Ganoderma spore lipid ameliorates docetaxel, cisplatin, and 5-fluorouracil chemotherapy-induced damage to bone marrow mesenchymal stem cells and hematopoiesis.

BACKGROUND: A triplet chemotherapy regimen of docetaxel, cisplatin, and 5-fluorouracil (TPF) is used to treat head and neck squamous cell carcinoma; however, it is toxic to bone marrow mesenchymal stem cells (BMSCs). We previously demonstrated that Ganoderma spore lipid (GSL) protect BMSCs against cyclophosphamide toxicity. In this study, we investigated the protective effects of GSL against TPF-induced BMSCs and hematopoietic damage. METHODS: BMSCs and C57BL/6 mice were divided into control, TPF, co-treatment (simultaneously treated with GSL and TPF for 2 days), and pre-treatment (treated with GSL for 7 days before 2 days of TPF treatment) groups. In vitro, morphology, phenotype, proliferation, senescence, apoptosis, reactive oxygen species (ROS), and differentiation of BMSCs were evaluated. In vivo, peripheral platelets (PLTs) and white blood cells (WBCs) from mouse venous blood were quantified. Bone marrow cells were isolated for hematopoietic colony-forming examination. RESULTS: In vitro, GSL significantly alleviated TPF-induced damage to BMSCs compared with the TPF group, recovering their morphology, phenotype, proliferation, and differentiation capacity (p < 0.05). Annexin V/PI and senescence-associated ß-galactosidase staining showed that GSL inhibited apoptosis and delayed senescence in TPF-treated BMSCs (p < 0.05). GSL downregulated the expression of caspase-3 and reduced ROS formation (p < 0.05). In vivo, GSL restored the number of peripheral PLTs and WBCs and protected the colony-forming capacity of bone marrow cells (p < 0.05). CONCLUSIONS: GSL efficiently protected BMSCs from damage caused by TPF and recovered hematopoiesis.

IPSC-Derived Sensory Neurons Directing Fate Commitment of Human BMSC-Derived Schwann Cells: Applications in Traumatic Neural Injuries.

The in vitro derivation of Schwann cells from human bone marrow stromal cells (hBMSCs) opens avenues for autologous transplantation to achieve remyelination therapy for post-traumatic neural regeneration. Towards this end, we exploited human induced pluripotent stem-cell-derived sensory neurons to direct Schwann-cell-like cells derived from among the hBMSC-neurosphere cells into lineage-committed Schwann cells (hBMSC-dSCs). These cells were seeded into synthetic conduits for bridging critical gaps in a rat model of sciatic nerve injury. With improvement in gait by 12-week post-bridging, evoked signals were also detectable across the bridged nerve. Confocal microscopy revealed axially aligned axons in association with MBP-positive myelin layers across the bridge in contrast to null in non-seeded controls. Myelinating hBMSC-dSCs within the conduit were positive for both MBP and human nucleus marker HuN. We then implanted hBMSC-dSCs into the contused thoracic cord of rats. By 12-week post-implantation, significant improvement in hindlimb motor function was detectable if chondroitinase ABC was co-delivered to the injured site; such cord segments showed axons myelinated by hBMSC-dSCs. Results support translation into a protocol by which lineage-committed hBMSC-dSCs become available for motor function recovery after traumatic injury to both peripheral and central nervous systems.

Nanotransducer-Enabled Deep-Brain Neuromodulation with NIR-II Light.

The second near-infrared window (NIR-II window), which ranges from 1000 to 1700 nm in wavelength, exhibits distinctive advantages of reduced light scattering and thus deep penetration in biological tissues in comparison to the visible spectrum. The NIR-II window has been widely employed for deep-tissue fluorescence imaging in the past decade. More recently, deep-brain neuromodulation has been demonstrated in the NIR-II window by leveraging nanotransducers that can efficiently convert brain-penetrant NIR-II light into heat. In this Perspective, we discuss the principles and potential applications of this NIR-II deep-brain neuromodulation technique, together with its advantages and limitations compared with other existing optical methods for deep-brain neuromodulation. We also point out a few future directions where the advances in materials science and bioengineering can expand the capability and utility of NIR-II neuromodulation methods.

