Bone marrow (BM) mesenchymal stem cells (MSCs) are critical components of the BM microenvironment and play an essential role in supporting hematopoiesis. Dysfunction of MSCs is associated with the ...impaired BM microenvironment that promotes leukemia development. However, whether and how restoration of the impaired BM microenvironment can inhibit leukemia development remain unknown. Using an established leukemia model and the RNA-Seq analysis, we discovered functional degeneration of MSCs during leukemia progression. Importantly, intra-BM instead of systemic transfusion of donor healthy MSCs restored the BM microenvironment, demonstrated by functional recovery of host MSCs, improvement of thrombopoiesis, and rebalance of myelopoiesis. Consequently, intra-BM MSC treatment reduced tumor burden and prolonged survival of the leukemia-bearing mice. Mechanistically, donor MSC treatment restored the function of host MSCs and reprogrammed host macrophages into arginase 1 positive phenotype with tissue-repair features. Transfusion of MSC-reprogrammed macrophages largely recapitulated the therapeutic effects of MSCs. Taken together, our study reveals that donor MSCs reprogram host macrophages to restore the BM microenvironment and inhibit leukemia development.
Grade repetition is practiced worldwide and varies considerably across the globe. Globally, around 32.2 million students repeated a grade at the primary education level in 2010. Although a large body ...of research has documented grade repetition's academic and non-academic effects, the limited evidence on associations between grade repetition and school bullying is inconsistent and ambiguous. This study aimed to investigate the global association of grade repetition with bullying victimization in a large-scale school-based cross-sectional study.
We used the latest global data from the Program for International Student Assessment (PISA) 2018. PISA 2018 was conducted between March and August 2018 in 80 countries and economies among students aged 15-16 years attending secondary education. The students reported their experiences of repeating a grade at any time point before the survey and of being bullied in the past 12 months. The outcome measures were 6 types of bullying victimization. We accounted for the complex survey design and used multivariate logistic regression models to estimate the odds ratios (ORs) with 95% confidence intervals (CIs) of grade repetition with bullying victimization after adjusting for potential confounders (sex; age group; migrant status; school type; economic, social, and cultural status; and parental emotional support). This study included 465,146 students (234,218 girls and 230,928 boys) with complete data on grade repetition and bullying victimization in 74 countries and economies. The lifetime prevalence of grade repetition was 12.26%, and 30.32% of students experienced bullying at least a few times a month during the past 12 months. Grade repetition was statistically significantly associated with each type of bullying victimization. The OR (95% CI) of overall bullying victimization for grade repeaters compared with their promoted peers was 1.42 (95% CI 1.32-1.52, p < 0.001). The sex-specific analysis produced similar results in both boys and girls. Furthermore, girls who repeated a grade had higher risks of being made fun of, being threatened, having possessions taken away, and being pushed around than boys. The major limitation is that this study only included students attending schools and therefore may be subject to possible selection bias. In addition, the cross-sectional design hinders us from establishing causality between grade repetition and bullying victimization.
In this study, we observed that, globally, both boys and girls who repeat a grade are at increased risk of being bullied compared with promoted peers, but girls may experience higher risks than boys of specific types of bullying associated with repeating a grade. These findings provide evidence for the association of grade repetition with bullying victimization. Sex differences in risk of experiencing some types of bullying suggest that tailored interventions for girls who repeat a grade may be warranted.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hematopoietic stem cells (HSC) are dominantly quiescent under homeostasis, which is a key mechanism of maintaining the HSC pool for life-long hematopoiesis. Dormant HSC are poised to be immediately ...activated in certain conditions and can return to quiescence after homeostasis has been regained. At present, the molecular networks of regulating the threshold of HSC dormancy, if existing, remain largely unknown. Here, we show that deletion of Nupr1, a gene preferentially expressed in HSC, activated quiescent HSC under homeostasis, which conferred a competitive engraftment advantage for these HSC without compromising their stemness or multi-lineage differentiation capacity in serial transplantation settings. Following an expansion protocol, the Nupr1-/- HSC proliferated more robustly than their wild-type counterparts in vitro. Nupr1 inhibits the expression of p53 and rescue of this inhibition offsets the engraftment advantage. Our data reveal a new role for Nupr1 as a regulator of HSC quiescence, which provides insights for accelerating the engraftment efficacy of HSC transplantation by targeting the HSC quiescence-controlling network.
Achievement of immunocompetent and therapeutic T lymphopoiesis from pluripotent stem cells (PSCs) is a central aim in T cell regenerative medicine. To date, preferentially reconstituting T ...lymphopoiesis in vivo from PSCs remains a practical challenge. Here we documented that synergistic and transient expression of Runx1 and Hoxa9 restricted in the time window of endothelial-to-hematopoietic transition and hematopoietic maturation stages in a PSC differentiation scheme (iR9-PSC) in vitro induced preferential generation of engraftable hematopoietic progenitors capable of homing to thymus and developing into mature T cells in primary and secondary immunodeficient recipients. Single-cell transcriptome and functional analyses illustrated the cellular trajectory of T lineage induction from PSCs, unveiling the T-lineage specification determined at as early as hemogenic endothelial cell stage and identifying the bona fide pre-thymic progenitors. The induced T cells distributed normally in central and peripheral lymphoid organs and exhibited abundant TCRαβ repertoire. The regenerative T lymphopoiesis restored immune surveillance in immunodeficient mice. Furthermore, gene-edited iR9-PSCs produced tumor-specific T cells in vivo that effectively eradicated tumor cells. This study provides insight into universal generation of functional and therapeutic T cells from the unlimited and editable PSC source.
