Extreme environments and human health: From the immune microenvironments to immune cells.

Exposure to extreme environments causes specific acute and chronic physiological responses in humans. The adaptation and the physiological processes under extreme environments predominantly affect multiple functional systems of the organism, in particular, the immune system. Dysfunction of the immune system affected by several extreme environments (including hyperbaric environment, hypoxia, blast shock, microgravity, hypergravity, radiation exposure, and magnetic environment) has been observed from clinical macroscopic symptoms to intracorporal immune microenvironments. Therefore, simulated extreme conditions are engineered for verifying the main influenced characteristics and factors in the immune microenvironments. This review summarizes the responses of immune microenvironments to these extreme environments during in vivo or in vitro exposure, and the approaches of engineering simulated extreme environments in recent decades. The related microenvironment engineering, signaling pathways, molecular mechanisms, clinical therapy, and prevention strategies are also discussed.

PLCε knockdown overcomes drug resistance to androgen receptor antagonist in castration-resistant prostate cancer by suppressing the wnt3a/ß-catenin pathway.

Most prostate cancers (Pcas) develop into castration-resistant prostate cancer (CRPC) after receiving androgen deprivation therapy (ADT). The expression levels of PLCε and wnt3a are increased in Pca and regulate androgen receptor (AR) activity. However, the biological function and mechanisms of PLCε and wnt3a in CRPC remain unknown. In this study, we found that the expression levels of PLCε, wnt3a, and AR were significantly increased in CRPC tissues as well as bicalutamide-resistant-LNCaP and enzalutamide-resistant-LNCaP cells. In addition, PLCε knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and enzalutamide by inhibiting the activity of the wnt3a/ß-catenin/AR signaling axis. Interestingly, the resistance of LNCaP cells docetaxel is related to PLCε but not the wnt3a/ß-catenin pathway. We also found that the combination of PLCε knockdown and enzalutamide treatment synergistically suppressed cell proliferation, tumor growth, and bone metastasis using in vitro and in vivo experiments. Our study revealed that PLCε is involved in the progression of drug-resistance in CRPC and could be a new target for the treatment of CRPC.

Obesity modulates hematopoietic stem cell fate decision via IL-1ß induced p38/MAPK signaling pathway.

BACKGROUND: Obesity is accompanied by inflammation, which significantly affects the homeostasis of the immune microenvironment. Hematopoietic stem cells (HSCs), residing primarily in the bone marrow, play a vital role in maintaining and producing diverse mature blood cell lineages for the adult hematopoietic and immune systems. However, how HSCs development is affected by obese-promoting inflammation, and the mechanism by which HSC hematopoietic potency is affected by inflammatory signals originating from the obese-promoting changes on bone marrow niche remain unclear. This study elucidates the relationship between obesity-promoting inflammation and HSC fate determination. METHODS: The obesity mice model was established by feeding C57BL/6J mice a high-fat diet (HFD) containing 60% kcal fat. After 6 weeks, HSCs were analyzed using flow cytometry and identified key inflammation cytokine. Transcriptome sequencing techniques were used to discern the distinct pathways in HSCs. Ultimately, confirming the biological mechanism of obesity-induced HSC fate changes via Anakinra blocking specific inflammatory signals. RESULTS: Obesity caused by HFD changed the physical and biochemical properties of the bone marrow niche. In the HFD mice, the population of long-term HSCs in the bone marrow was decreased and facilitated HSCs differentiation towards the myeloid lineage. In addition, HFD increased expression of the inflammatory factor IL-1ß in the bone marrow, and a significantly increased expression of IL-1r1 and active p38/MAPK signaling pathway were detected in the HSCs. Inhibition of IL-1ß further normalized the expression of genes in p38/MAPK pathway and reversed HSC fate. CONCLUSIONS: These findings have been demonstrated that the p38/MAPK signaling pathway in HSCs is activated by elevated levels of IL-1ß within the HSC niche in obese models, thereby regulating HSC differentiation. It suggested a direct link between obesity-promoting inflammation and myeloid differentiation bias of HSCs in the HFD mice.

Heterogeneous stiffness of the bone marrow microenvironment regulates the fate decision of haematopoietic stem and progenitor cells.

The bone marrow (BM) niches are the complex microenvironments that surround cells, providing various external stimuli to regulate a range of haematopoietic stem cell (HSC) behaviours. Recently, it has been proposed that the fate decision of HSCs is often correlated with significantly altered biophysical signals of BM niches. To thoroughly elucidate the effect of mechanical microenvironments on cell fates, we constructed 2D and 3D cell culture hydrogels using polyacrylamide to replicate the mechanical properties of heterogeneous sub-niches, including the inherent rigidity of marrow adipose tissue (2 kPa), perivascular tissue (8 kPa) and endosteum region (35 kPa) in BM. Our observations suggest that HSCs can respond to the mechanical heterogeneity of the BM microenvironment, exhibiting diversity in cell mechanics, haematopoietic pool maintenance and differentiated lineages. Hydrogels with higher stiffness promote the preservation of long-term repopulating HSCs (LT-HSCs), while those with lower stiffness support multi-potent progenitors (MPPs) viability in vitro. Furthermore, we established a comprehensive transcriptional profile of haematopoietic subpopulations to reflect the multipotency of haematopoietic stem and progenitor cells (HSPCs) that are modulated by niche-like stiffness. Our findings demonstrate that HSPCs exhibit completely distinct downstream differentiated preferences within hydrogel systems of varying stiffness. This highlights the crucial role of tissue-specific mechanical properties in HSC lineage decisions, which may provide innovative solutions to clinical challenges.

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.

Deciphering the Efficacy and Mechanism of Astragalus membranaceus on High Altitude Polycythemia by Integrating Network Pharmacology and In Vivo Experiments.

Hypoxic exposure makes plateau migrators susceptible to high altitude polycythemia (HAPC). Astragalus membranaceus (AM) is an edible and medicinal plant with remarkable immunomodulatory activities. The purpose of this study was to discover if AM could be a candidate for the prevention of HAPC and its mechanism. Here, network pharmacology was applied to screen active compounds, key targets, and enriched pathways of AM in the treatment of HAPC. Molecular docking evaluated the affinity between compounds and core targets. Subsequently, the mechanisms of AM were further verified using the hypoxia exposure-induced mice model of HAPC. The network pharmacology analysis and molecular docking results identified 14 core targets of AM on HAPC, which were predominantly mainly enriched in the HIF-1 pathway. In the HAPC animal models, we found that AM inhibited the differentiation of hematopoietic stem cells into the erythroid lineage. It also suppressed the production of erythrocytes and hemoglobin in peripheral blood by reducing the expression of HIF-1α, EPO, VEGFA, and Gata-1 mRNA. Furthermore, AM downregulated the expression of IL-6, TNF-α, and IFN-γ mRNA, thereby alleviating organ inflammation. In conclusion, AM supplementation alleviates hypoxia-induced HAPC in mice, and TNF-α, AKT1, HIF-1α, VEGFA, IL-6, and IL-1B may be the key targets.