Direct Lineage Reprogramming for Induced Keratinocyte Stem Cells: A Potential Approach for Skin Repair.

Severe trauma or chronic wounds can deplete the keratinocyte stem cells (KSCs) present in the epidermal basal layer or inhibit their migration leading to compromised wound healing. Supplementing KSCs is the key to solution while lineage reprogramming provides a new approach to acquiring KSCs. Through direct lineage reprogramming, induced KSCs (iKSCs) can be produced from somatic cells, which exhibit great application potential. Two strategies are currently being used to directly generate iKSCs, lineage transcription factor (TF)-mediated and pluripotency factors-mediated. This review focuses on lineage TF-mediated direct reprogramming and describes the conversion process along with the underlying epigenetic mechanisms. It also discusses other potential induction strategies to generate iKSCs and challenges associated with in situ reprogramming for skin repair.

The SDF-1/CXCR4 Signaling Pathway Directs the Migration of Systemically Transplanted Bone Marrow Mesenchymal Stem Cells Towards the Lesion Site in a Rat Model of Spinal Cord Injury.

BACKGROUND: It has been observed that bone marrow-derived mesenchymal stem cells (MSCs) migrate towards the injured spinal cord and promote functional recovery when systemically transplanted into the traumatized spinal cord. However, the mechanisms underlying their migration to the spinal cord remain poorly understood. METHODS: In this study, we systemically transplanted GFP- and luciferase-expressing MSCs into rat models of spinal cord injury and examined the role of the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis in regulating the migration of transplanted MSCs to the spinal cord. After intravenous injection, MSCs migrated to the injured spinal cord where the expression of SDF-1 was increased. Spinal cord recruitment of MSCs was blocked by pre-incubation with an inhibitor of CXCR4. Their presence correlated with morphological and functional recovery. In vitro, SDF-1 or cerebrospinal fluid (CSF) collected from SCI rats promoted a dose-dependent migration of MSCs in culture, which was blocked by an inhibitor of CXCR4 or SDF-1 antibody. RESULTS AND CONCLUSION: The study suggests that SDF-1/CXCR4 interactions recruit exogenous MSCs to injured spinal cord tissues and may enhance neural regeneration. Modulation of the homing capacity may be instrumental in harnessing the therapeutic potential of MSCs.

Palette of Rechargeable Mechanoluminescent Fluids Produced by a Biomineral-Inspired Suppressed Dissolution Approach.

Mechanoluminescent materials, which emit light in response to mechanical stimuli, have recently been explored as promising candidates for photonic skins, remote optogenetics, and stress sensing. All mechanoluminescent materials reported thus far are bulk solids with micron-sized grains, and their light emission is only produced when fractured or deformed in bulk form. In contrast, mechanoluminescence has never been observed in liquids and colloidal solutions, thus limiting its biological application in living organisms. Here, we report the synthesis of mechanoluminescent fluids via a suppressed dissolution approach. We demonstrate that this approach yields stable colloidal solutions comprising mechanoluminescent nanocrystals with bright emissions in the range of 470-610 nm and diameters down to 20 nm. These colloidal solutions can be recharged and discharged repeatedly under photoexcitation and hydrodynamically focused ultrasound, respectively, thus yielding rechargeable mechanoluminescent fluids that can store photon energy in a reversible manner. This rechargeable fluid can facilitate a systemically delivered light source gated by tissue-penetrant ultrasound for biological applications that require light in the tissue, such as optogenetic stimulation in the brain.

A biomineral-inspired approach of synthesizing colloidal persistent phosphors as a multicolor, intravital light source.

