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Cell and Extracellular Matrix Interactions in a Dynamic Biomechanical Environment:
Published in Michel R. Labrosse, Cardiovascular Mechanics, 2018
Like other GTPases, Rho is inactive when bound to guanosine diphosphate (GDP) and is activated by guanine-nucleotide exchange factors (GEFs), which catalyze the exchange of GDP for GTP (Lessey et al. 2012). Rho’s intrinsic GTPase activity can revert its active GTP-bound form to the inactive GDP-bound form, but this process can be catalyzed by GTPase-activating proteins (GAPs). Rho can be activated by a variety of mechanical forces, including shear stress, compression, and tension (Lessey et al. 2012). This process is mediated by GEFs and GAPs that associate with the cytoskeleton and focal adhesions (Schwartz 2004, Lessey et al. 2012). Notably, FAK can activate Rho directly by binding and phosphorylating p190RhoGEF (Lim et al. 2008) and can inactivate Rho indirectly through Src to phosphorylate p190RhoGAP (Schober et al. 2007). RhoA’s control of the actin–myosin machinery makes it an important signaling protein, mediating changes to cell structural behaviors such as cell shape response and migration in response to mechanical stimuli (Arthur and Burridge 2001, Peyton and Putnam 2005, Liu et al. 2014). While RhoA activity can change cell shape, cell shape itself can modulate RhoA levels and cytoskeletal tension and provide important developmental cues, with spread, flattened MSCs undergoing osteogenesis and unspread, rounded MSCs undergoing adipogenesis (McBeath et al. 2004). The ECM through structural organization, mechanical properties, and transmission of mechanical forces is an important regulator of cell shape, but cells can maintain a degree of control by actively remodeling the ECM with MMPs to assume cell shapes favorable to different differentiation fates (Figure 2.9) (Tang et al. 2013). Extracellular matrix stiffness also acts through RhoA signaling to direct MSC differentiation (Engler et al. 2006). RhoA activity controls the shuttling of transcriptional coactivators such as four and a half LIM domains protein 2 (FHL2) (Muller et al. 2002) and yes-associated protein (YAP)/tafazzin (TAZ) (Tang et al. 2013, Panciera et al. 2017) between the cytoplasm and the nucleus to regulate gene transcription.
Implications of CRISPR Technology in Biological Systems
Published in Jyoti Ranjan Rout, Rout George Kerry, Abinash Dutta, Biotechnological Advances for Microbiology, Molecular Biology, and Nanotechnology, 2022
Kikku Sharma, Souvik Sen Gupta
Cardiovascular diseases constitute a major and increasing health problem in today’s world. There are many challenges to gain deeper knowledge about the common and less common causes of cardiovascular mortality. Genetic testing and bioinformatic analyzes have helped to identify the susceptibility of subjects to particular cardiac diseases like coronary and peripheral artery disease (CAD and PAD), rheumatic, hypertensive and congenital heart disease, cerebrovascular disease (stroke), and arrhythmias. The innovative discovery of induced pluripotent stem cells revolutionized the field of genome editing and now the iPS cells are widely used in cardiomyogenesis. iPS cells derived from cardiomyocytes (CM) are used as a unique tool in the field, wherein several scientists have made efforts toward satisfactory in vitro maturation of iPS cells to generate a better model for cardiac pathologies. The iPS cell has many potential functions. For example, if an individual is affected with long QT interval then the iPS cells from this individual may be induced to generate functional CM, which may address the problem. In the case of individuals with structural cardiac defects such as dilated cardio-myopathy (DCM) and hypertrophic cardiomyopathy (HCM), the iPS cells show mutations. The iPS cells derived from DCM show a mutation in a gene that encodes for troponin which leads to abnormality in Ca2+ handling and also abnormal arrangement of sarcomeric actin that leads to a decrease in the contractility of the heart. A single missense mutation in the MYH7 gene of the iPS cells derived from HCM patients show unorganized sarcomere and decreased electrophysiological polarity that leads to serious problems. The CRISPR-CAS9 system has been experimentally used for gene knockin and knockout in human iPS cells. So this technology may be used to correct the genetic mutations in the iPS cell model. Barth syndrome is an X-linked genetic cardiac disease that may be eradicated by the combination of iPS cells and CAS9-mediated genome editing. Mutation in the tafazzin (TAZ) gene of iPS cells of a healthy donor by CAS9-mediated genome editing tools have helped to identify the relationship between TAZ gene mutations that cause the disease and mitochondrial phenotypes. The titin gene mutations in DCM have also been evaluated by the CRISPR-CAS9 system (Motta et al., 2017). The CRISPR-CAS9 system can also edit genes of somatic cells in vivo. It can disrupt the proprotein convertase subtilisin/Kexin type 9 (PCSK9) gene, which leads to the lowering of blood cholesterol resulting in the lowering of coronary heart disease. By rectifying the mutation in the calmodulin gene of iPS cells, we can overcome the problem of long QT syndrome. Long QT-associated calmodulin inactivation occurs due to the mutation in CALM1, CALM2 and CALM 3 gene. The long QT syndrome is mediated by the mutation in six calmodulin producing alleles and CRISPR interference technology can selectively rectify these mutated alleles. In this technique, the dCas9 and its associated g RNA bind to the promoter and inactivate RNA polymerase leading to transcriptional deactivation of the mutant alleles.
The individual and combined effects of spaceflight radiation and microgravity on biologic systems and functional outcomes
Published in Journal of Environmental Science and Health, Part C, 2021
Jeffrey S. Willey, Richard A. Britten, Elizabeth Blaber, Candice G.T. Tahimic, Jeffrey Chancellor, Marie Mortreux, Larry D. Sanford, Angela J. Kubik, Michael D. Delp, Xiao Wen Mao
Maintenance of stemness during microgravity exposure has also been demonstrated in several other stem cell populations including cardiovascular progenitor cells, mesenchymal stem cells (MSCs), hematopoietic (HSCs), and adipose derived stem cells. Specifically, studies using neonatal and adult cardiovascular progenitor cells exposed to microgravity on ISS and simulated microgravity in a clinostat resulted in altered cytoskeletal organization and migration in both cell populations.215,216 Several of these responses were found to be regulated by miRNAs, thereby indicating that miRNAs may be a key mediator of the cellular response to spaceflight exposure.215–217 MicroRNAs (miRNAs) are highly conserved non-coding RNA molecules that are involved in post-transcriptional regulation of gene expression. They function via base-pairing with complementary strands of mRNA, in turn silencing them by cleavage, destabilization, or hindering translation. Furthermore, the authors found reduced yes-associated protein 1 (YAP1) and Tafazzin (TAZ) signaling that can function to regulate transcription and is affected by mechanical load.217 Neonatal but not adult cardiovascular progenitor cells exposed to spaceflight exhibited increased expression of markers for early cardiovascular development and enhanced proliferative potential, possibly mediated through miRNA signaling.215,216