Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate.

Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium (HE) in the aorta- gonads-and mesonephros (AGM) region and reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). The signalling mechanisms that distinguish HSCs from HPCs are unknown. Notch signaling is essential for arterial specification, IAHC formation and HSC activity, but current studies on how Notch segregates these different fates are inconsistent.

Mesenchymal stem cells induce dynamic immunomodulation of airway and systemic immune cells but do not improve survival for mice with H1N1 virus-induced acute lung injury.

Influenza A virus (IAV)-induced acute lung injury (ALI) is characterized by pronounced proinflammatory activation and respiratory lung dysfunction. In this study, we performed deep immune profiling on airway and circulating immune cells to examine the effect of immunomodulation and therapeutic outcomes of mesenchymal stem cells (MSCs) therapy in mice with IAV-induced ALI. Animals were inoculated intranasally with H1N1 IAV, followed by intravenous administration of vehicle, or human clinical-grade, bone marrow-derived MSCs 24-h later, and monitored for six days to evaluate the survival.

Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging.

Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward.

Living a longer life: unique lessons from the naked mole-rat blood system.

Analysis of functional deterioration of the blood system during ageing has been largely confined to the mouse and human system. In this issue, Emmrich et al (2022) report the first comprehensive characterisation of the haematopoietic system of the naked mole-rat (NMR), an exceptionally long-lived rodent, highlighting its unique features and uncovering potential strategies to sustain haematopoiesis during an extended lifetime.

Fast and high-fidelity 3D imaging protocol for stem cells and niche components for mouse organs and tissues.

Quantitative 3D imaging of organ-wide cellular and subcellular components is central for revealing and understanding complex interactions between stem cells and their microenvironment. Here, we present a gentle but fast whole-mount immunofluorescence staining protocol for 3D confocal microscopy (iFAST3D) that preserves the 3D structure of the entire tissue and that of subcellular structures with high fidelity. The iFAST3D protocol enables reproducible and high-resolution 3D imaging of stem cells and various niche components for many mouse organs and tissues.

Interplay of Obesity, Ethanol, and Contaminant Mixture on Clinical Profiles of Cardiovascular and Metabolic Diseases: Evidence from an Animal Study.

Obesity, ethanol, and contaminants are known risk factors of cardiovascular and metabolic diseases (CMD). However, their interplay on clinical profiles of these diseases remains unclear, and thus were investigated in this study. Male lean or obese JCR rats were given water or 10% ethanol and orally treated with or without a contaminant mixture (CM) dissolved in corn oil and loaded on two cookies at 0, 1.

Poly(I:C) enhances mesenchymal stem cell control of myeloid cells from COVID-19 patients.

Mesenchymal stem cells (MSCs) are being studied for the treatment of COVID-19-associated critical illness, due to their immunomodulatory properties. Here, we hypothesized that viral mimic-priming improves MSCs' abilities to rebalance the dysregulated immune responses in COVID-19. Transcriptome analysis of poly(I:C)-primed MSCs (pIC-MSCs) showed upregulation of pathways in antiviral and immunomodulatory responses.

Cdc42-Borg4-Septin7 axis regulates HSC polarity and function.

Aging of hematopoietic stem cells (HSCs) is caused by the elevated activity of the small RhoGTPase Cdc42 and an apolar distribution of proteins. Mechanisms by which Cdc42 activity controls polarity of HSCs are not known. Binder of RhoGTPases proteins (Borgs) are known effector proteins of Cdc42 that are able to regulate the cytoskeletal Septin network.

An aged bone marrow niche restrains rejuvenated hematopoietic stem cells.

Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients.

Attrition of X Chromosome Inactivation in Aged Hematopoietic Stem Cells.

During X chromosome inactivation (XCI), the inactive X chromosome (Xi) is recruited to the nuclear lamina at the nuclear periphery. Beside X chromosome reactivation resulting in a highly penetrant aging-like hematopoietic malignancy, little is known about XCI in aged hematopoietic stem cells (HSCs). Here, we demonstrate that LaminA/C defines a distinct repressive nuclear compartment for XCI in young HSCs, and its reduction in aged HSCs correlates with an impairment in the overall control of XCI.

Gene engineered mesenchymal stem cells: greater transgene expression and efficacy with minicircle vs. plasmid DNA vectors in a mouse model of acute lung injury.

Background: Acute lung injury (ALI) and in its severe form, acute respiratory distress syndrome (ARDS), results in increased pulmonary vascular inflammation and permeability and is a major cause of mortality in many critically ill patients. Although cell-based therapies have shown promise in experimental ALI, strategies are needed to enhance the potency of mesenchymal stem cells (MSCs) to develop more effective treatments. Genetic modification of MSCs has been demonstrated to significantly improve the therapeutic benefits of these cells; however, the optimal vector for gene transfer is not clear.

