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by Keyword: d1

Astro, V, Ramirez-Calderon, G, Pennucci, R, Caroli, J, Saera-Vila, A, Cardona-Londono, K, Forastieri, C, Fiacco, E, Maksoud, F, Alowaysi, M, Sogne, E, Falqui, A, Gonzalez, F, Montserrat, N, Battaglioli, E, Mattevi, A, Adamo, A, (2022). Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism Iscience 25, 104665

The histone demethylase KDM1A is a multi- faceted regulator of vital developmental processes, including mesodermal and cardiac tube formation during gastrulation. However, it is unknown whether the fine-tuning of KDM1A splicing isoforms, already shown to regulate neuronal maturation, is crucial for the specification and maintenance of cell identity during cardiogenesis. Here, we discovered a temporal modulation of ubKDM1A and KDM1A+2a during human and mice fetal cardiac development and evaluated their impact on the regulation of cardiac differentiation. We revealed a severely impaired cardiac differentiation in KDM1A(-/-) hESCs that can be rescued by re-expressing ubKDM1A or catalytically impaired ubKDM1A-K661A, but not by KDM1A+2a or KDM1A+2a-K661A. Conversely, KDM1A+2a(-/-) hESCs give rise to functional cardiac cells, displaying increased beating amplitude and frequency and enhanced expression of critical cardiogenic markers. Our findings prove the existence of a divergent scaffolding role of KDM1A splice variants, independent of their enzymatic activity, during hESC differentiation into cardiac cells.

JTD Keywords: Bhlh transcription factor, Corest, Differentiation, Dna, Embryonic stem-cells, Heart, Lsd1, Phosphorylation, Proteins, Swirm domain


Chulia-Peris, L, Carreres-Rey, C, Gabasa, M, Alcaraz, J, Carretero, J, Pereda, J, (2022). Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play International Journal Of Molecular Sciences 23, 6894

Pulmonary fibrosis (PF) is characterized by aberrant extracellular matrix (ECM) deposition, activation of fibroblasts to myofibroblasts and parenchymal disorganization, which have an impact on the biomechanical traits of the lung. In this context, the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) is lost. Interestingly, several MMPs are overexpressed during PF and exhibit a clear profibrotic role (MMP-2, -3, -8, -11, -12 and -28), but a few are antifibrotic (MMP-19), have both profibrotic and antifibrotic capacity (MMP7), or execute an unclear (MMP-1, -9, -10, -13, -14) or unknown function. TIMPs are also overexpressed in PF; hence, the modulation and function of MMPs and TIMP are more complex than expected. EMMPRIN/CD147 (also known as basigin) is a transmembrane glycoprotein from the immunoglobulin superfamily (IgSF) that was first described to induce MMP activity in fibroblasts. It also interacts with other molecules to execute non-related MMP aactions well-described in cancer progression, migration, and invasion. Emerging evidence strongly suggests that CD147 plays a key role in PF not only by MMP induction but also by stimulating fibroblast myofibroblast transition. In this review, we study the structure and function of MMPs, TIMPs and CD147 in PF and their complex crosstalk between them.

JTD Keywords: Basigin, Cd147, Cell-surface, Emmprin, Extracellular-matrix, Gelatinase-b, Gene-expression profiles, Growth-factor-beta, Immunoglobulin superfamily, Induced lung injury, Inducer emmprin, Mmps, Pulmonary fibrosis, Timps, Tissue inhibitor, Transforming growth-factor-beta-1


Rätze, Max AK., Koorman, Thijs, Sijnesael, Thijmen, Bassey-Archibong, Blessing, van de Ven, Robert, Enserink, Lotte, Visser, Daan, Jaksani, Sridevi, Viciano, Ignacio, Bakker, Elvira RM., Richard, François, Tutt, Andrew, O’Leary, Lynda, Fitzpatrick, Amanda, Roca-Cusachs, Pere, van Diest, Paul J., Desmedt, Christine, Daniel, Juliet M., Isacke, Clare M., Derksen, Patrick WB., (2022). Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer Oncogene 41, 2932-2944

