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The transcription factor Foxm1 is essential for the quiescence and maintenance of hematopoietic stem cells

Nature Immunology volume 16, pages 810–818 (2015)Cite this article

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Abstract

Foxm1 is known as a typical proliferation-associated transcription factor. Here we found that Foxm1 was essential for maintenance of the quiescence and self-renewal capacity of hematopoietic stem cells (HSCs) in vivo in mice. Reducing expression of FOXM1 also decreased the quiescence of human CD34+ HSCs and progenitor cells, and its downregulation was associated with a subset of myelodysplastic syndrome (MDS). Mechanistically, Foxm1 directly bound to the promoter region of the gene encoding the receptor Nurr1 (Nr4a2; called 'Nurr1' here), inducing transcription, while forced expression of Nurr1 reversed the loss of quiescence observed in Foxm1-deficient cells in vivo. Thus, our studies reveal a previously unrecognized role for Foxm1 as a critical regulator of the quiescence and self-renewal of HSCs mediated at least in part by control of Nurr1 expression.

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Figure 1: Foxm1 loss leads to abnormal hematopoiesis.
Figure 2: Marked decrease in the size of HSC and HPC pools in Foxm1-deficient mice.
Figure 3: Depletion of Foxm1 decreases the self-renewal capacity of HSCs.
Figure 4: Foxm1-deficient HSCs have a significantly diminished repopulation capacity.
Figure 5: Deletion of Foxm1 leads to accumulation of cells in the S and G2-M phases of the cell cycle and loss of quiescence in HSCs and/or HPCs.
Figure 6: Genes and molecular pathways dysregulated in Foxm1-deficient HSCs.
Figure 7: Forced expression of Nurr1 'rescues' Foxm1 deletion–induced loss of quiescence in vivo.
Figure 8: Downregulation of FOXM1 is associated with a subset of patients with MDS with deletion of chromosome 5q, and reduced expression of FOXM1 in human primitive hematopoietic cells decreases quiescence.

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Acknowledgements

We thank M.A. Goodell (Baylor College of Medicine) for the plasmid MSCV-FlagNurr1. Supported by the US National Institutes of Health (RO1 CA140979 to Z.Q.).

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Authors and Affiliations

  1. Department of Medicine and Cancer Research Center, The University of Illinois Hospital and Health Sciences System, Chicago, Illinois, USA

    Yu Hou, Wen Li, Yue Sheng, Liping Li, Zhonghui Zhang, David Peace, John G Quigley, Wenshu Wu & Zhijian Qian

  2. Fudan University ZhongShan Hospital, Shanghai, China

    Liping Li & Tongyu Zhu

  3. Department of Medicine, Section of Gastroenterology, The University of Chicago, Chicago, Illinois, USA

    Yong Huang

  4. Department of Pharmocology, The University of Illinois Hospital and Health Sciences System, Chicago, Illinois, USA

    You-yang Zhao

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Contributions

Y.Ho., W.L., Y.S., L.L., Y.Hu. and Z.Z. performed research; T.Z., D.P., J.G.Q., W.W. and Y.Z. provided advice, reagents and/or analytic tools; Y.Ho. and Z.Q. designed the research and performed data analysis; and Y.Ho., D.P., J.G.Q. and Z.Q. wrote the paper.

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Correspondence to Zhijian Qian.

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Integrated supplementary information

Supplementary Figure 1 Foxm1 loss leads to bone marrow hypocellularity.

(a-b) Analysis of ablation of Foxm1 as determined by semiquantitative PCR analysis of genomic DNA (a) as well as qRT-PCR analysis of mRNAs (b) from BM cells from both Foxm1fl/fl Tie2-Cre and Foxm1fl/fl mice. (c) Histological analysis of hematoxylin and eosin-stained sternum from the representative Foxm1fl/fl Tie2-Cre and Foxm1fl/fl mice.

Supplementary Figure 2 Foxm1 loss leads to a decreased number of mature blood cells but does not interfere with lineage differentiation.

(a) Histograms represent the total number of myeloid cells (Mac-1+Gr-1+), B cells (B220+ IgM+), Megakaryocyte (CD41+) and Macrophage (F4/80+) in BM from Foxm1fl/fl Tie2-Cre and Foxm1fl/fl mice. Mean ± standard deviation (SD); n = 5. *, P<0.05. (b-e) Representative histograms show the frequency of myeloid cells (Mac-1+Gr+) (b), B cells (B220+IgM+) (c), Megakaryocyte (CD41+) (d) and Macrophage (F4/80+) (e) in BM from Foxm1fl/fl Tie2-Cre and Foxm1fl/fl mice. (f-i) The frequency and representative flow cytometric histograms of four differentiation stages of erythroblasts including R1 (CD71+Ter119–), R2 (CD71+Ter119+), R3 (CD71lowTer119+) and R4 (CD71–Ter119+) in BM cells (f,h) and spleen cells (g,i) from Foxm1fl/fl Tie2-Cre and Foxm1fl/fl mice at age of 6-8 weeks.

Supplementary Figure 3 Foxm1 is efficiently deleted in LSK cells from Foxm1fl/flMx1-Cre mice after injection of poly(I:C).

(a) Analysis of Foxm1 deletion as determined by semiquantitative PCR analysis of genomic DNA from LSK cells from Foxm1fl/fl Mx1-Cre and Foxm1fl/fl mice 3 weeks after 3 doses of pI-pC injection. (b) qRT-PCR analysis of mRNAs from LSK cells from both Foxm1fl/fl Mx1-Cre and Foxm1fl/fl mice 3 weeks after 3 doses of pI-pC injection. (c) The total number of BM cells were reduced in Foxm1fl/fl Mx1-Cre mice as compared to Foxm1fl/fl mice (n=5, P<0.05).