Many in vivo biological techniques, such as fluorescence imaging, photodynamic therapy, and optogenetics, require light delivery into biological tissues. The limited tissue penetration of visible light discourages the use of external light sources and calls for the development of light sources that can be delivered in vivo. A promising material for internal light delivery is persistent phosphors; however, there is a scarcity of materials with strong persistent luminescence of visible light in a stable colloid to facilitate systemic delivery in vivo. Here, we used a bioinspired demineralization (BID) strategy to synthesize stable colloidal solutions of solid-state phosphors in the range of 470 to 650 nm and diameters down to 20 nm. The exceptional brightness of BID-produced colloids enables their utility as multicolor luminescent tags in vivo with favorable biocompatibility. Because of their stable dispersion in water, BID-produced nanophosphors can be delivered systemically, acting as an intravascular colloidal light source to internally excite genetically encoded fluorescent reporters within the mouse brain.

Link Between Senescence and Cell Fate: Senescence-Associated Secretory Phenotype and Its Effects on Stem Cell Fate Transition.

Senescence is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells remain metabolically active and secrete a variety of factors collectively termed senescence-associated secretory phenotype (SASP). SASP is highly pleiotropic and can impact numerous biological processes in which it has both beneficial and deleterious roles. The underlying mechanisms by which SASP exerts its pleiotropic influence remain largely unknown. SASP serves as an environmental factor, which regulates stem cell differentiation and alters its routine. The latter can potentially be accomplished through dedifferentiation, transdifferentiation, or reprogramming. Behavioral changes that cells undergo when exposed to SASP are involved in several senescence-associated physiological and pathological phenomena. These findings provide clues for identifying possible interventions to reduce the deleterious effects without interfering in the beneficial outcomes. In this study, we discuss the multifaceted effects of SASP and the changes occurring in cellular states upon exposure to SASP factors.

Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window.

Neural circuitry is typically modulated via invasive brain implants and tethered optical fibres in restrained animals. Here we show that wide-field illumination in the second near-infrared spectral window (NIR-II) enables implant-and-tether-free deep-brain stimulation in freely behaving mice with stereotactically injected macromolecular photothermal transducers activating neurons ectopically expressing the temperature-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1). The macromolecular transducers, ~40 nm in size and consisting of a semiconducting polymer core and an amphiphilic polymer shell, have a photothermal conversion efficiency of 71% at 1,064 nm, the wavelength at which light attenuation by brain tissue is minimized (within the 400-1,800 nm spectral window). TRPV1-expressing neurons in the hippocampus, motor cortex and ventral tegmental area of mice can be activated with minimal thermal damage on wide-field NIR-II illumination from a light source placed at distances higher than 50 cm above the animal's head and at an incident power density of 10 mW mm-2. Deep-brain stimulation via wide-field NIR-II illumination may open up opportunities for social behavioural studies in small animals.

A transparent, self-powered photodetector based on p-CuI/n-TiO2heterojunction film with high on-off ratio.

Ultraviolet(UV) photodetectors(PDs) can monitor UV radiation, enabling it to be effective for many applications, such as communication, imaging and sensing. The rapid progress on portable and wearable optoelectronic devices places a great demand on self-powered PDs. However, high-performance self-powered PDs are still limited. Herein we display a transparent and self-powered PD based on a p-CuI/n-TiO2heterojunction, which exhibits a high on-off ratio (∼104at 310 nm) and a fast response speed (rise time/decay time = 0.11 ms/0.72 ms) without bias. Moreover, the device shows an excellent UV-selective sensitivity as a solar-blind UV PD with a high UV/visible rejection ratio (R300 nm/R400 nm= 5.3 × 102), which can be ascribed to the wide bandgaps of CuI and TiO2. This work provides a feasible route for the construction of transparent, self-powered PDs based on p-n heterojunctions.

Ultrafast Speed, Dark Current Suppression, and Self-Powered Enhancement in TiO2-Based Ultraviolet Photodetectors by Organic Layers and Ag Nanowires Regulation.

