Guide Cell Fate Research Articles

Scaffold Pore Curvature Influences ΜSC Fate through Differential Cellular Organization and YAP/TAZ Activity.

Tissue engineering aims to repair, restore, and/or replace tissues in the human body as an alternative to grafts and prostheses. Biomaterial scaffolds can be utilized to provide a three-dimensional microenvironment to facilitate tissue regeneration. Previously, we reported that scaffold pore size influences vascularization and extracellular matrix composition both in vivo and in vitro, to ultimately influence tissue phenotype for regenerating cranial suture and bone tissues, which have markedly different tissue properties despite similar multipotent stem cell populations. To rationally design biomaterials for specific cell and tissue fate specification, it is critical to understand the molecular processes governed by cell-biomaterial interactions, which guide cell fate specification. Building on our previous work, in this report we investigated the hypothesis that scaffold pore curvature, the direct consequence of pore size, modulates the differentiation trajectory of mesenchymal stem cells (MSCs) through alterations in the cytoskeleton. First, we demonstrated that sufficiently small pores facilitate cell clustering in subcutaneous explants cultured in vivo, which we previously reported to demonstrate stem tissue phenotype both in vivo and in vitro. Based on this observation, we cultured cell-scaffold constructs in vitro to assess early time point interactions between cells and the matrix as a function of pore size. We demonstrate that principle curvature directly influences nuclear aspect and cell aggregation in vitro. Scaffold pores with a sufficiently low degree of principle curvature enables cell differentiation; pharmacologic inhibition of actin cytoskeleton polymerization in these scaffolds decreased differentiation, indicating a critical role of the cytoskeleton in transducing cues from the scaffold pore microenvironment to the cell nucleus. We fabricated a macropore model, which allows for three-dimensional confocal imaging and demonstrates that a higher principle curvature facilitates cell aggregation and the formation of a potentially protective niche within scaffold macropores which prevents MSC differentiation and retains their stemness. Sufficiently high principle curvature upregulates yes-associated protein (YAP) phosphorylation while decreased principle curvature downregulates YAP phosphorylation and increases YAP nuclear translocation with subsequent transcriptional activation towards an osteogenic differentiation fate. Finally, we demonstrate that the inhibition of the YAP/TAZ pathway causes a defect in differentiation, while YAP/TAZ activation causes premature differentiation in a curvature-dependent way when modulated by verteporfin (VP) and 1-oleyl-lysophosphatidic acid (LPA), respectively, confirming the critical role of biomaterials-mediated YAP/TAZ signaling in cell differentiation and fate specification. Our data support that the principle curvature of scaffold macropores is a critical design criterion which guides the differentiation trajectory of mesenchymal stem cells’ scaffolds. Biomaterial-mediated regulation of YAP/TAZ may significantly contribute to influencing the regenerative outcomes of biomaterials-based tissue engineering strategies through their specific pore design.

Functional redundancy among Polycomb complexes in maintaining the pluripotent state of embryonic stem cells.

SummaryPolycomb group proteins assemble into multi-protein complexes, known as Polycomb repressive complexes 1 and 2 (PRC1 and PRC2), that guide cell fate decisions during embryonic development. PRC1 forms an array of biochemically distinct canonical PRC1 (cPRC1) or non-canonical PRC1 (ncPRC1) complexes characterized by the mutually exclusive presence of PCGF (PCGF1-PCGF6) paralog subunit; however, whether each one of these subcomplexes fulfills a distinct role remains largely controversial. Here, by performing a CRISPR-based loss-of-function screen in embryonic stem cells (ESCs), we uncovered a previously unappreciated functional redundancy among PRC1 subcomplexes. Disruption of ncPRC1, but not cPRC1, displayed severe defects in ESC pluripotency. Remarkably, coablation of non-canonical and canonical PRC1 in ESCs resulted in exacerbation of the phenotype observed in the non-canonical PRC1-null ESCs, highlighting the importance of functional redundancy among PRC1 subcomplexes. Together, our studies demonstrate that PRC1 subcomplexes act redundantly to silence lineage-specific genes and ensure robust maintenance of ESC identity.

Intermittent ERK oscillations downstream of FGF in mouse embryonic stem cells.

