The impact of gut microbial signals on hematopoietic stem cells and the bone marrow microenvironment.

Hematopoietic stem cells (HSCs) undergo self-renewal and differentiation in the bone marrow, which is tightly regulated by cues from the microenvironment. The gut microbiota, a dynamic community residing on the mucosal surface of vertebrates, plays a crucial role in maintaining host health. Recent evidence suggests that the gut microbiota influences HSCs differentiation by modulating the bone marrow microenvironment through microbial products. This paper comprehensively analyzes the impact of the gut microbiota on hematopoiesis and its effect on HSCs fate and differentiation by modifying the bone marrow microenvironment, including mechanical properties, inflammatory signals, bone marrow stromal cells, and metabolites. Furthermore, we discuss the involvement of the gut microbiota in the development of hematologic malignancies, such as leukemia, multiple myeloma, and lymphoma.

An Adjuvant Micelle-Based Multifunctional Nanosystem for Tumor Immunotherapy by Remodeling Three Types of Immunosuppressive Cells.

Immunotherapy is restricted by a complex tumor immunosuppressive microenvironment (TIM) and low drug delivery efficiency. Herein, a multifunctional adjuvant micelle nanosystem (PPD/MPC) integrated with broken barriers and re-education of three classes of immune-tolerant cells is constructed for cancer immunotherapy. The nanosystem significantly conquers the penetration barrier via the weakly acidic tumor microenvironment-responsive size reduction and charge reversal strategy. The detached core micelle MPC could effectively be internalized by tumor-associated macrophages (TAMs), tumor-infiltrating dendritic cells (TIDCs), and myeloid-derived suppressor cells (MDSCs) via mannose-mediated targeting endocytosis and electrostatic adsorption pathways, promoting the re-education of immunosuppressive cells for allowing them to reverse from pro-tumor to antitumor phenotypes by activating TLR4/9 pathways. This process in turn leads to the remodeling of TIM. In vitro and in vivo studies collectively indicate that the adjuvant micelle-based nanosystem not only relieves the intricate immune tolerance and remodels TIM via reprogramming the three types of immunosuppressive cells and regulating the secretion of relevant cytokines/immunity factors but also strengthens immune response and evokes immune memory, consequently suppressing the tumor growth and metastasis.

The spatiotemporal heterogeneity of the biophysical microenvironment during hematopoietic stem cell development: from embryo to adult.

Hematopoietic stem cells (HSCs) with the ability to self-renew and differentiate are responsible for maintaining the supply of all types of blood cells. The complex and delicate microenvironment surrounding HSCs is called the HSC niche and can provide physical, chemical, and biological stimuli to regulate the survival, maintenance, proliferation, and differentiation of HSCs. Currently, the exploration of the biophysical regulation of HSCs remains in its infancy. There is evidence that HSCs are susceptible to biophysical stimuli, suggesting that the construction of engineered niche biophysical microenvironments is a promising way to regulate the fate of HSCs in vitro and ultimately contribute to clinical applications. In this review, we introduced the spatiotemporal heterogeneous biophysical microenvironment during HSC development, homeostasis, and malignancy. Furthermore, we illustrated how these biophysical cues contribute to HSC behaviors, as well as the possible mechanotransduction mechanisms from the extracellular microenvironment into cells. Comprehending the important functions of these biophysical regulatory factors will provide novel approaches to resolve clinical problems.

Detachable MOF-Based Core/Shell Nanoreactor for Cancer Dual-Starvation Therapy With Reversing Glucose and Glutamine Metabolisms.

Tumor-dependent glucose and glutamine metabolisms are essential for maintaining survival, while the accordingly metabolic suppressive therapy is limited by the compensatory metabolism and inefficient delivery efficiency. Herein, a functional metal-organic framework (MOF)-based nanosystem composed of the weakly acidic tumor microenvironment-activated detachable shell and reactive oxygen species (ROS)-responsive disassembled MOF nanoreactor core is designed to co-load glycolysis and glutamine metabolism inhibitors glucose oxidase (GOD) and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES) for tumor dual-starvation therapy. The nanosystem excitingly improves tumor penetration and cellular uptake efficiency via integrating the pH-responsive size reduction and charge reversal and ROS-sensitive MOF disintegration and drug release strategy. Furthermore, the degradation of MOF and cargoes release can be self-amplified via additional self-generation H2 O2 mediated by GOD. Last, the released GOD and BPTES collaboratively cut off the energy supply of tumors and induce significant mitochondrial damage and cell cycle arrest via simultaneous restriction of glycolysis and compensatory glutamine metabolism pathways, consequently realizing the remarkable triple negative breast cancer killing effect in vivo with good biosafety via the dual starvation therapy.

