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HeLa cell stably expressing α-tubulin tagged with mCherry overexpressing IQGAP3 tagged with GFP (late anaphase/telophase to cytokinesis).

IQGAP3 expression in human cervical cancers

HeLa cell stably transfected with mCherry-α-tubulin transfected with siIQ3#1.

Controlling cell proliferation is critical for organism development, tissue homeostasis, disease, and regeneration. IQGAP3 has been shown to be required for proper cell proliferation and migration, and is associated to a number of cancers. Moreover, its expression is inversely correlated with the overall survival rate in the majority of cancers. Here, we show that IQGAP3 expression is elevated in cervical cancer and that in these cancers IQGAP3 high expression is correlated with an increased lethality. Furthermore, we demonstrate that IQGAP3 is a target of YAP, a regulator of cell cycle gene expression. IQGAP3 knockdown resulted in an increased percentage of HeLa cells in S phase, delayed progression through mitosis, and caused multipolar spindle formation and consequentially aneuploidy. Protein–protein interaction studies revealed that IQGAP3 interacts with MMS19, which is known in Drosophila to permit, by competitive binding to Xpd, Cdk7 to be fully active as a Cdk-activating kinase (CAK). Notably, IQGAP3 knockdown caused decreased MMS19 protein levels and XPD knockdown partially rescued the reduced proliferation rate upon IQGAP3 knockdown. This suggests that IQGAP3 modulates the cell cycle via the MMS19/XPD/CAK axis. Thus, in addition to governing proliferation and migration, IQGAP3 is a critical regulator of mitotic progression and genome stability.Implications:Our data indicate that, while IQGAP3 inhibition might be initially effective in decreasing cancer cell proliferation, this approach harbors the risk to promote aneuploidy and, therefore, the formation of more aggressive cancers.

HeLa cell stably transfected with mCherry-α-tubulin transfected with siCtrl.

Figure S1: IQGAP3 depletion does not affect apoptotic HeLa rate but affects cell proliferation. Figure S2: Efficiency of siRNA-mediated YAP/TAZ and B-MYB knockdown strategy in HeLa cells. Figure S3: IQGAP3 knockdown strategy in Hct116 cells. Figure S4: IQGAP3 binds to both Cdk11p58 and uMAP4.

HeLa cell stably expressing α-tubulin tagged with mCherry overexpressing IQGAP3 tagged with GFP (metaphase to cytokinesis).

The DNA damage response (DDR) and epithelial-to-mesenchymal transition (EMT) are two crucial cellular programs in cancer biology. While the DDR orchestrates cell cycle progression, DNA repair and cell death, EMT promotes invasiveness, cellular plasticity and intratumor heterogeneity. Therapeutic targeting of EMT transcription factors, such as ZEB1, remains challenging, but tumor-promoting DDR alterations elicit specific vulnerabilities. Using multi-omics, inhibitors and high-content microscopy, we discover a chemoresistant ZEB1 high expressing sub-population (ZEB1hi) with co-rewired cell cycle progression and proficient DDR across tumor entities. ZEB1 stimulates accelerated S-phase entry via CDK6, inflicting endogenous DNA replication stress. However, DDR buildups involving constitutive MRE11-dependent fork resection allow homeostatic cycling and enrichment of ZEB1hi cells during TGFβ-induced EMT and chemotherapy. Thus, ZEB1 promotes G1/S transition to launch a progressive DDR benefitting stress tolerance, which concurrently manifests a targetable vulnerability in chemoresistant ZEB1hi cells. Our study thus highlights the translationally relevant intercept of the DDR and EMT.&nbsp

Significance: Heart failure is among the leading causes of morbidity worldwide with a 5-year mortality rate of ∼50%. Therefore, major efforts are invested to reduce heart damage upon injury or main...