ABSTRACTSignal transduction networks generate characteristic dynamic activities to process extracellular signals and guide cell fate decisions such as to divide or differentiate. The differentiation of pluripotent cells is controlled by FGF/ERK signaling. However, only a few studies have addressed the dynamic activity of the FGF/ERK signaling network in pluripotent cells at high time resolution. Here, we use live cell sensors in wild-type and Fgf4-mutant mouse embryonic stem cells to measure dynamic ERK activity in single cells, for defined ligand concentrations and differentiation states. These sensors reveal pulses of ERK activity. Pulsing patterns are heterogeneous between individual cells. Consecutive pulse sequences occur more frequently than expected from simple stochastic models. Sequences become more prevalent with higher ligand concentration, but are rarer in more differentiated cells. Our results suggest that FGF/ERK signaling operates in the vicinity of a transition point between oscillatory and non-oscillatory dynamics in embryonic stem cells. The resulting heterogeneous dynamic signaling activities add a new dimension to cellular heterogeneity that may be linked to divergent fate decisions in stem cell cultures.

Emerging modulators for osteogenic differentiation: a combination of chemical and topographical cues for bone microenvironment engineering.

Bone presents an intrinsic ability for self-regeneration and repair, however critical defects and large fractures require invasive and time-consuming clinical interventions. As an alternative to current therapy, bone tissue engineering (BTE) has primarily aimed to recreate the bone microenvironment by delivering key biomolecules and/or by modification of scaffolds to guide cell fate towards the osteogenic lineage or other phenotypes that may benefit the bone regeneration mechanism. Considering that bone cells communicate, in their native microenvironment, through biochemical and physical signals, most strategies fail when considering only chemical, geometrical or mechanical cues. This is not representative of the physiological conditions, where the cells are simultaneously in contact and stimulated by several cues. Therefore, this review explores the synergistic effect of biochemical/physical cues in regulating cellular events, namely cell adhesion, proliferation, osteogenic differentiation, and mineralization, highlighting the importance of the combined modifications for the development of innovative bone regenerative therapies.

Photoactive 3D-Printed Hypertensile Metamaterials for Improving Dynamic Modeling of Stem Cells.

Current three-dimensional (3D) cell culture systems mainly rely on static cell culture and lack the ability to thoroughly manage cell intrinsic behaviors and biological characteristics, leading to unsatisfied cell activity. Herein, we have developed photoactive 3D-printed hypertensile metamaterials based dynamic cell culture system (MetaFold) for guiding cell fate. MetaFold exhibited high elasticity and photothermal conversion efficiency due to its metapattern architecture and micro/nanoscale polydopamine coating, allowing for responding to mechanical and light stimulation to construct dynamic culture conditions. In addition, MetaFold possessed excellent cell adhesion capability and could promote cell viability and function under dynamic stimulation, thereby maximizing cell activity. Importantly, MetaFold could improve the differentiation efficacy of stem cells into cardiomyocytes and even their maturation, offering high-quality precious candidates for cell therapy. Therefore, we present a dual stimuli-responsive dynamic culture system, which provides a physiologically realistic environment for cell culture and biological study.

Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives.

Simple SummaryThe Notch signaling pathway regulates cell proliferation, apoptosis, stem cell self-renewal, and differentiation in a context-dependent fashion both during embryonic development and in adult tissue homeostasis. Consistent with its pleiotropic physiological role, unproper activation of the signaling promotes or counteracts tumor pathogenesis and therapy response in distinct tissues. In the last twenty years, a wide number of studies have highlighted the anti-cancer potential of Notch-modulating agents as single treatment and in combination with the existent therapies. However, most of these strategies have failed in the clinical exploration due to dose-limiting toxicity and low efficacy, encouraging the development of novel agents and the design of more appropriate combinations between Notch signaling inhibitors and chemotherapeutic drugs with improved safety and effectiveness for distinct types of cancer.Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.

Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling.

A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogenesis of the FGFR-mediated genetic disorders. FGFR lesions are also found in cancer, raising a possibility of cilia involvement in the neoplastic transformation and tumor progression. Here, we focus on FGFR gene fusions, and discuss the possible mechanisms by which they function as oncogenic drivers. We show that a substantial portion of the FGFR fusion partners are proteins associated with the centrosome cycle, including organization of the mitotic spindle and ciliogenesis. The functions of centrosome proteins are often lost with the gene fusion, leading to haploinsufficiency that induces cilia loss and deregulated cell division. We speculate that this complements the ectopic FGFR activity and drives the FGFR fusion cancers.

