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Mesenchymal stem cells (MSCs) have been widely used as functional components in tissue engineering. However, the immunogenicity and limited pro-angiogenic efficacy of MSCs greatly limited their pro-regenerative ability in allogenic treatment. Herein, utilizing a chemically defined cocktail in the culture system, including cytokines, small molecules, structural protein, and other essential components, we generated the immunoprivileged and pro-angiogenic cells (IACs) derived from human adipose tissues. Conventional adipose-derived MSCs (cADSCs) were used as a control in all the experiments. IACs show typical MSC properties with enhanced stemness capacity and a robust safety profile. IACs induce a significantly milder immune response of allogenic peripheral blood mononuclear cells in an H3K27me3-HLA axis-dependent manner. IACs, through superior paracrine effects, further promote nitric oxide production, anti-apoptotic ability, and the tube formation of human vein endothelial cells. Embedded in a photo-reactive hydrogel (Gel) termed as GelMA/HA-NB/LAP for tissue engineering treatment, IACs promote faster tissue regeneration in a xenogeneic full-thickness skin defect model, eliciting a milder immune response and enhanced blood vessel formation in IACs-treated defect areas. Together with its excellent pro-regenerative potential and robust safety, our findings suggest that IACs may be a promising candidate for clinically relevant stem cell and tissue engineering therapeutics.

It is a common clinical phenomenon that blood infiltrates into the injured tendon caused by sports injuries, accidental injuries, and surgery. However, the role of blood infiltration into the injured tendon has not been investigated. We established a rat model in which the injured Achilles tendon was infiltrated with autologous whole blood and confirmed that blood caused acute inflammation in the short term and more severe heterotopic ossification (HO) in the long term. Then we found that blood treatment increased cell apoptosis and decreased cell adhesion and tenogenic gene expression of TSPCs. Furthermore, Blood treatment promoted osteochondrogenic differentiation of TSPCs. Next, we used RNA-seq to find that the PI3K/AKT signaling pathway was activated in blood-treated tendon tissues. By inhibiting PI3K with a small molecule drug LY294002, the expression of osteochondrogenic genes was markedly downregulated while the expression of tenogenic genes was significantly upregulated. Our findings indicate that the upregulated PI3K/AKT signaling pathway is implicated in the aggravation of tendon HO. Therefore, inhibitors targeting the PI3K/AKT pathway would be a promising approach to treat blood-induced tendon HO.

Formaldehyde (FA) is a common air pollutant. Exposure to exogenous FA can cause damage to the nervous system, such as learning and memory impairment, balance dysfunction, and sleep disorders. Excessive production of endogenous FA also causes memory impairment and is thought to be associated with Alzheimer's disease (AD). Tumor necrosis factor alpha-induced protein 1 (TNFAIP1) plays a crucial role in neurodevelopment and neurological diseases. However, the role of TNFAIP1 in FA-induced neurotoxicity is unclear. Herein, using a mouse neuroblastoma cell line (N2a cells), we explored the mechanism of TNFAIP1 in FA-induced neurotoxicity, the involvement of the Akt/CREB signaling pathway, and how the expression of TNFAIP1 is regulated by FA. We found that exposure to 100 μM or 200 μM FA for 24 h led to decreased cell viability, increased cell apoptosis and neurite retraction, increased reactive oxygen species (ROS) levels, upregulated protein expression of TNFAIP1 and decreased the levels of phosphorylated Akt and CREB in the Akt/CREB pathway. Knockdown of TNFAIP1 using a TNFAIP1 small interfering RNA (siRNA) expression vector prevented FA from inhibiting the Akt/CREB pathway, thus reducing cell apoptosis and restoring cell viability and neurite outgrowth. Clearance of ROS by vitamin E (Vit E) repressed the FA-mediated upregulation of TNFAIP1 expression. These results suggest that FA increases the expression of TNFAIP1 by inducing oxidative stress and that upregulated TNFAIP1 then inhibits the Akt/CREB pathway, consequently leading to cell apoptosis and neurite retraction. Therefore, TNFAIP1 is a potential target for alleviating FA-induced neurotoxicity and related neurological disorders.