Controlling cell proliferation is critical for organism development, tissue homeostasis, disease, and regeneration. IQGAP3 has been shown to be required for proper cell proliferation and migration, and is associated to a number of cancers. Moreover, its expression is inversely correlated with the overall survival rate in the majority of cancers. Here, we show that IQGAP3 expression is elevated in cervical cancer and that in these cancers IQGAP3 high expression is correlated with an increased lethality. Furthermore, we demonstrate that IQGAP3 is a target of YAP, a regulator of cell cycle gene expression. IQGAP3 knockdown resulted in an increased percentage of HeLa cells in S phase, delayed progression through mitosis, and caused multipolar spindle formation and consequentially aneuploidy. Protein–protein interaction studies revealed that IQGAP3 interacts with MMS19, which is known in Drosophila to permit, by competitive binding to Xpd, Cdk7 to be fully active as a Cdk-activating kinase (CAK). Notably, IQGAP3 knockdown caused decreased MMS19 protein levels and XPD knockdown partially rescued the reduced proliferation rate upon IQGAP3 knockdown. This suggests that IQGAP3 modulates the cell cycle via the MMS19/XPD/CAK axis. Thus, in addition to governing proliferation and migration, IQGAP3 is a critical regulator of mitotic progression and genome stability. Implications: Our data indicate that, while IQGAP3 inhibition might be initially effective in decreasing cancer cell proliferation, this approach harbors the risk to promote aneuploidy and, therefore, the formation of more aggressive cancers.

How adhesion G protein-coupled receptors (aGPCRs) control development remains unclear. The aGPCR Adgrg6/Gpr126 has been associated with heart trabeculation. Defects in this process cause cardiomyopathies and embryonic lethality. Yet, how cardiomyocytes attain trabecular identity is poorly understood. Here, we show that Gpr126 regulates Notch activity and N-cadherin localization that are necessary for attaining trabecular identity in zebrafish. Maternal zygotic gpr126stl47 early truncation mutants exhibit hypotrabeculation whereby N-cadherin distributes randomly at apical/basal membranes of compact layer cardiomyocytes. In contrast, gpr126st49 mutants expressing a N-terminal fragment lacking the GPS motif (NTFΔGPS) exhibit a multilayered ventricular wall consisting of polarized cardiomyocytes with normal N-cadherin expression and increased Notch signaling. Notably, endocardially expressed C-terminal fragment (CTF) reinstates trabeculation in gpr126st49 mutants. Collectively, our data indicate domain-specific roles of Gpr126 during trabeculation whereby the NTF maintains cell-cell adhesion and is required for compact wall integrity, while the CTF is essential to provide trabecular identity

While bone regenerates itself after an injury, a critical bone defect requires external interventions. Engineering approaches to restore bone provide a temporary scaffold to support the damage and provide beneficial biological cues for bone repair. Biomimetically generated scaffolds replicate the naturally occurring phenomena in bone regeneration. In this study, a gelatin-calcium phosphate nanocomposite was synthesized by an efficient and cost-effective double-diffusion biomimetic approach. Calcium and phosphate ions are impregnated in the gelatin, mimicking the natural bone mineralization process. Glutaraldehyde from 0.5 to 2 w/v% was used for gelatin cross-linking and mechanical properties of the scaffold, and its biological support for rat bone marrow mesenchymal stromal cells was analyzed. Analysis of scanning electron microscopy images of the nanocomposite scaffolds and Fourier transform infrared (FTIR) and X-ray diffraction (XRD) characterizations of these scaffolds confirmed precipitation of calcium phosphates in the gelatin. Moreover, lysozyme degradation assay showed that scaffold degradation reversely correlates with the concentration of the cross-linking agent. Increased glutaraldehyde concentrations enhanced the mechanical properties of the scaffolds, bringing them closer to those of cancellous bone. Rat bone marrow mesenchymal stromal cells maintained their viability on these scaffolds compared to standard cell culture plates. In addition, these cells showed differentiation into bone lineage as evaluated from alkaline phosphatase activity up to 21 days and Alizarin red staining of the cells over 28 days. Eventually, scaffolds were implanted in a cranial defect in a rat animal model with a 5 mm diameter. Bone regeneration was studied over 90 days. Analysis of histological sections of the injury and computer tomography images revealed that nanocomposite scaffolds cross-linked with 1% w/v glutaraldehyde provide the maximum bone regeneration after 90 days. Collectively, our data show that nanocomposite scaffolds developed here provide effective regeneration for extensive bone defects