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•Construction of a Hoxb5 knockout reporter mouse model at the HSC level for the first time.•In the primary recipients, depletion of Hoxb5 in established LT-HSCs transiently affected ...their lineage differentiation bias.•Depletion of Hoxb5 in established LT-HSCs did not impair their long-term self-renewal capacity.
Hoxb5 exhibits preferential expression in hematopoietic stem cells (HSCs) and uniquely marks the long-term HSCs (LT-HSCs). Previous studies have demonstrated the remarkable capability of Hoxb5 to alter cell fates when enforced expression in blood progenitors, such as B cell progenitors and multipotent progenitors. Additionally, Hoxb5 deficiency does not hinder the generation of LT-HSCs. However, the specific impact of Hoxb5 deletion on LT-HSCs has remained unexplored. To address this, we developed a conditional Hoxb5 knockout-reporter mouse model, wherein Hoxb5 was knock out by the Vav-cre recombinase, and the endogenous Hoxb5 promoter drove the expression of the blue fluorescent protein (BFP). Our findings revealed that the primary recipients, who transplanted with HSCs indicating Hoxb5 deficiency by the presence of BFP (BFP-positive HSCs), exhibited comparable levels of donor chimerism and lineage chimerism to recipients transplanted with HSCs that spontaneously did not express Hoxb5 and thus lacked BFP expression (BFP-negative HSCs). However, during the secondary transplantation, recipients receiving total bone marrow (BM) from the primary recipients with BFP-positive HSCs showed significantly higher levels of donor chimerism and more robust multi-lineage chimerism compared to those receiving total BM from the primary recipients with BFP-negative HSCs. Our results indicate that deleting Hoxb5 in LT-HSCs transiently influences their lineage differentiation bias without compromising their long-term self-renewal capacity. These findings highlight the primary role of Hoxb5 in regulating lineage commitment decisions in LT-HSCs, while emphasizing that its presence is not indispensable for the maintenance of long-term self-renewal capacity.
Numerous efforts have been attempted to regenerate T cells in culture dish from pluripotent stem cells (PSCs). However, in vitro generated T cells exhibited extremely low activity and compromised ...immunocompetency in vivo. Here, we describe a two-step protocol for regenerating functional T cells using an inducible
-PSC (iR9-PSCs) line. The procedure mainly includes generation of induced hematopoietic progenitor cells (iHPCs) in vitro, transplantation, and development of functional induced T cells (iT) in vivo via transplantation. The entire induction process in vitro requires 21 days before iHPCs transplantation. The development of mature T cells in vivo takes 4 to 6 weeks post-transplantation. We provide a simple and reproducible approach for functional T cell regeneration from iR9-PSCs for research purpose.
Human pluripotent stem cell (hPSC)-induced NK (iNK) cells are a source of off-the-shelf cell products for universal immune therapy. Conventional methods for iNK cell regeneration from hPSCs include ...embryoid body (EB) formation and feeder-based expansion steps, which are time-consuming and cause instability and high costs of manufacturing. Here, we develop an EB-free, organoid aggregate method for NK cell regeneration from hPSCs. In a short time-window of 27-day induction, millions of hPSC input can output over billions of iNK cells without the necessity of NK cell expansion feeders. The iNK cells highly express classical toxic granule proteins, apoptosis-inducing ligands, as well as abundant activating and inhibitory receptors. Functionally, the iNK cells eradicate human tumor cells via mechanisms of direct cytotoxicity, apoptosis, and antibody-dependent cellular cytotoxicity. This study provides a reliable scale-up method for regenerating human NK cells from hPSCs, which promotes the universal availability of NK cell products for immune therapy.
In the field of hematopoietic regeneration, deriving hematopoietic stem cells (HSCs) from pluripotent stem cells with engraftment potential is the central mission. Unstable hematopoietic ...differentiation protocol due to variation factors such as serums and feeder cells, remains a major technical issue impeding the screening of key factors for the derivation of HSCs. In combination with hematopoietic cytokines, UM171 has the capacity to facilitate the maintenance and expansion of human primary HSCs in vitro. Here, using a serum-free, feeder-free, and chemically defined induction protocol, we observed that UM171 enhanced hematopoietic derivation through the entire process of hematopoietic induction in vitro. UM171 facilitated generation of robust CD34+CD45+ derivatives that formed more and larger sized CFU-GM as well as larger sized CFU-Mix. In our protocol, the derived hematopoietic progenitors failed to engraft in NOG mice, indicating the absence of long-term HSC from these progenitors. In combination with other factors and protocols, UM171 might be broadly used for hematopoietic derivation from human pluripotent stem cells in vitro.
•UM171 promotes hematopoietic derivation from human pluripotent stem cells.•UM171 enhances the derivation of hematopoietic cells at multiple developmental steps.•Hematopoietic progenitors from the UM171 group form multiple lineages in vitro.
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