LiMnPO4 (LMP) microwave dielectric ceramics were manufactured at different temperatures via a standard solid-state reaction method, and the LMP ceramic sintered at 750 °C displayed dielectric properties of εr = 7.82, Q × f = 29,189 (f = 12.7 GHz). The lattice vibrational characteristics of LMP ceramics were studied utilizing both infrared reflection and Raman scattering spectroscopy to clarify the basic principle of the dielectric response. The intrinsic properties that were fitted and simulated based on the infrared spectra agreed with the measured property values. The low-frequency vibrational modes contributed more to the dielectric properties than the high-frequency modes. Upon increasing the temperature, the permittivity was positively correlated with the bond length but showed the opposite trend of the Raman shift of mode 9 Ag(υ1). The Q × f value was positively correlated with the packing fraction but negatively correlated with the FWHM of mode 10 Ag(υ3). Thus, the structure-property relationships of LMP ceramics were established as a function of sintering temperature.

Biomaterials are indispensable for tissue engineering, which plays a pivotal role in the skeletal tissue repair. However, biomaterials currently used such as animal extracts and chemically synthesized polymers display unsatisfactory bioactivity and safety. In recent years, modular protein engineering-based (MPE) biomaterials composed of polypeptides produced by molecular cloning and protein synthesis have greatly developed due to their lower batch-to-batch variation, avoidance of possible pathogens and, most importantly, sequence-tunable property. In this review, we first briefly describe the properties of different MPE biomaterials classified by the structural domains of polypeptides, and techniques to engineer the polypeptide sequence and synthesize MPE biomaterials at will. Then, we focus on the application of bio-designed MPE biomaterials in skeletal tissue engineering. Different structural domains of polypeptides are used individually or covalently fused with different bioactive motifs to generate a variety of MPE biomaterials. The sequence (protein modules) of MPE biomaterials would determine and guide their cytocompatibility, their effects on cell fate and ECM formation, the mechanical properties and functions during the in vivo skeletal tissue repair. Moreover, we propose several bio-design strategies and potential directions to develop MPE biomaterials for better performing skeletal tissue engineering and to achieve fast skeletal tissue regeneration. Combinations of material science and protein engineering would provide solutions to the obstacles in regenerative medicine. This article provides a board review of skeletal tissue engineering in a polypeptide sequence-guided way by using MPE biomaterials.

Corneal injury-induced inflammation may result in permanent vision loss. In situ forming adhesive hydrogels offer a promising tissue substitute for repair of partial-thickness corneal wounds, but the uncertainty of biodegradation rate potentially fails to form new tissues in vivo. To overcome this problem, a methacrylated collagen (ColMA) hydrogel is newly developed as a wound dressing to repair partial-thickness corneal defects using a two-stage approach. Such a hydrogel can maintain the viability and adhesion of human corneal epithelial cells (HCECs) as well as promoting their migration in vitro. During surgery, we initially photopolymerized ColMA hydrogel to form a in situ coating at defects. The hydrogel is further designed to be dislodged off after implantation and thus avoid the potential risks from the uncontrollable gel biodegradation. In both rabbit and pig corneal defect models, this collagen hydrogel not only serves as a physical barrier to prevent bacterial penetration and corneal wound dehydration, but also produces nanogranules to highly promote re-epithelization, thereby contributing to the decrease of scar formation and improvement of corneal epithelial-stromal regeneration via reducing myofibroblast activation. This study presents a useful platform system that can be adapted and extended towards the repair of diverse tissues or organs through the addition of bioactive molecules, encouraging the ColMA hydrogel wound dressing to be translated into advanced regenerative therapies.

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer. It has neurotoxicity and exposure to it causes impairment of neurodevelopment, behavior and cognition. However, the molecular mechanisms responsible for the DEHP-induced neurotoxicity are not yet clearly defined. Tumor necrosis factor-induced protein 1 (TNFAIP1) was first discovered in umbilical vein endothelial cells and was further found to be important in the progress of Alzheimer's disease. Herein we explore the mechanism of TNFAIP1 in DEHP-induced neurotoxicity with the involvement of cyclic AMP response elements binding protein (CREB) signaling pathway in a mouse neuroblastoma cell line (N2a cells). We found that exposure to DEHP induced apoptosis and downregulated the expression of brain-derived neurotrophic factor (BDNF), synaptic proteins PSD 95 and synapsin-1 while upregulated the expression of TNFAIP1 and decreased the levels of phosphorylated Akt, CaMK Ⅳ, catalytic subunits of PKA and CREB in CREB signaling pathway. Knockdown of TNFAIP1 using TNFAIP1 small interfering RNA (siRNA) expression vector prevented DEHP from inhibiting CREB pathway, thus reduced apoptosis and restored expression of BDNF, PSD 95 and synapsin-1. Our data indicate that downregulation of TNFAIP1 prevents DEHP-induced neurotoxicity via activating CREB pathway. Therefore, TNFAIP1 is a potential target for relieving the DEHP-induced neurotoxicity and related neurological disorders.