Zebrafish xenografts are an established model in cancer biology, with a steadily rising number of models and users. However, as of yet, there is no platform dedicated to standardizing protocols and sharing data regarding zebrafish xenograft phenotypes. Here, we present the Xenograft Phenotype Interactive Repository (XePhIR,www.xephir.org) as an independent data sharing platform to deposit, share and repurpose zebrafish xenograft data. Deposition of data and publication with XePhIR will be done after the acceptation of the original publication. This will enhance the reach of the original research article, enhance visibility, and does not interfere with publication or copyrights of the original article. With XePhIR, we strive to fulfill these objectives and reason that this resource will enhance reproducibility and showcase the appeal and applicability of the zebrafish xenograft model.

Cardiac tissue engineering is a promising strategy to generate human cardiac tissues for modeling cardiac diseases, screening for therapeutic drugs, and repairing the injured heart. Yet, several issues remain to be resolved including the generation of tissues with high cardiomyocyte density. Here, it is shown that the integration of the glycogen synthase kinase-3β inhibitor CHIR99021 in collagen I hydrogels promotes proliferation of human-induced pluripotent stem cell-derived (hiPSC) cardiomyocytes post-fabrication improving contractility of and calcium flow in engineered 3D cardiac microtissues. CHIR99021 has no effect on the gelation kinetics or the mechanical properties of collagen I hydrogels. Analysis of cell density and proliferation based on Ki-67 staining indicates that integration of CHIR99021 together with external CHIR99021 stimulation increases hiPSC-cardiomyocyte number by ≈2-fold within 7 d post-fabrication. Analysis of the contractility of engineered cardiac tissues after another 3 d in the absence of external CHIR99021 shows that CHIR99021-induced hiPSC-cardiomyocyte proliferation results in synchronized calcium flow, rhythmic beating, increased speed of contraction and contraction amplitude, and reduced peak-to-peak time. The CHIR99021-stimulated engineered cardiac microtissues exhibit spontaneous rhythmic contractions for at least 35 d. Collectively, the data demonstrate the potential of induced cardiomyocyte proliferation to enhance engineered cardiac microtissues by increasing cardiomyocyte density.

Induction of cardiomyocyte proliferation is a promising option to regenerate the heart. Thus, it is important to elucidate mechanisms that contribute to the cell cycle arrest of mammalian cardiomyocytes. Here, we assessed the contribution of the pericentrin (Pcnt) S isoform to the cell cycle arrest in postnatal cardiomyocytes. Immunofluorescence staining of Pcnt isoforms combined with siRNA-mediated depletion indicates that Pcnt S preferentially localizes to the nuclear envelope, while the Pcnt B isoform is enriched at centrosomes. This is further supported by the localization of ectopically expressed FLAG-tagged Pcnt S and Pcnt B in postnatal cardiomyocytes. Analysis of centriole configuration upon Pcnt depletion revealed that Pcnt B but not Pcnt S is required for centriole cohesion. Importantly, ectopic expression of Pcnt S induced centriole splitting in a heterologous system, ARPE-19 cells, and was sufficient to impair DNA synthesis in C2C12 myoblasts. Moreover, Pcnt S depletion enhanced serum-induced cell cycle re-entry in postnatal cardiomyocytes. Analysis of mitosis, binucleation rate, and cell number suggests that Pcnt S depletion promotes progression of postnatal cardiomyocytes through the cell cycle resulting in cell division. Collectively, our data indicate that alternative splicing of Pcnt contributes to the establishment of cardiomyocyte cell cycle arrest shortly after birth.

