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Homeodomain Transcription Factor Meis1 Is a Critical Regulator of Adult Bone Marrow Hematopoiesis

Ariki, Reina, Morikawa, Satoru, Mabuchi, Yo, Suzuki, Sadafumi, Nakatake, Mayuka, Yoshioka, Kentaro, Hidano, Shinya, Nakauchi, Hiromitsu, Matsuzaki, Yumi, Nakamura, Takuro, Goitsuka, Ryo·2014·PLoS ONE
DOI 10.1371/journal.pone.0087646PMC PMC3911998
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Figure 1 Loss of Meis1 leads to a depletion of hematopoietic progenitor cells from the bone marrow. (A) Representative flow cytometric profiles of hematopoietic progenitor cell populations from Mx1-Cre + Meis1 fl/fl and control Meis1 fl/fl mice three weeks after poly(I:C) treatment. Gates used to identify progenitor populations are outlined, and rightward arrows within the plots indicate their relationship to subsequent plots showing the progenitor populations. Numbers adjacent to outlined areas indicate percentage of gated cells in total BM mononuclear cells. (B) Absolute numbers of the indicated cell populations per two femurs in poly(I:C)–treated Mx1-Cre + Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 4). (C) Representative flow cytometric profiles of lineage-committed cell populations. (D) Absolute numbers of the indicated cell populations per two femurs in poly(I:C)–treated Mx1-Cre + Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 4). Pro- and pre-B cells (B220low IgM−), immature B cells (B220low IgM+), mature B cells (B220+ IgM+), granulocytes (Gr-1+CD11b+), monocytes (Gr-1− CD11b+), proerythroblasts (I; Ter119low CD71high), basophilic erythroblast (II; Ter119high CD71high) and late erythroblasts (III; Ter119high CD71int and IV; Ter119high CD71low). *p<0.05 and **p<0.01.
Figure 1 Loss of Meis1 leads to a depletion of hematopoietic progenitor cells from the bone marrow. (A) Representative flow cytometric profiles of hematopoietic progenitor cell populations from Mx1-Cre + Meis1 fl/fl and control Meis1 fl/fl mice three weeks after poly(I:C) treatment. Gates used to identify progenitor populations are outlined, and rightward arrows within the plots indicate their relationship to subsequent plots showing the progenitor populations. Numbers adjacent to outlined areas indicate percentage of gated cells in total BM mononuclear cells. (B) Absolute numbers of the indicated cell populations per two femurs in poly(I:C)–treated Mx1-Cre + Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 4). (C) Representative flow cytometric profiles of lineage-committed cell populations. (D) Absolute numbers of the indicated cell populations per two femurs in poly(I:C)–treated Mx1-Cre + Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 4). Pro- and pre-B cells (B220low IgM−), immature B cells (B220low IgM+), mature B cells (B220+ IgM+), granulocytes (Gr-1+CD11b+), monocytes (Gr-1− CD11b+), proerythroblasts (I; Ter119low CD71high), basophilic erythroblast (II; Ter119high CD71high) and late erythroblasts (III; Ter119high CD71int and IV; Ter119high CD71low). *p<0.05 and **p<0.01.CC BY · PubMed Central
Figure 2 Loss of Meis1 causes profound defects in the HSC compartment. (A) Representative flow cytometric profiles of LSK cells in BM depleted of lineage-positive cells from Mx1-Cre + Meis1 fl/fl and control Meis1 fl/fl mice three weeks after poly(I:C) treatment. Gates used to identify LSK cell populations are outlined, and downward arrows indicate their relationship to subsequent histograms showing the expression of CD34 or Flt3 in these cell populations. Numbers in the histograms indicate percent events in each gate. (B) Absolute numbers of the indicated LSK cell populations per two femurs from poly(I:C)–treated Mx1-Cre+ Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 4). *p<0.05 and **p<0.01. (C) Representative flow cytometric profiles of side population (SP) cells within the LSK population from Mx1-Cre + Meis1 fl/fl and control mice one week after poly(I:C) treatment. Bar graphs shown on the right represent the percentage of SP cells in the LSK cell population from poly(I:C)–treated Mx1-Cre + Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 3). *p<0.005.