Cascade amplification of tumor chemodynamic therapy and starvation with re-educated TAMs via Fe-MOF based functional nanosystem.

Tumor microenvironment is characterized by the high concentration of reactive oxygen species (ROS), which is an effective key used to open the Pandora's Box against cancer. Herein, a tumor-targeted nanosystem HFNP@GOX@PFC composed of ROS-cleaved Fe-based metal-organic framework, hyaluronic acid (HA), glucose oxidase (GOX) and perfluorohexane (PFC) has been developed for tumor cascade amplified starvation and chemodynamic therapy (CDT). In response to the high concentration of hydrogen peroxide (H2O2) intratumorally, HFNP@GOX@PFC endocytosed by tumor cells can specially be disassembled and release GOX, PFC and Fe2+, which can collectively starve tumor and self-produce additional H2O2 via competitively glucose catalyzing, supply oxygen to continuous support GOX-mediated starvation therapy, initiate CDT and cascade amplify oxidative stress via Fe2+-mediated Fenton reaction, leading to the serious tumor damage with activated p53 signal pathway. Moreover, HFNP@GOX@PFC also significantly initiates antitumor immune response via re-educating tumor-associated macrophages (TAMs) by activating NF-κB and MAPK signal pathways. In vitro and in vivo results collectively demonstrate that nanosystem not only continuously initiates starvation therapy, but also pronouncedly cascade-amplify CDT and polarize TAMs, consequently efficiently inhibiting tumor growth with good biosafety. The functional nanosystem combined the cascade amplification of starvation and CDT provides a new nanoplatform for tumor therapy.

Tumor-targeted dual-starvation therapy based on redox-responsive micelle nanosystem with co-loaded LND and BPTES.

The starvation therapy mediated by the lonidamine (LND) was limited by the low drug delivery efficiency, off-target effect and compensative glutamine metabolism. Herein, a hyaluronic acid (HA)-modified reduction-responsive micellar nanosystem co-loaded with glycolysis and glutamine metabolism inhibitor (LND and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl)ethyl sulfide, BPTES) was constructed for tumor-targeted dual-starvation therapy. The in vitro and in vivo results collectively suggested that the fabricated nanosystem could effectively endocytosed by tumor cells via HA receptor-ligand recognition, and rapidly release starvation-inducers LND and BPTES in response to the GSH-rich intratumoral cytoplasm. Furthermore, the released LND and BPTES were capable of inducing glycolysis and glutamine metabolism suppression, and accompanied by significant mitochondrial damage, cell cycle arrest and tumor cells apoptosis, eventually devoting to the blockade of the energy and substance supply and tumor killing with high efficiency. In summary, HPPPH@L@B nanosystem significantly inhibited the compensatory glycolysis and glutamine metabolism via the dual-starvation therapy strategy, blocked the indispensable energy and substance supply of tumors, consequently leading to the desired tumor starvation and effective tumor killing with reliable biosafety.

Multifunctional metal-organic framework-based nanoreactor for starvation/oxidation improved indoleamine 2,3-dioxygenase-blockade tumor immunotherapy.

Inhibited immune response and low levels of delivery restrict starvation cancer therapy efficacy. Here, we report on the co-delivery of glucose oxidase (GOx) and indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan using a metal-organic framework (MOF)-based nanoreactor, showing an amplified release for tumor starvation/oxidation immunotherapy. The nanosystem significantly overcomes the biobarriers associated with tumor penetration and improves the cargo bioavailability owing to the weakly acidic tumor microenvironment-activated charge reversal and size reduction strategy. The nanosystem rapidly disassembles and releases cargoes in response to the intracellular reactive oxygen species (ROS). GOx competitively consumes glucose and generates ROS, further inducing the self-amplifiable MOF disassembly and drug release. The starvation/oxidation combined IDO-blockade immunotherapy not only strengthens the immune response and stimulates the immune memory through the GOx-activated tumor starvation and recruitment of effector T cells, but also effectively relieves the immune tolerance by IDO blocking, remarkably inhibiting the tumor growth and metastasis in vivo.

Single-cell RNA sequencing to track novel perspectives in HSC heterogeneity.

As the importance of cell heterogeneity has begun to be emphasized, single-cell sequencing approaches are rapidly adopted to study cell heterogeneity and cellular evolutionary relationships of various cells, including stem cell populations. The hematopoietic stem and progenitor cell (HSPC) compartment contains HSC hematopoietic stem cells (HSCs) and distinct hematopoietic cells with different abilities to self-renew. These cells perform their own functions to maintain different hematopoietic lineages. Undeniably, single-cell sequencing approaches, including single-cell RNA sequencing (scRNA-seq) technologies, empower more opportunities to study the heterogeneity of normal and pathological HSCs. In this review, we discuss how these scRNA-seq technologies contribute to tracing origin and lineage commitment of HSCs, profiling the bone marrow microenvironment and providing high-resolution dissection of malignant hematopoiesis, leading to exciting new findings in HSC biology.