A Wnt5a-Cdc42 axis controls aging and rejuvenation of hair-follicle stem cells.

Normal hair growth occurs in cycles, comprising growth (anagen), cessation (catagen) and rest (telogen). Upon aging, the initiation of anagen is significantly delayed, which results in impaired hair regeneration. Hair regeneration is driven by hair follicle stem cells (HFSCs).

Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice.

Cdc42 is a small RhoGTPase regulating multiple functions in eukaryotic cells. The activity of Cdc42 is significantly elevated in several tissues of aged mice, while the Cdc42 gain-of-activity mouse model presents with a premature aging-like phenotype and with decreased lifespan. These data suggest a causal connection between elevated activity of Cdc42, aging, and reduced lifespan.

Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway.

The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (T) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that T heterogeneity results from differential engagement of Wnt signaling.

Acute Myeloid Leukemia: Aging and Epigenetics.

Acute myeloid leukemia (AML) is an aggressive hematological disorder mainly affecting people of older age. AML initiation is primarily attributed to mutations in crucial cellular regulators such as epigenetic factors, transcription factors, and signaling genes. AML's aggressiveness and responsiveness to treatment depends on the specific cell type where leukemia first arose.

Understanding intrinsic hematopoietic stem cell aging.

Hematopoietic stem cells (HSC) sustain blood production over the entire life-span of an organism. It is of extreme importance that these cells maintain self-renewal and differentiation potential over time in order to preserve homeostasis of the hematopoietic system. Many of the intrinsic aspects of HSC are affected by the aging process resulting in a deterioration in their potential, independently of their microenvironment.

Haematopoietic stem cells in perisinusoidal niches are protected from ageing.

With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches.

Dissociation of natriuresis and diuresis by oxytocin molecular forms in rats.

In the rat, oxytocin (OT) produces dose-dependent diuretic and natriuretic responses. Post-translational enzymatic conversion of the OT biosynthetic precursor forms both mature and C-terminally extended peptides. The plasma concentrations of these C-terminally extended peptides (OT-G; OT-GK and OT-GKR) are elevated in newborns and pregnant rats.

Hematopoietic Stem Cell Dynamics Are Regulated by Progenitor Demand: Lessons from a Quantitative Modeling Approach.

The prevailing view on murine hematopoiesis and on hematopoietic stem cells (HSCs) in particular derives from experiments that are related to regeneration after irradiation and HSC transplantation. However, over the past years, different experimental techniques have been developed to investigate hematopoiesis under homeostatic conditions, thereby providing access to proliferation and differentiation rates of hematopoietic stem and progenitor cells in the unperturbed situation. Moreover, it has become clear that hematopoiesis undergoes distinct changes during aging with large effects on HSC abundance, lineage contribution, asymmetry of division, and self-renewal potential.

LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells.

Background: The decline of hematopoietic stem cell (HSC) function upon aging contributes to aging-associated immune remodeling and leukemia pathogenesis. Aged HSCs show changes to their epigenome, such as alterations in DNA methylation and histone methylation and acetylation landscapes. We previously showed a correlation between high Cdc42 activity in aged HSCs and the loss of intranuclear epigenetic polarity, or epipolarity, as indicated by the specific distribution of H4K16ac.

Rational identification of a Cdc42 inhibitor presents a new regimen for long-term hematopoietic stem cell mobilization.

Mobilization of hematopoietic stem cells (HSCs) from bone marrow (BM) to peripheral blood (PB) by cytokine granulocyte colony-stimulating factor (G-CSF) or the chemical antagonist of CXCR4, AMD3100, is important in the treatment of blood diseases. Due to clinical conditions of each application, there is a need for continued improvement of HSC mobilization regimens. Previous studies have shown that genetic ablation of the Rho GTPase Cdc42 in HSCs results in their mobilization without affecting survival.

Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts.

Experimental and/or epidemiological studies suggest that prenatal exposure to bisphenol A (BPA) may delay fetal lung development and maturation and increase the susceptibility to childhood respiratory disease. However, the underlying mechanisms remain to be elucidated. In our previous study with cultured human fetal lung fibroblasts (HFLF), we demonstrated that 24-h exposure to 1 and 100 µM BPA increased GPR30 protein in the nuclear fraction.

Septin 6 regulates engraftment and lymphoid differentiation potential of murine long-term hematopoietic stem cells.

Septins are a family of filament-forming GTP-binding proteins that serve as scaffolds and diffusion barriers in various cellular processes. Septin 6 is known as a fusion partner of mixed-lineage leukemia in infant acute myeloid leukemia. The occurrence of the fusion gene is associated with a reduced expression of septin 6 itself.

Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells.

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