Invasive lobular breast carcinoma (ILC) is characterized by proliferative indolence and long-term latency relapses. This study aimed to identify how disseminating ILC cells control the balance between quiescence and cell cycle re-entry. In the absence of anchorage, ILC cells undergo a sustained cell cycle arrest in G0/G1 while maintaining viability. From the genes that are upregulated in anchorage independent ILC cells, we selected Inhibitor of DNA binding 2 (Id2), a mediator of cell cycle progression. Using loss-of-function experiments, we demonstrate that Id2 is essential for anchorage independent survival (anoikis resistance) in vitro and lung colonization in mice. Importantly, we find that under anchorage independent conditions, E-cadherin loss promotes expression of Id2 in multiple mouse and (organotypic) human models of ILC, an event that is caused by a direct p120-catenin/Kaiso-dependent transcriptional de-repression of the canonical Kaiso binding sequence TCCTGCNA. Conversely, stable inducible restoration of E-cadherin expression in the ILC cell line SUM44PE inhibits Id2 expression and anoikis resistance. We show evidence that Id2 accumulates in the cytosol, where it induces a sustained and CDK4/6-dependent G0/G1 cell cycle arrest through interaction with hypo-phosphorylated Rb. Finally, we find that Id2 is indeed enriched in ILC when compared to other breast cancers, and confirm cytosolic Id2 protein expression in primary ILC samples. In sum, we have linked mutational inactivation of E-cadherin to direct inhibition of cell cycle progression. Our work indicates that loss of E-cadherin and subsequent expression of Id2 drive indolence and dissemination of ILC. As such, E-cadherin and Id2 are promising candidates to stratify low and intermediate grade invasive breast cancers for the use of clinical cell cycle intervention drugs.

JTD Keywords: anoikis resistance, carcinoma, d1, differentiation, gene-expression, growth, id2, proliferation, repression, Mammary epithelial-cells


Rubí-Sans, G., Recha-Sancho, L., Pérez-Amodio, S., Mateos-Timoneda, M. Á., Semino, C. E., Engel, E., (2020). Development of a three-dimensional bioengineered platform for articular cartilage regeneration Biomolecules 10, (1), 52

Degenerative cartilage pathologies are nowadays a major problem for the world population. Factors such as age, genetics or obesity can predispose people to suffer from articular cartilage degeneration, which involves severe pain, loss of mobility and consequently, a loss of quality of life. Current strategies in medicine are focused on the partial or total replacement of affected joints, physiotherapy and analgesics that do not address the underlying pathology. In an attempt to find an alternative therapy to restore or repair articular cartilage functions, the use of bioengineered tissues is proposed. In this study we present a three-dimensional (3D) bioengineered platform combining a 3D printed polycaprolactone (PCL) macrostructure with RAD16-I, a soft nanofibrous self-assembling peptide, as a suitable microenvironment for human mesenchymal stem cells’ (hMSC) proliferation and differentiation into chondrocytes. This 3D bioengineered platform allows for long-term hMSC culture resulting in chondrogenic differentiation and has mechanical properties resembling native articular cartilage. These promising results suggest that this approach could be potentially used in articular cartilage repair and regeneration.

JTD Keywords: 3D printing, Chondrogenic differentiation, Polycaprolactone, RAD16-I self-assembling peptide


Gil, Vanessa, del Río, José Antonio, (2019). Functions of plexins/neuropilins and their ligands during hippocampal development and neurodegeneration Cells 8, (3), 206

There is emerging evidence that molecules, receptors, and signaling mechanisms involved in vascular development also play crucial roles during the development of the nervous system. Among others, specific semaphorins and their receptors (neuropilins and plexins) have, in recent years, attracted the attention of researchers due to their pleiotropy of functions. Their functions, mainly associated with control of the cellular cytoskeleton, include control of cell migration, cell morphology, and synapse remodeling. Here, we will focus on their roles in the hippocampal formation that plays a crucial role in memory and learning as it is a prime target during neurodegeneration.

JTD Keywords: PlexinD1, Sema3E, Neuropilins, Neuronal migration, Synapse formation