The early stages of human lymphopoiesis are poorly characterized. Here, we compared the lymphoid potential of a novel umbilical cord blood CD34 ؉ CD45RA hi CD7 ؉ hematopoietic progenitor cell (HPC) population with that of CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs, previously proposed as candidate common lymphoid progenitors. Limitingdilution and clonal analysis, fetal thymic organ cultures, and culture onto Notch ligand Delta-like-1-expressing OP9 cells, showed that although CD34 ؉ CD45RA hi CD7 ؉ HPCs could generate cells of the 3 lymphoid lineages, their potential was skewed toward the T/natural killer (T/NK) lineages. In contrast, CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs predominantly exhibited a B-cell potential. Gene expression profiling with DNA microarrays confirmed that CD34 ؉ CD45RA hi CD7 ؉ HPCs selectively expressed T-lymphoid and NK lineage-committed genes while retaining expression of genes affiliated to the granulomonocytic lineage, whereas CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs displayed a typical pro-B-cell transcription profile and essentially lacked genes unrelated to the B lineage. In addition, both populations could be generated in vitro from CD34 ؉ CD45RA int CD7 ؊ and CD34 ؉ CD45RA hi Lin ؊ HPCs with mixed lymphomyeloid potential, from which they emerged independently with different growth/ differentiation factor requirements. These findings indicate that CD34 ؉ CD45RA hi CD7 ؉ and CD34 ؉ CD45RA hi Lin ؊ CD10 ؉ HPCs correspond to multipotent early lymphoid progenitors polarized toward either the T/NK or B lineage, respectively. IntroductionThe immediate progeny of pluripotent hematopoietic stem cells is thought to correspond to common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). CMPs are assumed to give rise to granulocytes and macrophages, as well as to the erythroid and megakaryocytic lineages, whereas CLPs are committed to generate either B lymphocytes (BLs) or T lymphocytes (TLs) and natural killer (NK) cells. 1,2 Evidence for a primary segregation between CLPs and CMPs stems from in vivo transfer experiments in adult mice, where 2 populations of c-Kit lo Sca lo IL-7R ϩ and Fc␥R lo CD34 ϩ hematopoietic progenitor cells (HPCs) isolated from the postnatal bone marrow (BM) were shown to selectively reconstitute either the lymphoid 3 or erythromegakaryocytic and granulomonocytic lineages. 4 Such a dichotomous model of hematopoiesis remains however debated because there is also evidence that multilineage precursors coexpress lymphoid as well as myeloerythroid genes [5][6][7] and that populations of early lymphoid progenitors (ELPs) retain some degree of multipotency. [8][9][10][11] For example, AA4.1 ϩ Fc␥R ϩ fetal precursors with TL and BL potential retain significant macrophage potential but fail to generate erythroid or granulocytic cells. 8 In line with these findings, early GFP lo c-kit hi Sca-1 ϩ BL precursors from RAG1/GFP (recombination activating gene 1/green fluorescent protein) knock-in mice still express TL and macrophage potential when cultured under appropriate conditions...
Here, we identify fetal bone marrow (BM)-derived CD34hiCD45RAhiCD7+ hematopoietic progenitors as thymus-colonizing cells. This population, virtually absent from the fetal liver (FL), emerges in the BM by development weeks 8-9, where it accumulates throughout the second trimester, to finally decline around birth. Based on phenotypic, molecular, and functional criteria, we demonstrate that CD34hiCD45RAhiCD7+ cells represent the direct precursors of the most immature CD34hiCD1a- fetal thymocytes that follow a similar dynamics pattern during fetal and early postnatal development. Histological analysis of fetal thymuses further reveals that early immigrants predominantly localize in the perivascular areas of the cortex, where they form a lymphostromal complex with thymic epithelial cells (TECs) driving their rapid specification toward the T lineage. Finally, using an ex vivo xenogeneic thymus-colonization assay, we show that BM-derived CD34hiCD45RAhiCD7+ progenitors are selectively recruited into the thymus parenchyma in the absence of exogenous cytokines, where they adopt a definitive T cell fate.
Background: Quarantine/confinement is an effective measure to face the Coronavirus disease 2019 (COVID-19). Consequently, in response to this stressful situation, people confined to their homes may change their everyday eating behavior. Therefore, the primary objective of this study is to evaluate the association between quarantine/ confinement stressors and eating behavior during the COVID-19 outbreak. The secondary objective is to compare the association of quarantine/confinement stressors and diet behavior between two groups of participants, those attending diet clinics and those not (general population). Method: A cross-sectional web-based online survey carried out between April 3 and 18, 2020, enrolled 407 participants from the Lebanese population. Eating Disorder Examination-Questionnaire (EDE-Q) were used to measure the behavioral features of eating disorders. Results: More than half of the sample (53.0%) abide by the home quarantine/confinement, 95.4% were living with someone in the quarantine/confinement, and 39.6% continued to work from home. Higher fear of COVID-19 was found in 182 (44.8%) participants, higher boredom in 200 (49.2%) participants, higher anger in 187 (46.3%), and higher anxiety in 197 (48.5%) participants. Higher fear of COVID-19 (Beta = 0.02), higher BMI (Beta = 0.05), and physical activity (Beta = 1.04) were significantly associated with a higher restraint score. Higher anxiety, higher fear of COVID-19, higher BMI, practicing physical exercise, and a higher number of adults living in the quarantine/ confinement were significantly associated with higher shape and weight concerns. Conclusion: Our results showed that the fear of COVID-19 was correlated with more eating restraint, weight, and shape concerns in the whole sample, but more specifically in the dietitian clients group. Public health control measures are needed to reduce the detrimental effects of psychological distress associated with quarantine/ confinement on eating behaviors during the COVID-19 outbreak.
