Scaffold-Based Tissue Engineering Strategies for Osteochondral Repair

Over centuries, several advances have been made in osteochondral (OC) tissue engineering to regenerate more biomimetic tissue. As an essential component of tissue engineering, scaffolds provide structural and functional support for cell growth and differentiation. Numerous scaffold types, such as porous, hydrogel, fibrous, microsphere, metal, composite and decellularized matrix, have been reported and evaluated for OC tissue regeneration in vitro and in vivo, with respective advantages and disadvantages. Unfortunately, due to the inherent complexity of organizational structure and the objective limitations of manufacturing technologies and biomaterials, we have not yet achieved stable and satisfactory effects of OC defects repair. In this review, we summarize the complicated gradients of natural OC tissue and then discuss various osteochondral tissue engineering strategies, focusing on scaffold design with abundant cell resources, material types, fabrication techniques and functional properties.

Surface Modification of Polycaprolactone Scaffold With Improved Biocompatibility and Controlled Growth Factor Release for Enhanced Stem Cell Differentiation

Polycaprolactone (PCL) has been widely used as a scaffold material for tissue engineering. Reliable applications of the PCL scaffolds require overcoming their native hydrophobicity and obtaining the sustained release of signaling factors to modulate cell growth and differentiation. Here, we report a surface modification strategy for electrospun PCL nanofibers using an azide-terminated amphiphilic graft polymer. With multiple alkylation and pegylation on the side chains of poly-L-lysine, stable coating of the graft polymer on the PCL nanofibers was achieved in one step. Using the azide-alkyne “click chemistry”, we functionalized the azide-pegylated PCL nanofibers with dibenzocyclooctyne-modified nanocapsules containing growth factor, which rendered the nanofiber scaffold with satisfied cell adhesion and growth property. Moreover, by specific immobilization of pH-responsive nanocapsules containing bone morphogenetic protein 2 (BMP-2), controlled release of active BMP-2 from the PCL nanofibers was achieved within 21 days. When bone mesenchyme stem cells were cultured on this nanofiber scaffold, enhanced ossification was observed in correlation with the time-dependent release of BMP-2. The established surface modification can be extended as a generic approach to hydrophobic nanomaterials for longtime sustainable release of multiplex signaling proteins for tissue engineering.

Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

The JAK-STAT pathway is a crucial cellular signaling cascade, including an intricate network of Protein–protein interactions (PPIs) responsible for its regulation. It mediates the activities of several cytokines, interferons, and growth factors and transduces extracellular signals into transcriptional programs to regulate cell growth and differentiation. It is essential for the development and function of both innate and adaptive immunities, and its aberrant deregulation was highlighted in neuroinflammatory diseases and in crucial mechanisms for tumor cell recognition and tumor-induced immune escape. For its involvement in a multitude of biological processes, it can be considered a valuable target for the development of drugs even if a specific focus on possible side effects associated with its inhibition is required. Herein, we review the possibilities to target JAK–STAT by focusing on its natural inhibitors as the suppressor of cytokine signaling (SOCS) proteins. This protein family is a crucial checkpoint inhibitor in immune homeostasis and a valuable target in immunotherapeutic approaches to cancer and immune deficiency disorders.

Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer

Despite improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM.

MicroRNAs in Woody Plants

MicroRNAs (miRNAs) are small (∼21-nucleotides) non-coding RNAs found in plant and animals. MiRNAs function as critical post-transcriptional regulators of gene expression by binding to complementary sequences in their target mRNAs, leading to mRNA destabilization and translational inhibition. Plant miRNAs have some distinct characteristics compared to their animal counterparts, including greater evolutionary conservation and unique miRNA processing methods. The lifecycle of a plant begins with embryogenesis and progresses through seed germination, vegetative growth, reproductive growth, flowering and fruiting, and finally senescence and death. MiRNAs participate in the transformation of plant growth and development and directly monitor progression of these processes and the expression of certain morphological characteristics by regulating transcription factor genes involved in cell growth and differentiation. In woody plants, a large and rapidly increasing number of miRNAs have been identified, but their biological functions are largely unknown. In this review, we summarize the progress of miRNA research in woody plants to date. In particular, we discuss the potential roles of these miRNAs in growth, development, and biotic and abiotic stresses responses in woody plants.