Materials made of recombinant spider silk proteins are promising candidates for cardiac tissue engineering, and their suitability has so far been investigated utilizing primary rat cardiomyocytes. Herein, we expanded the tool box of available spider silk variants and demonstrated for the first time that human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes attach, contract, and respond to pharmacological treatment using phenylephrine and verapamil on explicit spider silk films. The hiPSC-cardiomyocytes contracted for at least 14 days on films made of positively charged engineered Araneus diadematus fibroin 4 (eADF4(κ16)) and three different arginyl-glycyl-aspartic acid (RGD)-tagged spider silk variants (positively or negatively charged and uncharged). Notably, hiPSC-cardiomyocytes exhibited different morphologies depending on the spider silk variant used, with less spreading and being smaller on films made of eADF4(κ16) than on RGD-tagged spider silk films. These results indicate that spider silk engineering is a powerful tool to provide new materials suitable for hiPSC-based cardiac tissue engineering., Graphical abstract Image 1, Highlights • hiPSC-cardiomyocytes attach and contract on positively charged and/or RGD-tagged spider silk variants. • hiPSC-cardiomyocytes exhibit spider silk variant-dependent morphology upon adhesion. • Explicit spider silk variants promote long-term contractility of hiPSC-cardiomyocytes. • hiPSC-cardiomyocytes grown on spider silk materials respond to pharmacological treatment.

Gpr126 (Adgrg6), a member of the adhesion G protein-coupled receptor family, has been associated with a variety of human diseases. Yet, despite its clinical importance, the mechanisms regulating Gpr126 expression are poorly understood. Here, we aimed at identifying upstream regulatory mechanisms of Gpr126 expression utilizing the heart as model organ in which Gpr126 regulates trabeculation. Here, we focused on possible regulation of Gpr126 regulation by microRNAs, which have emerged as key players in regulating development, have a critical role in disease progression, and might serve as putative therapeutic targets. In silico analyses identified one conserved binding site in the 3' UTR of Gpr126 for microRNA 27a and 27b (miR-27a/b). In addition, miR-27a/b and Gpr126 expression were differentially expressed during rat heart development. A regulatory role of miR-27a/b in controlling Gpr126 expression was substantiated by reduced Gpr126 mRNA levels upon ectopic expression of miR-27a/b in HEK293T cells and miR-27b in zebrafish embryos. Regulation of Gpr126 expression by direct binding of miR-27a/b to the 3' UTR of Gpr126 was verified by luciferase reporter assays in HEK293T cells. Finally, the modulation of gpr126 expression in zebrafish by injection of either miR-27b or miR-27b inhibitor in single cell-stage embryos resulted in hypo- or hypertrabeculation, respectively. Collectively, the data indicate that Gpr126 expression is regulated by miR-27a/b.

GPR126 (ADGRG6) is an adhesion G protein-coupled receptor that plays an important role in a variety of tissues/organs, such as heart, sciatic nerve, cartilage, and ear. Moreover, GPR126 (ADGRG6) mutations are associated with human diseases, like adolescent idiopathic scoliosis, lung disease, bladder cancer, and intellectual disability. Despite its clinical importance, it remains elusive how GPR126 is activated and mediates signal transduction and what cellular processes depend on GPR126 signaling. Here, we generated a lacZ reporter mouse line to determine endogenous Gpr126 (Adgrg6) expression in a cell type-specific manner during embryonic development, at postnatal day 5 and in adult animals. Our results confirm Gpr126 expression data previously obtained utilizing antibodies and in situ hybridization in embryonic heart and sciatic nerve. In addition, we provide data with cellular resolution for previously described RT-PCR-based data, including lung and bladder. Moreover, new Gpr126-expressing tissues and cell types were identified, such as ureter and acinar secretory cells. Collectively, our data demonstrate that the newly generated lacZ reporter mouse is a suitable model to study Gpr126 expression during development and adulthood, provide detailed insight into Gpr126 expression at the cellular level, and reveal that all identified Gpr126-expressing cells are known to be exposed to mechanical stimuli.