Supplementary Figure 4 Induction of Foxm1 deletion reduces HSC and HPC pools in Foxm1fl/flMx1-Cre chimeric mice.

(a) Comparison of engraftment frequency of Foxm1fl/fl Mx1-Cre (CD45.2+) or control Foxm1fl/fl BM cells (CD45.2+) in WT (CD45.1+) recipient mice by flow cytometric analysis of peripheral blood at 6 weeks after transplantation. (b) Total number of LSK, LSKCD34– and LT-HSC in BM from chimeric Foxm1fl/fl Mx1-Cre and Foxm1fl/fl mice at 6 weeks after pI-pC injection. (mean±SD, n=5). *, P<0.05. (c) Total number of HPC, CMP, GMP and MEP in BM from Foxm1fl/fl Mx1-Cre and Foxm1fl/fl chimeric mice at 6 weeks after pI-pC injection (mean±SD, n=5)*. P<0.05.

Supplementary Figure 5 Foxm1 deletion results in a decreased repopulation capacity but does not affect the lineage differentiation of BM cells.

(a-c) The ratio of donor-derived CD45.2+CD45.1– from Foxm1fl/flTie2-Cre or Foxm1fl/fl vs competitor-cell-derived CD45.1+CD45.2+ in myeloid cells, B cells, and T cells in PB from first and secondary recipient mice were analyzed (mean ± SD, n = 4-5). (d) Flow cytometric analysis of the frequency of LSK, LSK CD34– in the competitive repopulated recipient mice 4 months after secondary transplantation. (e) Flow cytometric analysis of CD45.2+CD45.1– and CD45.1+CD45.2+ cells in LSK and LSK CD34– stem cell–enriched population in the competitive repopulated recipient mice 4 months after secondary transplantation. Donor cells were from Foxm1fl/flTie2-Cre or Foxm1fl/fl. (f) Lineage differentiation in the recipient mice transplanted with BM cells from Foxm1fl/flTie2-Cre and Foxm1fl/fl chimeric mice. Histogram shows percentage of donor-derived (CD45.2+CD45.1–) myeloid cells (Gr-1+Mac+), B cells (B220+), and T cells (CD3+) in PB analyzed 4 months after the first and secondary transplantation (mean ± SD, n = 4-5).

Supplementary Figure 6 Induction of Foxm1 deletion alters cell-cycle progression in HSCs and HPCs from Foxm1fl/flMx1-Cre mice and chimeric Foxm1fl/flMx1-Cre mice.

(a-c) The histograms depicting the cell cycle profile of HPCs (a), LSK cells (b) and LT-HSCs (c) in Foxm1fl/fl Mx1-Cre and Foxm1fl/fl mice (mean±SD, n=3). *, P<0.05, **, P<0.005. (d) The histogram depicting cell cycle status of LSK cells in Foxm1fl/fl Mx1-Cre and Foxm1fl/fl mice (mean±SD, n= 5). *, P<0.05, **, P<0.005. (e-g) The histograms depicting the cell cycle profile of HPCs (e), LSK cells (f) and LT-HSCs (g) in chimeric Foxm1fl/fl Mx1-Cre and Foxm1fl/fl mice (mean±SD, n=5). *, P<0.05; **, P<0.005; ***, P<0.0005. (h) The histogram depicting cell cycle status of LSK cells in chimeric Foxm1fl/fl Mx1-Cre and Foxm1fl/fl mice (mean±SD, n= 5). *, P<0.05; **, P<0.005.

Supplementary Figure 7 Loss of Foxm1 increases the apoptosis of HPCs and LSK cells under stress.

(a) Histogram shows the mean frequency of apoptosis of HPCs and LSK cells from Foxm1fl/fl Tie2-Cre and Foxm1fl/fl mice (mean ± SD; n = 11). (b) Histogram shows the mean frequency of apoptosis of HPCs and LSK cells from Foxm1fl/fl Tie2-Cre and Foxm1fl/fl chimeric mice (mean ± SD; n = 5). *, P<0.05. (c) Histogram shows the mean frequency of apoptosis of HPCs and LSK cells from Foxm1fl/fl Mx1-Cre and Foxm1fl/fl chimeric mice. (mean ± SD; n = 5). *, P<0.05.

Supplementary Figure 8 Expression of the genes encoding p21 and p27 is upregulated by Nurr1 overexpression.

(a) Doxycycline-induced expression of Flag-Nurr1 in BM cells from the chimeric mice. The Flag-Nurr1 expression in BM cells was determined by Western Blot. The Foxm1△/△ BM cells expressing pLVX-Tet-On and pLVX-tight-puro-Nurr1 or pLVX-tight-puro or Foxm1fl/fl BM cells expressing pLVX-Tet-On and pLVX-tight-puro from chimeric mice received two-week-induction of Doxycyline. (b) qRT-PCR analysis of p21, p27 and p16 expression in LSK cells. The LSK cells, isolated from Foxm1fl/fl Tie2-Cre or control Foxm1fl/fl mice, were infected with MSCV-puro-Nurr1 or control vector and cultured with Stemspan medium with cytokines. The cells were treated with Puromycin for 2 days before analysis. Gene expression was initially normalized to Actb expression. Values represent the fold changes in gene expression relative to that in Foxm1fl/fl LSK cells expressing control vector. *, P<0.05.

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Hou, Y., Li, W., Sheng, Y. et al. The transcription factor Foxm1 is essential for the quiescence and maintenance of hematopoietic stem cells. Nat Immunol 16, 810–818 (2015). https://doi.org/10.1038/ni.3204

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