The online version of this article has a Supplementary Appendix. BackgroundExpansion of hematopoietic stem cells represents an important objective for improving cell and gene therapy protocols. Retroviral transduction of the HoxB4 homeogene in mouse and human hematopoietic stem cells and hematopoietic progenitors is known to promote the cells' expansion. A safer approach consists in transferring homeobox proteins into hematopoietic stem cells taking advantage of the natural ability of homeoproteins to cross cell membranes. Thus, HOXB4 protein transfer is operative for expanding human hematopoietic cells, but such expansion needs to be improved. Design and MethodsTo that aim, we evaluated the effects of HOXC4, a protein encoded by a HOXB4 paralog gene, by co-culturing HOXC4-producing stromal cells with human CD34 + hematopoietic cells. Numbers of progenitors and stem cells were assessed by in vitro cloning assays and injection into immuno-deficient mice, respectively. We also looked for activation or inhibition of target downstream gene expression. ResultsWe show that the HOXC4 homeoprotein expands human hematopoietic immature cells by 3 to 6 times ex vivo and significantly improves the level of in vivo engraftment. Comparative transcriptome analysis of CD34 + cells subjected or not to HOXB4 or HOXC4 demonstrated that both homeoproteins regulate the same set of genes, some of which encode key hematopoietic factors and signaling molecules. Certain molecules identified herein are factors reported to be involved in stem cell fate or expansion in other models, such as MEF2C, EZH2, DBF4, DHX9, YPEL5 and Pumilio. ConclusionsThe present study may help to identify new HOX downstream key factors potentially involved in hematopoietic stem cell expansion or in leukemogenesis.
Hematopoiesis generated from human embryonic stem cells (ES) and induced pluripotent stem cells (iPS) are unprecedented resources for cell therapy. We compared hematopoietic differentiation potentials from ES and iPS cell lines originated from various donors and derived them using integrative and non-integrative vectors. Significant differences in differentiation toward hematopoietic lineage were observed among ES and iPS. The ability of engraftment of iPS or ES-derived cells in NOG mice varied among the lines with low levels of chimerism. iPS generated from ES cell-derived mesenchymal stem cells (MSC) reproduce a similar hematopoietic outcome compared to their parental ES cell line. We were not able to identify any specific hematopoietic transcription factors that allow to distinguish between good versus poor hematopoiesis in undifferentiated ES or iPS cell lines. There is a relatively unpredictable variation in hematopoietic differentiation between ES and iPS cell lines that could not be predicted based on phenotype or gene expression of the undifferentiated cells. These results demonstrate the influence of genetic background in variation of hematopoietic potential rather than the reprogramming process.
Highlights d Hypoxia favors human lymphoid development from early hemato-lymphoid progenitors d HIF-1/2a factors enhance the lymphoid gene expression program of LMPP and pro-T/NK cells d HIF-1/2a factors are required for lymphoid cell production from LMPP and pro-T/NK cells
The ETS-domain transcription factors divide into subfamilies based on protein similarities, DNA-binding sequences, and interaction with cofactors. They are regulated by extracellular clues and contribute to cellular processes, including proliferation and transformation. ETS genes are targeted through genomic rearrangements in oncogenesis. The PU.1/SPI1 gene is inactivated by point mutations in human myeloid malignancies. We identifi ed a recurrent somatic mutation (Q226E) in PU.1/SPI1 in Waldenström macroglobulinemia, a B-cell lymphoproliferative disorder. It affects the DNA-binding affi nity of the protein and allows the mutant protein to more frequently bind and activate promoter regions with respect to wild-type protein. Mutant SPI1 binding at promoters activates gene sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration of DNA binding leading to cellular proliferation and differentiation arrest. SIGNIFICANCE : The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors.
The HOXB4 homeoprotein is known to promote the expansion of mouse and human hematopoietic stem cells (HSCs) and progenitors of the myeloid lineages. However, the putative involvement of HOXB4 in lymphopoiesis and particularly in the expansion of early lymphoid progenitor cells has remained elusive. Based on the ability of the HOXB4 protein to passively enter hematopoietic cells, our group previously designed a long-term culture procedure of human HSCs that allows ex vivo expansion of these cells. Here, this method has been further used to investigate whether HOXB4 could cause similar expansion on cells originating from CD34؉ hematopoietic progenitor cells (HPCs) committed at various levels toward the lymphoid lineages. We provide evidence that HOXB4 protein delivery promotes the expansion of primitive HPCs that generate lymphoid progenitors. Moreover, HOXB4 acts on lymphomyeloid HPCs and committed T/natural killer HPCs but not on primary B-cell progenitors. Our results clarify the effect of HOXB4 in the early stages of human lymphopoiesis, emphasizing the contribution of this homeoprotein in the maintenance of the intrinsic lymphomyeloid differentiation potential of defined HPC subsets. Finally, this study supports the potential use of HOXB4 protein for HSC and HPC expansion in a therapeutic setting and furthers our understanding of the mechanisms of the molecular regulation of hematopoiesis. STEM CELLS 2008;26:312-322 Disclosure of potential conflicts of interest is found at the end of this article.
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