The chorio-allantoic placenta forms through the fusion of the allantois (progenitor tissue of the umbilical cord), with the chorionic plate. The murine placenta contains high levels of hematopoietic stem cells, and is therefore a stem cell niche. However, it is not known whether the placenta is a site of hematopoietic cell emergence, or whether hematopoietic cells originate from other sites in the conceptus and then colonize the placenta. Here, we show that the allantois and chorion, isolated prior to the establishment of circulation, have the potential to give rise to myeloid and definitive erythroid cells following explant culture. We further show that the hematopoietic potential of the allantois and chorion does not require their union, indicating that it is an intrinsic property of these tissues. These results suggest that the placenta is not only a niche for, but also a source of, hematopoietic cells.

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Summary. Telomere shortening has been causally linked to replicative senescence in human cells. To characterize telomere-length heterogeneity in peripheral blood cells of normal individuals, we analysed the mean length of telomeric repeat sequences in subpopulations of peripheral blood leucocytes, using fluorescence in situ hybridization and flow cytometry (flow-FISH). Although the telomere length of most haematopoietic subsets was within the same range, the mean telomere length was found to be 15% higher in B compared with T lymphocytes in adult peripheral blood. Whereas telomere loss with ageing corresponded to 33 base pairs (bp) per year in T cells, telomere shortening was slower in B cells, corresponding to 15 bp per year. Separation of adult B-lymphocyte subpopulations based on CD27 expression revealed that telomere length was almost 2 kb longer in CD19 + CD27 + (memory) compared with CD19 + CD27 -(naive) cells. Furthermore, peripheral blood B cells were activated in vitro. Whereas B-cell activation with Staphylococcus aureus Cowan strain (SAC) did not increase telomere length, a striking telomere elongation was observed when cells were stimulated with SAC and interleukin 2 to induce plasma cell differentiation. Our observations support the concept that telomere dynamics in B cells are distinct from other haematopoietic cell lineages and that telomere elongation may play an essential role in the generation of long-term B memory cells.

ABSTRACT

The family of core-binding factors includes the DNA-binding subunits Runx1-3 and their common non-DNA-binding partner CBF␤. We examined the collective role of core-binding factors in hematopoiesis with a hypomorphic Cbfb allelic series. Reducing CBF␤ levels by 3-or 6-fold caused abnormalities in bone development, megakaryocytes, granulocytes, and T cells. T-cell development was very sensitive to an incremental reduction of CBF␤ levels: mature thymocytes were decreased in number upon a 3-fold reduction in CBF␤ levels, and were virtually absent when CBF␤ levels were 6-fold lower. Partially penetrant consecutive differentiation blocks were found among early T-lineage progenitors within the CD4 ؊ CD8 ؊ double-negative 1 and downstream double-negative 2 thymocyte subsets. Our data define a critical CBF␤ threshold for normal T-cell development, and situate an essential role for corebinding factors during the earliest stages of T-cell development. IntroductionHypomorphic alleles have long been known to cause developmental disorders in model organisms and in humans, and can reveal additional functions for genes in pathways that are completely obliterated when the gene's function is eliminated. For example, the many different spontaneous, chemically induced, and targeted mutant alleles of the Kit gene have illuminated c-kit's multiple roles in gametogenesis, melanogenesis, and hematopoiesis, and in the interstitial cells of Cajal. [1][2][3] Hypomorphic alleles can reveal differences in the requirements of certain developmental pathways for a protein's concentration, and help pinpoint lineage decisions that are influenced by that protein. Many mutations in cancercausing genes may cause a functional dosage reduction as part of their overall activity, and the study of hypomorphic alleles may allow an assessment of this contribution.In this study, we used a hypomorphic allele of the core-binding factor ␤ (Cbfb) gene to unveil new developmental requirements for all 3 core-binding factors. Core-binding factors (CBFs) are a small family of transcription factors consisting of a DNA-binding subunit encoded by the Runx1, Runx2, or Runx3 genes, and a common non-DNA-binding CBF␤ subunit. Runx1 is required for hematopoietic stem cell (HSC) emergence in the fetus, 4 and during postnatal hematopoiesis for megakaryocyte, B-, and T-lymphocyte development. [5][6][7] Runx1 participates in CD4 silencing during the CD4 Ϫ CD8 Ϫ double-negative (DN) and CD8 ϩ stages of T-cell development and is necessary at the DN2 to DN3 and DN3 to DN4 transitions. [5][6][7][8] Runx2 is required for bone formation, both for osteoblast differentiation and chondrocyte hypertrophy. [9][10][11][12] Runx3 contributes to the maturation of chondrocytes during bone formation 13 and is necessary for CD4 silencing at the CD8 ϩ stage of T-cell development, for Langerhans-cell development, and its deletion accelerates the maturation of dendritic cells resulting in an allergic airway inflammation. 7,8,14 We used a hypomorphic Cbfb allele in conjunction with a nonfunction...