TiO2-based photodetectors (PDs) have been hotspots in recent years for their excellent thermal stabilities and optoelectronic performance under ultraviolet (UV) light. However, the high dark current caused by defects in TiO2 films has limited the detectivity (D) of these PDs. Here, the dark current of a TiO2-based PD was effectively reduced by 3 magnitudes (from 0.1 mA to 20 nA) and D was increased to 1.2 × 1014 Jones by introducing PC71BM. The TiO2/PC71BM heterojunction also made the PD self-powered, and by further introducing an interface layer of PEDOT:PSS and finely optimizing the electrode Ag nanowires (Ag NWs), the self-powered responsivity (R) was increased to 33 mA/W. Ultrafast rise/decay times (129 ns/1 ms at -1 V and 0.06 s/<1 µs at 0 V) were achieved. This work successfully applied an organic-inorganic heterojunction, an organic interface, and Ag NWs to suppress the dark current and enhance the self-powered photocurrent/R of inorganic PDs, providing a feasible strategy in high-performance UV PDs' design.

Long-term toxicological studies on the Chinese medicine 2036 Specialty-Qiangxin recipe in rats.

CONTEXT: The traditional medicine 2036 Specialty-Qiangxin recipe (2036S-QXR) has been widely used in China to improve cardiac function, prevent stroke, and strengthen the immune system. However, its long-term toxicity remains unknown. OBJECTIVE: The present study evaluates the long-term toxicity of 2036S-QXR in rats. MATERIALS AND METHODS: 2036S-QXR (0.6, 1.2, and 2.4 g/kg body weight per day) was orally administered for 26 weeks to Wistar rats, while the rats in the control group received distilled water. The effects on urinary, hematological, biochemical, and histopathological parameters were investigated during the study period. RESULTS: No significant changes in all tested parameters were observed in the 0.6 and 1.2 g/kg groups, compared with the control group (p < 0.05). Higher levels of alanine aminotransferase (46.00 ± 12.85 vs. 25.40 ± 3.36) and aspartate aminotransferase (152.40 ± 32.52 vs. 111.40 ± 18.78) were observed after 13 weeks in the female rats in the 2.4 g/kg group compared with the control group (p < 0.05), but these returned to the control levels after the recovery period (p > 0.05). Several cases displayed the presence of urine protein (3/7 males and 3/7 females) and mild lesions in the kidney (10/20) and thymus (5/20) in the 2.4 g/kg group, without significant changes compared with the control group (p > 0.05). DISCUSSION AND CONCLUSIONS: The present study shows that 2036S-QXR does not cause long-term toxicity, supporting its therapeutic use. To further determine the optimal doses, future studies should test more doses and include more animals in each group.

Enhanced Electrical Properties of Lithography-Free Fabricated MoS2 Field Effect Transistors with Chromium Contacts.

Molybdenum disulfide (MoS2) as a two-dimensional semiconductor material has been actively explored for field-effect-transistors (FETs). The current prevailing method for MoS2 FET fabrication involves multiple complex steps, including electron beam (e-beam) lithography, annealing, etc., which are time-consuming and require polymer resists. As a consequence, the MoS2 exposed to chemicals during the patterning process may be unfavorably affected by residues and the performance of the final FET could be impaired while the annealing limits materials for FETs. Therefore, there is an urgent need to free the fabrication of FETs from e-beam lithography and annealing. In this study, we introduce an e-beam lithography-free method to fabricate MoS2 FETs by employing maze-like source/drain electrodes. In addition, an ohmic contact in multilayer MoS2 FETs using chromium (Cr) as source/drain electrodes is achieved without annealing. The underlying mechanism for contact performance is studied, and the tightness of the contact and the type of metal are found to be responsible because they determine the contact resistance. Furthermore, the long-term device degradation is explored, in which the oxidation of metal dominates. The facile fabrication process and mechanism explanation in this work might provide a new platform for future electronic devices.