A Programmable Toolkit to Dynamically Signal Cells Using Peptide Strand Displacement

The native extracellular matrix communicates and interacts with cells by dynamically displaying signals to control their behavior. Mimicking this dynamic environment in vitro is essential in order to unravel how cell-matrix interactions guide cell fate. Here, we present a synthetic platform for the temporal display of cell-adhesive signals using coiled-coil peptides. By designing an integrin-engaging coiled-coil pair to have a toehold (unpaired domain), we were able to use a peptide strand displacement reaction to remove the cell cue from the surface. This allowed us to test how the user-defined display of RGDS ligands at variable duration and periodicity of ligand exposure influence cell spreading degree and kinetics. Transient display of αVβ3-selective ligands instructed fibroblast cells to reversibly spread and contract in response to changes in ligand exposure over multiple cycles, exhibiting a universal kinetic response. Also, cells that were triggered to spread and contract repeatedly exhibited greater enrichment of integrins in focal adhesions versus cells cultured on persistent RGDS-displaying surfaces. This dynamic platform will allow us to uncover the molecular code by which cells sense and respond to changes in their environment and will provide insights into ways to program cellular behavior.

Viscoelastic Cell Microenvironment: Hydrogel‐Based Strategy for Recapitulating Dynamic ECM Mechanics

AbstractThe native extracellular matrix (ECM) generally exhibits dynamic mechanical properties and displays time‐dependent responses to deformation or mechanical loading, in terms of viscoelastic behaviors (e.g., stress relaxation and creep). Viscoelasticity of the ECM plays a critical role in development, homeostasis, and tissue regeneration, and its implication in disease progression has also been recognized recently. Hydrogels with tunable viscoelastic properties hold a great promise to recapitulate such time‐dependent mechanics found in native ECM, which have been recently used to regulate cell behavior and guide cell fate. Here the importance of tissue viscoelasticity is first highlighted, the molecular mechanisms of hydrogel viscoelasticity are summarized, and characterization techniques used at the macroscale and microscale are reviewed. Then, recent advances in developing novel hydrogels with tunable viscoelasticity through varying crosslinking strategies, engineering of viscoelastic cell microenvironment and its substantial effects on cell behavior and fate are described, and the underlying mechanobiology mechanisms are subsequently discussed. Finally, the ongoing challenges and future perspectives on the design and modulation of viscoelastic hydrogels and the mechanobiology mechanisms on cellular responses to viscoelastic cell microenvironment are proposed.

Mechanotransduction in fibrosis: Mechanisms and treatment targets.

To perceive and integrate the environmental cues, cells and tissues sense and interpret various physical forces like shear, tensile, and compression stress. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical and mechanical signals to guide cell fate and achieve tissue homeostasis. Disruption of this mechanical homeostasis by tissue injury elicits multiple cellular responses leading to pathological matrix deposition and tissue stiffening, and consequent evolution toward pro-inflammatory/pro-fibrotic phenotypes, leading to tissue/organ fibrosis. This review focuses on the molecular mechanisms linking mechanotransduction to fibrosis and uncovers the potential therapeutic targets to halt or resolve fibrosis.

Epitope‐Imprinted Nanoparticles as Transforming Growth Factor‐β3 Sequestering Ligands to Modulate Stem Cell Fate

AbstractGrowth factors (GFs) are biomolecules with potent biological effects but inherent limitations hinder their potential as therapeutic agents and cell culture supplements in tissue engineering and regenerative medicine (TERM). Biomaterials that sequester endogenous GFs by affinity binding might circumvent such limitations and thus are being increasingly investigated. Here, molecularly imprinted nanoparticles (MINPs) are proposed as specific abiotic ligands for GFs. As a proof of concept, a conformational epitope of transforming growth factor‐β3 (TGF‐β3) is designed and surface imprinted onto polyacrylamide‐based nanoparticles by inverse microemulsion polymerization. It is found that, depending on the polymerization mixture composition, MINPs can recognize and preferentially bind TGF‐β3, either in noncompetitive assays or from a complex human fluid (platelet lysate). Substrates functionalized with MINPs are then used for 2D culture of adipose‐derived stem cells. Remarkably, gene and protein expression profiles show a marked upregulation of SOX‐9, suggesting activation of TGF‐β3 signaling pathways without requiring supplementation with exogenous GF. Likewise, culturing these cells in pellets incorporating MINPs previously incubated with platelet lysate results in higher collagen II‐rich matrix deposition, compared to pellets incorporating non‐imprinted nanoparticles. In summary, results suggest MINPs can be used as cost‐effective, stable, and scalable alternative abiotic GF ligands to guide cell fate in TERM applications.