One great achievement in medical practice is the reduction in acute mortality of myocardial infarction due to identifying risk factors, antiplatelet therapy, optimized hospitalization and acute percutaneous coronary intervention. Yet, the prevalence of heart failure is increasing presenting a major socio-economic burden. Thus, there is a great need for novel therapies that can reverse damage inflicted to the heart. In recent years, data have accumulated suggesting that induction of cardiomyocyte proliferation might be a future option for cardiac regeneration. Here, we review the relevant literature since September 2015 concluding that it remains a challenge to verify that a therapy induces indeed cardiomyocyte proliferation. Most importantly, it is unclear that the detected increase in cardiomyocyte cell cycle activity is required for an associated improved function. In addition, we review the literature regarding the evidence that binucleated and polyploid mononucleated cardiomyocytes can divide, and put this in context to other cell types. Our analysis shows that there is significant evidence that binucleated cardiomyocytes can divide. Yet, it remains elusive whether also polyploid mononucleated cardiomyocytes can divide, how efficient proliferation of binucleated cardiomyocytes can be induced, what mechanism regulates cell cycle progression in these cells, and what fate and physiological properties the daughter cells have. In summary, we propose to standardize and independently validate cardiac regeneration studies, encourage the field to study the proliferative potential of binucleated and polyploid mononucleated cardiomyocytes, and to determine whether induction of polyploidization can enhance cardiac function post-injury.

Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF. © Published on behalf of the European Society of Cardiology. All rights reserved.

Vascularization remains one of the greatest yet unmet challenges in tissue engineering. When engineered tissues are scaled up to therapeutically relevant dimensions, their demand of oxygen and nutrients can no longer be met by diffusion. Thus, there is a need for perfusable vascular structures. Hypoxia-inducible factors (HIF) act as transcriptional oxygen sensors and regulate a multitude of genes involved in adaptive processes to hypoxia, including angiogenesis. Thus, targeting HIFs is a promising strategy to induce vascularization of engineered tissues.Here we review current vascularization strategies and summarize the present knowledge regarding activation of HIF signaling by ions, iron chelating agents, α-Ketoglutarate (αKG) analogues, and the lipid-lowering drug simvastatin to induce angiogenesis. Specifically, we focus on the incorporation of HIF-activating agents into biomaterials and scaffolds for controlled release.Vascularization of tissue constructs through activation of upstream regulators of angiogenesis offers advantages but also suffers from drawbacks. HIFs can induce a complete angiogenic program; however, this program appears to be too slow to vascularize larger constructs before cell death occurs. It is therefore crucial that HIF-activation is combined with cell protective strategies and prevascularization techniques to obtain fully vascularized, vital tissues of therapeutically relevant dimensions.

Physiological and pathological cardiac stress induced by exercise and hypertension, respectively, increase the hemodynamic load for the heart and trigger specific hypertrophic signals in cardiomyocytes leading to adaptive or maladaptive cardiac hypertrophy responses involving a mechanosensitive remodeling of the contractile cytoskeleton. Integrins sense load and have been implicated in cardiac hypertrophy, but how they discriminate between the two types of cardiac stress and translate mechanical loads into specific cytoskeletal signaling pathways is not clear. Here, we report that the focal adhesion protein β-parvin is highly expressed in cardiomyocytes and facilitates the formation of cell protrusions, the serial assembly of newly synthesized sarcomeres, and the hypertrophic growth of neonatal rat ventricular cardiomyocytes (NRVCs) in vitro. In addition, physiological mechanical loading of NRVCs by either the application of cyclic, uni-axial stretch, or culture on physiologically stiff substrates promotes NRVC elongation in a β-parvin-dependent manner, which is achieved by binding of β-parvin to α/β-PIX, which in turn activates Rac1. Importantly, loss-of-function studies in mice also revealed that β-parvin is essential for the exercise-induced cardiac hypertrophy response in vivo. Our results identify β-parvin as a novel mechano-responsive signaling hub in hypertrophic cardiomyocytes that drives cell elongation in response to physiological mechanical loads.