Generation of keratinocyte stem-like cells from human fibroblasts via a direct reprogramming approach.

Skin repair and reconstruction are important after severe wound and trauma. Keratinocyte stem cells (KSCs) in the basal layer of the epidermis can regrow the stratified epidermis but are almost depleted after skin injury. Thus, generating enough KSCs is indispensable for skin regeneration. Pluripotent stem cells such as ESC and iPSC can differentiate into KSCs, but their applications are challenged by ethical issues and risks of tumor formation. Lineage reprogramming from one cell type into another one makes it feasible to generate the desired cell type. Here, we develop a method to convert human fibroblasts into induced keratinocyte stem-like cells (iKSC) by coupling transient expression of reprogramming factors with a chemically defined culture medium, without the formation of iPSC. iKSC resemble normal KSC in the morphological and phenotypic features and can differentiate in vitro and regenerate stratified epidermis after transplantation in vivo. Therefore, iKSC may provide abundant cellular sources for skin repair and regeneration.

Patient-Specific Cells for Modeling and Decoding Amyotrophic Lateral Sclerosis: Advances and Challenges.

Motor neuron loss or degeneration is the typical characteristic of amyotrophic lateral sclerosis (ALS), which often leads to weakness, paralysis, or even death. The underlying mechanisms of motor neuron degeneration and ALS progression remain elusive, and there is no effective treatment for ALS. The advances of stem cells and reprogramming techniques has made it possible to generate patient-specific motor neurons as cell models for studying disease mechanisms and drug discovery. This review comprehensively discusses recent approaches to generate motor neurons from stem cells and somatic cells and highlights the application of induced motor neurons to modeling ALS diseases, dissecting the pathogenesis, and screening new drugs. New perspectives are also discussed on generating patient-specific motor neuron subtypes that are affected by ALS or creating 3D spinal cord organoid models for better recapitulating and understanding ALS.

Ganoderma spore lipid protects mouse bone marrow mesenchymal stem cells and hematopoiesis from the cytotoxicity of the chemotherapeutic agent.

Cancer chemotherapeutic agents are frequently toxic to bone marrow and impair bone marrow functions. It is unclear whether ganoderma spore lipid (GSL) can protect bone marrow cells from the cytotoxicity of chemotherapy. To investigate the protective effects of GSL on bone marrow mesenchymal stem cells (MSCs) and hematopoiesis, we examined the effects of GSL on MSCs in vitro and hematopoiesis in vivo after treatment with the chemotherapeutic agent cyclophosphamide. MSCs and peripheral blood cells were isolated and counted from the bone marrow of normal mice were pre-treated with GSL before CTX treatment or co-treated with GSL and CTX, followed by examining the changes in phenotype, morphology, proliferation, apoptosis, and differentiation potentials. The results showed that GSL could reduce the CTX-induced changes in the phenotype of MSCs and maintain the elongated fibroblast-like morphology. MTT and annexin V/propidium iodide (PI) analyses found that GSL pre-treatment and co-treatment increased the proliferation and decreased the apoptosis in CTX-treated MSCs. Furthermore, GSL improved the osteogenic and adipogenic differentiation potentials of CTX-treated MSCs. In vivo, GSL treatment increased the number of peripheral blood cells including white blood cells (WBC) and platelets (PLT) in the CTX-treated mice and enhanced the in vitro formation of hematopoietic lineage colonies (erythrocyte colony forming unit, CFU-E; erythroid burst-forming units, BFU-E; and granulocyte macrophage colony-forming units, CFU-GM) from bone marrow cells in these mice. These findings suggest GSL could protect MSCs and hematopoiesis from the cytotoxicity of CTX and might become an effective adjuvant to attenuate side effects of chemotherapy during cancer treatment.

Materials and Designs for Wearable Photodetectors.