Enhanced proliferation and differentiation of neural stem cells by peptide-containing temperature-sensitive hydrogel scaffold.

Hydrogel has attracted great attention in the past few years as a widely used material for repairing central nerve damage. However, conventional hydrogel bio-scaffold, such as chitosan, gelatin, and sodium alginate, lack sufficient biological activity and have limited nerve repair capabilities. Therefore, to explore biologically active and intelligent hydrogel materials is particularly important and necessary for central nerve repair. Herein, we developed a temperature-sensitive hydrogel grafted with a bioactive peptide IKVAV (Ile-Lys-Val-Ala-Val, IKVAV). The hydrogel was prepared by copolymerization of N-propan-2-ylprop-2-enamide (NIPAM) and AC-PEG-IKVAV copolymers via reversible addition-fracture chain transfer (RAFT) polymerization, using polyethylene glycol (PEGDA) and N, N'-Methylenebisacrylamide (BISAM) as cross-linking agents. The prepared hydrogel scaffold demonstrates a series of excellent properties such as rapid (de)swelling performance, good biocompatibility, regular three-dimensional porous structure, and in particular good biological activity, which can guide cell fate and mediate neuron's differentiation. Therefore, the developed peptide hydrogel scaffold provides a new strategy for designing biomaterials that are widely used in tissue engineering for central nervous system injury.

Assembly of lung progenitors into developmentally-inspired geometry drives differentiation via cellular tension

During organogenesis groups of differentiating cells self-organize into a series of structural intermediates with defined architectural forms. Evidence is emerging that such architectural forms are important in guiding cell fate, yet in vitro methods to guide cell fate have focused primarily on un-patterned exposure of stems cells to developmentally relevant chemical cues. We set out to ask if organizing differentiating lung progenitors into developmentally relevant structures could be used to influence differentiation status. Specifically, we use elastomeric substrates to guide self-assembly of human pluripotent stem cell-derived lung progenitors into developmentally-relevant sized tubes and assess the impact on differentiation. Culture in 100 μm tubes reduced the percentage of SOX2+SOX9+ cells and reduced proximal fate potential compared to culture in 400 μm tubes or on flat surfaces. Cells in 100 μm tubes curved to conform to the tube surface and experienced increased cellular tension and reduced elongation. Pharmacologic disruption of tension through inhibition of ROCK, myosin II activity and actin polymerization in tubes resulted in maintenance of SOX2+SOX9+ populations. Furthermore, this effect required canonical WNT signaling. This data suggests that structural forms, when developmentally relevant, can drive fate choice during directed differentiation via a tension-based canonical WNT dependent mechanism.

Tumor-associated macrophages promote prostate cancer progression via exosome-mediated miR-95 transfer.

Tumor-associated macrophages (TAMs) are vital constituents in mediating cell-to-cell communication within the tumor microenvironment. However, the molecular mechanisms underlying the interplay between TAMs and tumor cells that guide cell fate are largely undetermined. Extracellular vesicles, also known as exosomes, which are derived from TAMs, are the components exerting regulatory effects. Thus, understanding the underlying mechanism of "onco-vesicles" is of crucial importance for prostate cancer (PCa) therapy. In this study, we analyzed micro RNA sequences in exosomes released by THP-1 and M2 macrophages and found a significant increase in miR-95 levels in TAM-derived exosomes, demonstrating the direct uptake of miR-95 by recipient PCa cells. In vitro and in vivo loss-of-function assays suggested that miR-95 could function as a tumor promoter by directly binding to its downstream target gene, JunB, to promote PCa cell proliferation, invasion, and epithelial-mesenchymal transition. The clinical data analyses further revealed that higher miR-95 expression results in worse clinicopathological features. Collectively, our results demonstrated that TAM-mediated PCa progression is partially attributed to the aberrant expression of miR-95 in TAM-derived exosomes, and the miR-95/JunB axis provides the groundwork for research on TAMs to further develop more-personalized therapeutic approaches for patients with PCa.

