, Src kinase, and connexins in gap junctions, which are then transmitted through the cytoskeleton. The LINC complex is located in the nuclear envelope (Kmonickova et al., 2020; Rothballer et al., 2013; Zhang et al., 2001) and consists of SUN proteins
Conclusions
This review summarizes the molecular mechanisms by which mechanical force signals induce somatic cell reprogramming to stem cells, and focuses on the internal relationships among ECM, YAP/TAZ, and ENH proteins. Altering the ECM may be a useful approach to controlling YAP/TAZ activity to induce reprogramming of somatic cells to stem cells in vitro to support regenerative medicine (Corsa and MacDougald, 2018; Jopling et al., 2011; Poloni et al., 2015b).
We have summarized ways in which the ECM can
Author contributions
Lan Liu and Mengchang Liu involved in interpretation and article drafting.DefuXie, Xingke Liu participated in the drafting of the picture.Hong Yan involved in designing the work, drafting the article and critically revising important knowledge content, and final approval of the version to be submitted.
Declaration of competing interest
The authors have stated explicitly that there are no conflicts of interest in connection with this article.
Acknowledgment
We are grateful to the Affiliated Hospital of Southwest Medical University for its support of our work.
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Soft substrates promote direct chemical reprogramming of fibroblasts into neurons
2022, Acta BiomaterialiaCitation Excerpt :ITGB4 is one of the representative genes in the integrin and cytoskeleton pathway; we biochemically perturbed ITGB4 to illustrate the role of integrins and the cytoskeleton in soft substrates that promote neural reprogramming and found that the cytoskeleton played an important role in maintaining neuronal morphology [71,72]. The relationship between mechanosignal-sensitive pathways suggested by sequencing has been reported, and when exogenous signals activate integrins, they mature into focal adhesions, which in turn drive the cytoskeleton reprogramming [21], and our results also further suggested that the Hippo signalling pathway was crucial in reprogramming [73–77]. Tension in the cytoskeleton stretches the nucleus [78,79], causing the nuclear pore to widen, allowing YAP to enter the nucleus and activate gene transcription [80].
Mechanical signals induces reprogramming of mature adipocytes through the YAP/TAZ-binding motif
2022, Experimental Cell ResearchCitation Excerpt :However, an increasing number of studies do not agree[2–8]. The results of our previous studies[9] also indicate that there was no significant difference between the oxygen content of the culture medium in the ceiling culture and that of ordinary culture conditions. Therefore, in this study, we attempted to improve the ceiling culture dish method, and MAs were culture d directly under a flexible plastic climbing sheet-covered culture dish.
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These authors contributed equally to the work and both should be considered co-first authors.