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. 2013 Mar 14;121(11):1986-94.
doi: 10.1182/blood-2012-05-433755. Epub 2013 Jan 11.

VSports注册入口 - The function of hematopoietic stem cells is altered by both genetic and inflammatory factors in lupus mice

Haitao Niu  1 , Guoqiang Fang, Yiting Tang, Luokun Xie, Huan Yang, Laurence Morel, Betty Diamond, Yong-Rui Zou
Affiliations

The function of hematopoietic stem cells is altered by both genetic and inflammatory factors in lupus mice (VSports手机版)

Haitao Niu et al. Blood. .

Abstract

Hematopoietic stem cells (HSCs) are protected in a metabolically dormant state within the bone marrow stem cell niche. Inflammation has been shown to disrupt HSC dormancy and cause multiple functional changes. Here, we investigated whether HSC functions were altered in systemic lupus erythematosus (SLE)-prone mice and whether this contributed to clinical manifestations of SLE. We found that HSCs were significantly expanded in lupus mice. The increase in HSC cellularity was caused by both genetic lupus risk factors and inflammatory cytokines in lupus mice. In addition, the inflammatory conditions of lupus led to HSC mobilization and lineage-biased hematopoiesis. Strikingly, these functionally altered HSCs possessed robust self-renewal capacity and exhibited repopulating advantages over wild-type HSCs. A single-nucleotide polymorphism in the cdkn2c gene encoding p18(INK4c) within a SLE susceptibility locus was found to account for reduced p18(INK4c) expression and the increase in HSC self-renewal capacity in lupus mice. Lupus HSCs with enhanced self-renewal capacity and resistance to stress may compete out transplanted healthy HSCs, thereby leading to relapses after HSC transplantation. VSports手机版.