Multi-peptide presentation and hydrogel mechanics jointly enhance therapeutic duo-potential of entrapped stromal cells

The native extracellular matrix (ECM) contains a host of matricellular proteins and bioactive factors that regulate cell behavior, and many ECM components have been leveraged to guide cell fate. However, the large size and chemical characteristics of these constituents complicate their incorporation into biomaterials without interfering with material properties, motivating the need for alternative approaches to regulate cellular responses. Mesenchymal stromal cells (MSCs) can promote osseous regeneration in vivo directly or indirectly through multiple means including (1) secretion of proangiogenic and mitogenic factors to initiate formation of a vascular template and recruit host cells into the tissue site or (2) direct differentiation into osteoblasts. As MSC behavior is influenced by the properties of engineered hydrogels, we hypothesized that the biochemical and biophysical properties of alginate could be manipulated to promote the dual contributions of encapsulated MSCs toward bone formation. We functionalized alginate with QK peptide to enhance proangiogenic factor secretion and RGD to promote adhesion, while biomechanical-mediated osteogenic cues were controlled by modulating viscoelastic properties of the alginate substrate. A 1:1 ratio of QK:RGD resulted in the highest levels of both proangiogenic factor secretion and mineralization in vitro. Viscoelastic alginate outperformed purely elastic gels in both categories, and this effect was enhanced by stiffness up to 20 kPa. Furthermore, viscoelastic constructs promoted vessel infiltration and bone regeneration in a rat calvarial defect over 12 weeks. These data suggest that modulating viscoelastic properties of biomaterials, in conjunction with dual peptide functionalization, can simultaneously enhance multiple aspects of MSC regenerative potential and improve neovascularization of engineered tissues.

Spatiotemporal variations of contact stress between liquid-crystal films and fibroblasts Guide cell fate and skin regeneration

The inductions of both the mechanical microenvironment on cell behaviour and the polymeric scaffold on tissue regeneration have been well-proved. This study is aimed to investigate the possibility of guiding cell fate and tissue regeneration by the spatiotemporal controlling of contact stress between matrix materials and cells and to elucidate the mechanisms underlying. A series liquid crystal polymers of cholesteryl-oligo(lactic acid) (CLA) and an amorphous polymer of poly(lactic acid) were used as the growth substrates for fibroblast and skin tissue regeneration. The cellular and animal experiments show that, in the initial stage of wound healing, the liquid crystal texture of CLA films can provide an induced stress for the formation of focal adhesions and the activation of integrin β1/AKT signal pathway, resulting in advanced phenotypic transformation of fibroblasts to myofibroblasts, promoted collagen secretion and fast wound filling. But the gradually weakening cellular contact stress, induced by the decreasing of liquid crystal domains of matrix polymer during degradation, triggers the apoptosis of fibroblasts and myofibroblasts, resulting in non-excessive collagen accumulation. Finally, the CLA groups exhibit no obvious scar formation, more regular cell arrangement and significantly lower type I collagen proportion in regenerated tissue than other groups. This study may inspire a new, effective and safe strategy for tissue regeneration.

Nanofibrous Carbon Multifunctional Smart Scaffolds for Simultaneous Cell Differentiation and Dopamine Detection.

Advances in stem-cell therapy rely on new, multifunctional smart scaffolds (MSS) to promote growth while simultaneously characterizing stem cells undergoing selective differentiation. Nondestructive cell characterization techniques, such as electrochemical detection of lineage-specific metabolites, play a critical role in translational stem-cell therapy by providing clinicians with real-time information to evaluate cell-readiness for transplant. However, electrochemical sensors that provide biophysical cues capable of guiding cell fate, while preserving electroactive functionality, remain unavailable. In this work, a carbon MSS is fabricated by pyrolyzing polyacrylonitrile (PAN) with optimal multiwalled carbon nanotube (MWCNT) loading to optimize electrochemical activity and with a tunable surface to promote cell growth and organization. Carbon MSS is used to (1) enhance the morphology and differentiation of mouse neural stem/progenitor cells (mNSPCs) derived from different regions of the developing brain and (2) simultaneously detect a neurotransmitter, dopamine, from a model dopaminergic cell line growing on the electrode. The study presents a carbon multifunctional smart scaffold for advancing stem-cell therapy toward clinically relevant applications.