Photodetectors (PDs), as an indispensable component in electronics, are highly desired to be flexible to meet the trend of next-generation wearable electronics. Unfortunately, no in-depth reviews on the design strategies, material exploration, and potential applications of wearable photodetectors are found in literature to date. Thus, this progress report first summarizes the fundamental design principles of turning "hard" photodetectors "soft," including 2D (polymer and paper substrate-based devices) and 1D PDs (fiber shaped devices). In short, the flexibility of PDs is realized through elaborate substrate modification, material selection, and device layout. More importantly, this report presents the current progress and specific requirements for wearable PDs according to the application: monitoring, imaging, and optical communication. Challenges and future research directions in these fields are proposed at the end. The purpose of this progress report is not only to shed light on the basic design principles of wearable PDs, but also serve as the roadmap for future exploration in wearable PDs in various applications, including health monitoring and Internet of Things.

A Real-Time Wearable UV-Radiation Monitor based on a High-Performance p-CuZnS/n-TiO2 Photodetector.

Solar radiation, especially ultraviolet (UV) light, is a major hazard for most skin-related cancers. The growing needs for wearable health monitoring systems call for a high-performance real-time UV sensor to prevent skin diseases caused by excess UV exposure. To this end, here a novel self-powered p-CuZnS/n-TiO2 UV photodetector (PD) with high performance is successfully developed (responsivity of 2.54 mA W-1 at 0 V toward 300 nm). Moreover, by effectively replacing the Ti foil with a thin Ti wire for the anodization process, the conventional planar rigid device is artfully turned into a fiber-shaped flexible and wearable one. The fiber-shaped device shows an outstanding responsivity of 640 A W-1 , external quantum efficiency of 2.3 × 105 %, and photocurrent of ≈4 mA at 3 V, exceeding those of most current UV PDs. Its ultrahigh photocurrent enables it to be easily integrated with commercial electronics to function as a real-time monitor system. Thus, the first real-time wearable UV radiation sensor that reads out ambient UV power density and transmits data to smart phones via wifi is demonstrated. This work not only presents a promising wearable health monitor, but also provides a general strategy for designing and fabricating smart wearable electronic devices.

Human Induced Pluripotent Stem Cell-Derived Sensory Neurons for Fate Commitment of Bone Marrow Stromal Cell-Derived Schwann Cells.

Here we describe the in vitro derivation of sensory neurons for use in effecting fate commitment of Schwann cell-like cells derived from human bone marrow stromal cells (hBMSCs). We adopt a novel combination of small molecules in an 8-day program that induces the differentiation of human induced pluripotent stem cells into sensory neurons. In co-cultures, the derived sensory neurons present contact-dependent cues to direct hBMSC-derived Schwann cell-like cells toward the Schwann cell fate. These derived human Schwann cells survive passaging and cryopreservation, retain marker expression despite withdrawal of glia-inducing medium and neuronal cues, demonstrate capacity for myelination, and therefore promise application in autologous transplantation and re-myelination therapy.

Directed Differentiation of Human Bone Marrow Stromal Cells to Fate-Committed Schwann Cells.

Our ultimate goal of in vitro derivation of Schwann cells (SCs) from adult bone marrow stromal cells (BMSCs) is such that they may be used autologously to assist post-traumatic nerve regeneration. Existing protocols for derivation of SC-like cells from BMSCs fall short in the stability of the acquired phenotype and the functional capacity to myelinate axons. Our experiments indicated that neuro-ectodermal progenitor cells among the human hBMSCs could be selectively expanded and then induced to differentiate into SC-like cells. Co-culture of the SC-like cells with embryonic dorsal root ganglion neurons facilitated contact-mediated signaling that accomplished the switch to fate-committed SCs. Microarray analysis and in vitro myelination provided evidence that the human BMSC-derived SCs were functionally mature. This was reinforced by repair and myelination phenotypes observable in vivo with the derived SCs seeded into a nerve guide as an implant across a critical gap in a rat model of sciatic nerve injury.