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Figure 1
Figure 1
Lupus TC mice possess an expanded population of HSPCs with enhanced self-renewal capacity. (A) The total number of nucleated BM cells from lupus TC and age-matched B6 mice were enumerated. Each symbol shows data from 1 mouse. (B) Lineage-negative BM cells from lupus TC and B6 control mice are displayed by c-Kit and Sca-1 staining in the contour plots. The LSK population in the rectangular gate is shown with percentages ± SD. The absolute number of LSK cells (middle panel) and long-term HSCs (right panel) in the BM from each mouse is shown by each dot. ***P < .001; **P < .01. (C) Irradiated B6.SJL mice were engrafted with 2 × 106 BM cells of lupus TC or B6 mice, and analyzed for donor-derived LSK cells in the BM 4 to 5 months after transplantation. Each dot corresponds to the percentage of BM LSK cells in each mouse. (D) The frequencies of donor-derived peripheral blood leukocytes (PBL) in recipients at each round of serial transplantation are shown by gray bars representing the mean ± SD (n = 10). (E) Survival curve of recipient mice after quaternary transplantation with BM cells of B6 or lupus TC origin (B6, n = 20; TC, n = 25). BMT, bone marrow transplantation; ns, not significant.
Figure 2
Figure 2
Expansion of HSPCs with higher repopulating capacity occurs before lupus onset. Eight- to 10-week-old B6 and healthy TC mice were used for this study. (A) Percentages of LSK cells in the BM of B6 and TC mice are displayed as mean ± SD in contour plots. Right panel shows the total number of BM LSK cells with each dot symbolizing the value from 1 mouse. (B) B6 and TC mice were labeled with BrdU for 16 hours. The histogram shows a representative profile of BrdU staining of LSK cells. The percentage of BrdU+ cells in the BM LSK population in B6 and TC mice is shown by individual open and closed dots. (C) Competitive transplantation was done by transferring 106 BM cells from TC mice (CD45.2+) together with 106 BM cells from B6.SJL mice (CD45.1+) into irradiated B6.SJL F1 mice (CD45.1+). Hematopoietic repopulation by cotransferred TC and B6.SJL BM cells was analyzed 18 weeks after transplantation by determining the percentages of CD45 isotype expressing PBL. Each dot corresponds to the percentage of donor-derived BM LSK cells in each mouse. (D) The frequencies of donor-derived PBL in recipients at each round of serial transplantation are shown by gray bars representing the mean ± SD (n = 6). (E) An equal number of LSK cells purified from TC or B6 mice were cultured in medium containing 50 ng/mL stem cell factor, 10 ng/mL IL-6 and 10 ng/ml IL-3. Seven days later, cells were harvested and counted. A total of 106 cells derived from TC or B6 LSK cells were transferred into irradiated B6.SJL mice. Reconstitution was examined 10 months later. Left: Bars depict the number of total nucleated cells harvested from the 7-day culture. Right: Bars show the percentage of donor-derived PBL. Data are presented as mean ± SD (n = 4).
Figure 3
Figure 3
p18INK4c, which negatively regulates HSC repopulating potential, is undetectable in HSPCs from TC mice. (A) Quantitative RT-PCR analysis was performed with fluorescence-activated cell sorted LSK cells from 2 TC or B6 mice. cDNA input was normalized to the level of β-actin. Relative expression levels of each gene transcript in TC LSK cells relative to those in B6 controls are shown as the mean ± SD of 3 independent experiments. *P < .05; ***P < .001. (B) The relative expression level of p18INK4c in Lin− BM cells from BM chimeras engrafted with MSCV-p18 transduced BM cells (p18) is presented as fold induction compared with that detected in B6 Lin− BM cells (WT). ***P < .001, n = 3. (C) Peripheral engraftment was examined by fluorescence-activated cell sorting analysis with antibodies against CD45.1 and CD45.2. Percentages of donor (CD45.2) and recipient PBL (CD45.1) are indicated in the dot plots. Histograms show GFP expression within the donor population. (D) Left contour plots show the percentage of LSK cells in mice reconstituted with BM cells transduced with control MSCV retroviral vector (mock) or with MSCV-p18 vector (p18). Right contour plots show the chimerisms of the LSK population.
Figure 4
Figure 4
Disease conditions of lupus correlate with HSPC mobilization and lineage biased hematopoietic output. (A) Each symbol represents the number of LSK cells in the spleen of each mouse of indicated groups. (B) CFU assays were performed to evaluate relative frequencies of clonogenic HSPCs in total splenocytes of mice for indicated groups. Each symbol represents the value of 1 mouse. (C) Each symbol displays the absolute number of B220+ cells in the BM of mice for indicated groups. (D) Each symbol displays the absolute number of Gr1+ cells in the BM of mice for indicated groups. (E) Dot plots show fluorescence-activated cell sorting analysis of myeloid progenitors. The absolute numbers of GMPs in each mouse of indicated groups are shown by each symbol. *P < .05; ***P < .001. B6-O, old B6 mice at 10 months of age; B6-Y, young B6 mice at 8 to 10 weeks of age; TC-H, healthy TC mice at 8 to 10 weeks of age; TC-L, lupus TC mice at 10 months of age.
Figure 5
Figure 5
Production of proinflammatory cytokines is increased in lupus TC mice. (A) Serum levels of IL-6 were determined. Data were shown by symbols representing the value of each mouse. (B) Serum levels of IL-10 were shown by symbols representing the value of each mouse. (C) Expression levels of TNFα in BM cells were determined by qRT-PCR. cDNA input was normalized to the level of RNA polymerase IIa. Mean values ± SD obtained from at least 4 experiments are shown. (D) Expression levels of Mx1 in LSK cells measured by qRT-PCR are indicated as means ± SD (n = 3). *P < .05; **P < .01; ***P < .001. B6-O, old B6 mice at 10 months of age; B6-Y, young B6 mice at 8 to 10 weeks of age; TC-H, healthy TC mice at 8 to 10 weeks of age; TC-L, lupus TC mice at 10 months of age.
Figure 6
Figure 6
Increased levels of HMGB1 in the plasma of lupus TC mice can induce production of inflammatory cytokines by BM cells and promote myeloid development. (A) Levels of HMGB1 detected in the plasma of healthy and lupus TC mice. Each symbol shows data from 1 mouse. (B) B6 BM cells were cultured with or without 500 ng/mL HMGB1 for 24 hours. Relative expression levels of cytokines were quantified by qRT-PCR and are shown as the ratio of each gene transcript in the presence versus absence of HMGB1 after being normalized to the level of β-actin. (C) Hematopoietic cytokines in the methylcellulose-based medium were diluted to establish a suboptimal condition (10% MethoCult M3434) under which the number of CFU reduced to approximately 50% of those formed in the optimal medium (100% MethoCult M3434). Colonies formed under the suboptimal condition with serum from lupus TC mice or with different doses of HMGB1 were counted at day 14 of culture and presented as bars with mean ± SD from 3 independent experiments. *P < .05; **P < .01.
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