Lumen Expansion Facilitates Epiblast-Primitive Endoderm Fate Specification during Mouse Blastocyst Formation.

SummaryEpithelial tissues typically form lumina. In mammalian blastocysts, in which the first embryonic lumen forms, many studies have investigated how the cell lineages are specified through genetics and signaling, whereas potential roles of the fluid lumen have yet to be investigated. We discover that in mouse pre-implantation embryos at the onset of lumen formation, cytoplasmic vesicles are secreted into intercellular space. The segregation of epiblast and primitive endoderm directly follows lumen coalescence. Notably, pharmacological and biophysical perturbation of lumen expansion impairs the specification and spatial segregation of primitive endoderm cells within the blastocyst. Luminal deposition of FGF4 expedites fate specification and partially rescues the reduced specification in blastocysts with smaller cavities. Combined, our results suggest that blastocyst lumen expansion plays a critical role in guiding cell fate specification and positioning, possibly mediated by luminally deposited FGF4. Lumen expansion may provide a general mechanism for tissue pattern formation.

Modulation of the mechanosensing of mesenchymal stem cells by laser-induced patterning for the acceleration of tissue reconstruction through the Wnt/β-catenin signaling pathway activation

Growing evidence suggests that the physical microenvironment can guide cell fate. However, cells sense cues from the adjacent physical microenvironment over a limited distance. In the present study, murine mesenchymal stem cells (MSCs) and murine preosteoblastic cells (MC3T3-E1) behaviors are regulated by the cell–material interface using ordered-micro and disordered-nano patterned structures on Ti implants. The optimal bone formation structure is a stable wave (horizontal direction: ridge, 2.7 µm; grooves, 5.3 µm; and vertical direction: distance, 700 µm) with the appropriate density of nano-branches (6.0 per µm2). The repeated waves provide cells with directional guidance, and the disordered branches influence cell geometry by providing different spacing and density nanostructure. And micro-nano patterned structure can provide biophysical cues to direct cell phenotype development, including cell size, shape, and orientation, to influence cellular processes including survival, growth, and differentiation. Thus, the overlaid isotropic and anisotropic cues, ordered-micro and disordered-nano patterned structures, could transfer further and alter cell shape and induce nuclear orientation by activating Wnt/β-catenin signaling to promote integrin α5, integrin β1, cadherin 2, Runx2, Opn, and Ocn. That canonical Wnt signaling inhibitor dickkopf1 further demonstrates osteogenic differentiation induced by ordered-micro and disordered-nano patterned structures, which is related to Wnt/β-catenin signaling. Our findings show the role of ordered microstructures and disordered nanostructures in modulating stem cell differentiation with potential medical applications. Statement of significanceIt remains a challenge to modify poor osteogenic and osteoconductive properties of titanium alloy bases on the inherent poverty of titanium. We demonstrate that ordered microtopography and disordered nano topography pattern structure could lead to osteogenic differentiation in vitro and bone regeneration in vivo. Furthermore, the pattern structure is created through selective laser melting and alkali heat. And the structure only takes advantage of titanium itself and does not bring in active film, such as hydroxyapatite. On the other hand, we find that cell shape and orientation show angle-orientation tendency due to the polarity, which involves with mechanical signal created via patterned structure. Meanwhile, the Wnt/Ca2+ signaling pathway is activated.

Post-translational modification of SOX family proteins: Key biochemical targets in cancer?

Sox proteins are a family of lineage-associated transcription factors. They regulate expression of genes involved in control of self-renewal and multipotency in both developmental and adult stem cells. Overexpression of Sox proteins is frequently observed in many different human cancers. Despite their importance as therapeutic targets, Sox proteins are difficult to ‘drug’ using structure-based design. However, Sox protein localisation, activity and interaction partners are regulated by a plethora of post-translational modifications (PTMs), such as: phosphorylation, acetylation, sumoylation, methylation, and ubiquitylation. Here we review the various reported post-translational modifications of Sox proteins and their potential functional importance in guiding cell fate processes. The enzymes that regulate these PTMs could be useful targets for anti-cancer drug discovery.