Long-term, multidomain analyses to identify the breed and allelic effects in MSTN-edited pigs to overcome lameness and sustainably improve nutritional meat production.

Beef and mutton production has been aided by breeding to integrate allelic diversity for myostatin (MSTN), but a lack of diversity in the MSTN germplasm has limited similar advances in pig farming. Moreover, insurmountable challenges with congenital lameness and a dearth of data about the impacts of feed conversion, reproduction, and meat quality in MSTN-edited pigs have also currently blocked progress. Here, in a largest-to-date evaluation of multiple MSTN-edited pig populations, we demonstrated a practical alternative edit-site-based solution that overcomes the major production obstacle of hindlimb weakness. We also provide long-term and multidomain datasets for multiple breeds that illustrate how MSTN-editing can sustainably increase the yields of breed-specific lean meat and the levels of desirable lipids without deleteriously affecting feed-conversion rates or litter size. Apart from establishing a new benchmark for the data scale and quality of genome-edited animal production, our study specifically illustrates how gene-editing site selection profoundly impacts the phenotypic outcomes in diverse genetic backgrounds.

TGF-ß blockade-improved chemo-immunotherapy with pH/ROS cascade-responsive micelle via tumor microenvironment remodeling.

Immunosuppressive tumor microenvironment and low delivery efficiency severely impede the tumor chemotherapy effect. To address this issue, we develop a pH/ROS cascade-responsive prodrug micelle to deliver siTGF-ß with size-shrinkage and charge-reversal property, leading to synergistical tumor microenvironment remodeling. The nanosystem highly improved endocytosis efficiency and tumor penetration depth through charge reversal and size reduction upon exposure to weakly acidic tumor microenvironment. Moreover, the nanocarrier would rapidly escape from endo/lysosome, disassemble and release siTGF-ß and hydroxycamptothecin in response to high intracellular ROS. Furthermore, the nanosystem significantly boosted antitumor immune response and reduced immune tolerance with remodeling tumor microenvironment, which significantly prolonged the survival time of tumor-bearing mice (75% survival rate upon 35 days). It is realized by the combined effects of chemotherapy-enhanced immunogenicity and recruitment of effector T cells, TGF-ß-blockade immunotherapy-activated inhibition immunosuppressive tumor microenvironment and epithelial-to-mesenchymal transition (EMT), and regulation physical tumor microenvironment via reducing the dense tumor extracellular matrix and the high tumor interstitial pressure obstacles. To this end, the nanosystem not only overcame biobarriers and reinforced antitumor immune response, but also effectively inhibited tumor growth, metastasis and recurrence in vivo.

Applications of nanomaterials in tissue engineering.

Recent advancement in nanotechnology has brought prominent benefits in tissue engineering, which has been used to repair or reconstruct damaged tissues or organs and design smart drug delivery systems. With numerous applications of nanomaterials in tissue engineering, it is vital to choose appropriate nanomaterials for different tissue engineering applications because of the tissue heterogeneity. Indeed, the use of nanomaterials in tissue engineering is directly determined by the choice. In this review, we mainly introduced the use of nanomaterials in tissue engineering. First, the basic characteristics, preparation and characterization methods of the types of nanomaterials are introduced briefly, followed by a detailed description of the application and research progress of nanomaterials in tissue engineering and drug delivery. Finally, the existing challenges and prospects for future applications of nanomaterials in tissue engineering are discussed.

Myostatin regulates fatty acid desaturation and fat deposition through MEF2C/miR222/SCD5 cascade in pigs.

Myostatin (MSTN), associated with the "double muscling" phenotype, affects muscle growth and fat deposition in animals, whereas how MSTN affects adipogenesis remains to be discovered. Here we show that MSTN can act through the MEF2C/miR222/SCD5 cascade to regulate fatty acid metabolism. We generated MSTN-knockout (KO) cloned Meishan pigs, which exhibits typical double muscling trait. We then sequenced transcriptome of subcutaneous fat tissues of wild-type (WT) and MSTN-KO pigs, and intersected the differentially expressed mRNAs and miRNAs to predict that stearoyl-CoA desaturase 5 (SCD5) is targeted by miR222. Transcription factor binding prediction showed that myogenic transcription factor 2C (MEF2C) potentially binds to the miR222 promoter. We hypothesized that MSTN-KO upregulates MEF2C and consequently increases the miR222 expression, which in turn targets SCD5 to suppress its translation. Biochemical, molecular and cellular experiments verified the existence of the cascade. This novel molecular pathway sheds light on new targets for genetic improvements in pigs.