Emerging Principles in the Transcriptional Control by YAP and TAZ

Yes-associated protein (YAP) and TAZ are transcriptional cofactors that sit at the crossroad of several signaling pathways involved in cell growth and differentiation. As such, they play essential functions during embryonic development, regeneration, and, once deregulated, in cancer progression. In this review, we will revise the current literature and provide an overview of how YAP/TAZ control transcription. We will focus on data concerning the modulation of the basal transcriptional machinery, their ability to epigenetically remodel the enhancer–promoter landscape, and the mechanisms used to integrate transcriptional cues from multiple pathways. This reveals how YAP/TAZ activation in cancer cells leads to extensive transcriptional control that spans several hallmarks of cancer. The definition of the molecular mechanism of transcriptional control and the identification of the pathways regulated by YAP/TAZ may provide therapeutic opportunities for the effective treatment of YAP/TAZ-driven tumors.

Ovarian Decellularized Bioscaffolds Provide an Optimal Microenvironment for Cell Growth and Differentiation In Vitro

Ovarian failure is the most common cause of infertility. Although numerous strategies have been proposed, a definitive solution for recovering ovarian functions and restoring fertility is currently unavailable. One innovative alternative may be represented by the development of an “artificial ovary” that could be transplanted in patients for re-establishing reproductive activities. Here, we describe a novel approach for successful repopulation of decellularized ovarian bioscaffolds in vitro. Porcine whole ovaries were subjected to a decellularization protocol that removed the cell compartment, while maintaining the macrostructure and microstructure of the original tissue. The obtained bioscaffolds were then repopulated with porcine ovarian cells or with epigenetically erased porcine and human dermal fibroblasts. The results obtained demonstrated that the decellularized extracellular matrix (ECM)-based scaffold may constitute a suitable niche for ex vivo culture of ovarian cells. Furthermore, it was able to properly drive epigenetically erased cell differentiation, fate, and viability. Overall, the method described represents a powerful tool for the in vitro creation of a bioengineered ovary that may constitute a promising solution for hormone and fertility restoration. In addition, it allows for the creation of a suitable 3D platform with useful applications both in toxicological and transplantation studies.

AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation

Contact inhibition is a key cellular phenomenon that prevents cells from hyper-proliferating upon reaching confluence. Although not fully characterized, a critical driver of this process is the Hippo signaling pathway, whose downstream effector yes-associated protein plays pivotal roles in cell growth and differentiation. Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408. Mono-ubiquitinated AMOTL2, in turn, interacts with the kinase LATS2, which facilitates recruitment of the upstream Hippo pathway component SAV1 and ultimately promotes yes-associated protein phosphorylation and subsequent cytoplasmic sequestration and/or degradation. Furthermore, contact inhibition induced by high cell density promoted the localization and stabilization of WWP1 at cell junctions, where it interacted with Crumbs polarity proteins. Notably, the Crumbs complex was functionally important for AMOTL2 mono-ubiquitination and LATS activation under high cell density conditions. These findings delineate a functionally important molecular mechanism in which AMOTL2 mono-ubiquitination by WWP1 at cell junctions and LATS activation are tightly coupled to upstream cell density cues.

The Pathophysiology and the Therapeutic Potential of Cannabinoids in Prostate Cancer

Prostate cancer is the second most frequently occurring cancer diagnosed among males. Recent preclinical evidence implicates cannabinoids as powerful regulators of cell growth and differentiation. In this review, we focused on studies that demonstrated anticancer effects of cannabinoids and their possible mechanisms of action in prostate cancer. Besides the palliative effects of cannabinoids, research from the past two decades has demonstrated their promising potential as antitumor agents in a wide variety of cancers. This analysis may provide pharmacological insights into the selection of specific cannabinoids for the development of antitumor drugs for the treatment of prostate cancer.