BackgroundFasting is the most widely prescribed and self-imposed strategy for treating excessive weight gain and obesity, and has been shown to exert a number of beneficial effects. The aim of the present study was to determine the exact role of fasting and subsequent refeeding on fat distribution in mice.MethodsC57/BL6 mice fasted for 24 to 72 h and were then subjected to refeeding for 72 h. At 24, 48 and 72 h of fasting, and 12, 24, 48 and 72 h of refeeding, the mice were sacrificed, and serum and various adipose tissues were collected. Serum biochemical parameters, adipose tissue masses and histomorphological analysis of different depots were detected. MRNA was isolated from various adipose tissues, and the expressions of thermogenesis, visceral signature and lipid metabolism-related genes were examined. The phenotypes of adipose tissues between juvenile and adult mice subjected to fasting and refeeding were also compared.ResultsFasting preferentially consumed mesenteric fat mass and decreased the cell size of mesenteric depots; however, refeeding recovered the mass and morphology of inguinal adipose tissues preferentially compared with visceral depots. Thermogenesis-related gene expression in the inguinal WAT and interscapular BAT were suppressed. Mitochondrial biogenesis was affected by fasting in a depot-specific manner. Furthermore, a short period of fasting led to an increase in visceral signature genes (Wt1, Tcf21) in subcutaneous adipose tissue, while the expression of these genes decreased sharply as the fasting time increased. Additionally, lipogenesis-related markers were enhanced to a greater extent greater in subcutaneous depots compared with those in visceral adipose tissues by refeeding. Although similar phenotypic changes in adipose tissue were observed between juvenile mice and adult mice subjected to fasting and refeeding, the alterations appeared earlier and more sensitively in juvenile mice.ConclusionsFasting preferentially consumes lipids in visceral adipose tissues, whereas refeeding recovers lipids predominantly in subcutaneous adipose tissues, which indicated the significance of plasticity of adipose organs for fat distribution when subject to food deprivation or refeeding.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-016-0159-x) contains supplementary material, which is available to authorized users.

Remarkable progress has been achieved in the characterization and isolation of primitive hematopoietic stem cells (HSC). HSC represent a very small subset of hematopoietic cells and provide self-renewal, possess differentiation capacity and allow a constant supply of the entire hematopoietic cell spectrum. Until recently, CD34 has been used as a convenient marker for HSC, since CD34 ؉ cells have been shown to possess colony-forming potential in short-term assays, maintain long-term colony-forming potential in in vitro cultures and allow the expression and differentiation of blood cells from different hematopoietic lineages in in vivo models. Clinical and experimental protocols have targeted CD34 ؉ cells enriched by a variety of selection models and have readily used these for transplantation, purging and gene therapies and targets for future organ replacement. Recent studies in murine and human models, however, have indicated that CD34 ؊ HSC exist as well, which possess engraftment potential and distinct HSC characteristics. These studies challenge the dogma that HSC are uniformly found in the CD34 ؉ subset, and question whether primitive HSC are CD34 ؉ or CD34 ؊ . In this review, results on murine and human CD34 ؉ and CD34 ؊ HSC, differences between them and their possible interactions are examined.

Insulin promotes bone formation via a well-studied canonical signaling pathway. An adapter in this pathway, insulin-receptor substrate (IRS)-1, has been implicated in the diabetic osteopathy provoked by impaired insulin signaling. To further investigate IRS-1’s role in the bone metabolism, we generated Irs-1-deficient Irs-1smla/smla mice. These null mice developed a spontaneous mutation that led to an increase in trabecular thickness (Tb.Th) in 12-mo-old, but not in 2-mo-old mice. Analyses of the bone marrow stromal cells (BMSCs) from these mice revealed their differential expression of osteogenesis-related genes and miRNAs. The expression of miR-342, predicted and then proven to target the gene encoding collagen type Iα2 (COL1A2), was reduced in BMSCs derived from Irs-1-null mice. COL1A2 expression was then shown to be age dependent in osteoblasts and BMSCs derived from Irs-1smla/smla mice. After the induction of osteogenesis in BMSCs, miR-342 expression correlated inversely with that of Col1a2. Further, Col1a2-specific small interfering RNA (siRNA) reduced alkaline phosphatase (ALP) activity and inhibited BMSC differentiation into osteocyte-like cells, both in wild-type (WT) and Irs-1smla/smla mice. Conversely, in Irs-1smla/smla osteocytes overexpressing COL1A2, ALP-positive staining was stronger than in WT osteocytes. In summary, we uncovered a temporal regulation of BMSC differentiation/bone formation, controlled via Irs-1/miR-342 mediated regulation of Col1a2 expression.—Guo, Y., Tang, C.-Y., Man, X.-F., Tang, H.-N., Tang, J., Wang, F., Zhou, C.-L., Tan, S.-W., Feng, Y.-Z., Zhou, H.-D. Insulin receptor substrate-1 time-dependently regulates bone formation by controlling collagen Iα2 expression via miR-342.