This is a pre-copyedited, author-produced version of an article accepted for publication in Cardiovascular Research (CVR) following peer review. The version of record Perrino, Ferdinandy, Bøtker, Brundel, Collins, Davidson, Den Ruijter, Engel, Gerdts, Girao, Gyöngyösi, Hausenloy, Lecour, Madonna, Marber, Murphy, Pesce, Regitz-Zagrosek, Sluijter, Steffens, Gollmann-Tepeköylü, Van Laake, Van Linthout, Schulz, Ytrehus. Improving translational research in sex-specific effects of comorbidities and risk factors in ischaemic heart disease and cardioprotection: Position paper and recommendations of the ESC Working Group on Cellular Biology of the Heart. Cardiovascular Research (CVR). 2021;117(2):367-385, is available online at: https://doi.org/10.1093/cvr/cvaa155. Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here.

Non-centrosomal microtubule organizing centers (MTOC) are pivotal for the function of multiple cell types, but the processes initiating their formation are unknown. Here, we find that the transcription factor myogenin is required in myoblasts for the localization of MTOC proteins to the nuclear envelope. Moreover, myogenin is sufficient in fibroblasts for nuclear envelope MTOC (NE-MTOC) formation and centrosome attenuation. Bioinformatics combined with loss- and gain-of-function experiments identified induction of AKAP6 expression as one central mechanism for myogenin-mediated NE-MTOC formation. Promoter studies indicate that myogenin preferentially induces the transcription of muscle- and NE-MTOC-specific isoforms of Akap6 and Syne1, which encodes nesprin-1α, the NE-MTOC anchor protein in muscle cells. Overexpression of AKAP6β and nesprin-1α was sufficient to recruit endogenous MTOC proteins to the nuclear envelope of myoblasts in the absence of myogenin. Taken together, our results illuminate how mammals transcriptionally control the switch from a centrosomal MTOC to an NE-MTOC and identify AKAP6 as a novel NE-MTOC component in muscle cells.

In order to take advantage of the continuously increasing number of transcriptome studies, it is important to develop strategies that integrate multiple expression datasets addressing the same biological question to allow a robust analysis. Here, we propose a meta-analysis framework that integrates enriched pathways identified through the Gene Set Enrichment Analysis (GSEA) approach and calculates for each meta-pathway an empirical p-value. Validation of our approach on benchmark datasets showed comparable or even better performance than existing methods and an increase in robustness with increasing number of integrated datasets. We then applied the meta-analysis framework to 15 functional genomics datasets of physiological and pathological cardiac hypertrophy. Within these datasets we grouped expression sets measured at time points that represent the same hallmarks of heart tissue remodeling (‘aggregated time points’) and performed meta-analysis on the expression sets assigned to each aggregated time point. To facilitate biological interpretation, results were visualized as gene set enrichment networks. Here, our meta-analysis framework identified well-known biological mechanisms associated with pathological cardiac hypertrophy (e.g., cardiomyocyte apoptosis, cardiac contractile dysfunction, and alteration in energy metabolism). In addition, results highlighted novel, potentially cardioprotective mechanisms in physiological cardiac hypertrophy involving the down-regulation of immune cell response, which are worth further investigation.

Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.

Distinctly organized microtubule networks contribute to the function of differentiated cell types such as neurons, epithelial cells, skeletal myotubes, and cardiomyocytes. In striated (i.e., skeletal and cardiac) muscle cells, the nuclear envelope acts as the dominant microtubule-organizing center (MTOC) and the function of the centrosome—the canonical MTOC of mammalian cells—is attenuated, a common feature of differentiated cell types. We summarize the mechanisms known to underlie MTOC formation at the nuclear envelope, discuss the significance of the nuclear envelope MTOC for muscle function and cell cycle progression, and outline potential mechanisms of centrosome attenuation.