Figure 2 Loss of Meis1 causes profound defects in the HSC compartment. (A) Representative flow cytometric profiles of LSK cells in BM depleted of lineage-positive cells from Mx1-Cre + Meis1 fl/fl and control Meis1 fl/fl mice three weeks after poly(I:C) treatment. Gates used to identify LSK cell populations are outlined, and downward arrows indicate their relationship to subsequent histograms showing the expression of CD34 or Flt3 in these cell populations. Numbers in the histograms indicate percent events in each gate. (B) Absolute numbers of the indicated LSK cell populations per two femurs from poly(I:C)–treated Mx1-Cre+ Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 4). *p<0.05 and **p<0.01. (C) Representative flow cytometric profiles of side population (SP) cells within the LSK population from Mx1-Cre + Meis1 fl/fl and control mice one week after poly(I:C) treatment. Bar graphs shown on the right represent the percentage of SP cells in the LSK cell population from poly(I:C)–treated Mx1-Cre + Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 3). *p<0.005.CC BY · PubMed Central
Figure 3 Meis1 regulates self-renewal of HSCs in a cell autonomous manner. (A) Experimental strategy for analyzing the function of Meis1 in HSCs. Mice with chimeric BM were generated by transplanting CD34− LSK cells (50 cells/mouse) from Mx1-Cre + Meis1 fl/fl or control Meis1 fl/fl mice (CD45.2) and an equal number of CD34− LSK cells from wild-type mice (CD45.1/CD45.2) with CD45.1 BM supports cells in lethally irradiated CD45.1 recipient mice. A subset of mice was treated with poly(I:C) three months after transplantation. (B) Mean percentages of CD45.2+ cells ± SD in the peripheral blood derived from Meis1 fl/fl (n = 6; open circles) and Mx1-Cre+ Meis1 fl/fl (n = 6; closed circles) CD34− LSK cells after poly(I:C) treatment. Initial engraftment of CD45.2+ was normalized to 100% for each mouse. *p<0.05 and **p<0.01. (C) Histogram represents mean (± SD) contribution of the indicated splenic cell populations derived from Meis1 fl/fl (n = 6; open bars) and Mx1-Cre + Meis1 fl/fl (n = 6; solid bars) CD34− LSK cells three months after poly(I:C) treatment. *p<0.05 and **p<0.01. (D) Mean percentages of CD45.2+ cells ± SD in the peripheral blood derived from Meis1 fl/fl (n = 6; open circles) or Mx1-Cre+ Meis1 fl/fl (n = 6; closed circles) CD34− LSK cells after secondary transplantation. *p<0.05 and **p<0.01. (E) Total numbers (left) and proportions (right) of different colony types produced by CD34− LSK cells from poly(I:C)-treated Mx1-Cre+ Meis1 fl/fl and control Meis1 fl/fl mice (n = 3 per each group). Cultures were assessed on day 14 for granulocyte (CFU-G), monocytes (CFU-M), granulocyte-monocyte (CFU-GM), erythroid (BFU-E) and mixed (CFU-GEMM) colony formation. The data are the means of three-independent experiments. (F) Representative photographs of 14 day colonies derived from CD34− LSK cells from poly(I:C)-treated Mx1-Cre+ Meis1 fl/fl- and control Meis1 fl/fl mice (×40 magnification).
Figure 3 Meis1 regulates self-renewal of HSCs in a cell autonomous manner. (A) Experimental strategy for analyzing the function of Meis1 in HSCs. Mice with chimeric BM were generated by transplanting CD34− LSK cells (50 cells/mouse) from Mx1-Cre + Meis1 fl/fl or control Meis1 fl/fl mice (CD45.2) and an equal number of CD34− LSK cells from wild-type mice (CD45.1/CD45.2) with CD45.1 BM supports cells in lethally irradiated CD45.1 recipient mice. A subset of mice was treated with poly(I:C) three months after transplantation. (B) Mean percentages of CD45.2+ cells ± SD in the peripheral blood derived from Meis1 fl/fl (n = 6; open circles) and Mx1-Cre+ Meis1 fl/fl (n = 6; closed circles) CD34− LSK cells after poly(I:C) treatment. Initial engraftment of CD45.2+ was normalized to 100% for each mouse. *p<0.05 and **p<0.01. (C) Histogram represents mean (± SD) contribution of the indicated splenic cell populations derived from Meis1 fl/fl (n = 6; open bars) and Mx1-Cre + Meis1 fl/fl (n = 6; solid bars) CD34− LSK cells three months after poly(I:C) treatment. *p<0.05 and **p<0.01. (D) Mean percentages of CD45.2+ cells ± SD in the peripheral blood derived from Meis1 fl/fl (n = 6; open circles) or Mx1-Cre+ Meis1 fl/fl (n = 6; closed circles) CD34− LSK cells after secondary transplantation. *p<0.05 and **p<0.01. (E) Total numbers (left) and proportions (right) of different colony types produced by CD34− LSK cells from poly(I:C)-treated Mx1-Cre+ Meis1 fl/fl and control Meis1 fl/fl mice (n = 3 per each group). Cultures were assessed on day 14 for granulocyte (CFU-G), monocytes (CFU-M), granulocyte-monocyte (CFU-GM), erythroid (BFU-E) and mixed (CFU-GEMM) colony formation. The data are the means of three-independent experiments. (F) Representative photographs of 14 day colonies derived from CD34− LSK cells from poly(I:C)-treated Mx1-Cre+ Meis1 fl/fl- and control Meis1 fl/fl mice (×40 magnification).CC BY · PubMed Central
Figure 4 Meis1 regulates cell cycle of the HSC compartment. (A) Representative flow cytometric profiles showing Annexin V and 7-AAD staining of LSK cells from Mx1-Cre+ Meis1 fl/fl and control mice one week after poly(I:C) treatment. Bar graphs on the right represent the percentages of apoptotic LSK cells (anexin V+ 7-AAD−) cells from poly(I:C)–treated Mx1-Cre + Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 3). (B) Representative flow cytometric profiles showing BrdU incorporation and 7-AAD staining of LSK cells from Mx1-Cre Meis1 fl/fl and control mice one week after poly(I:C) treatment. Bar graphs shown on the right represent the percentages of cells in G0/G1-, S- and G2/M-phase of the cell cycle in the LSK cell population from poly(I:C)–treated Mx1-Cre + Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 3). **p<0.01.
Figure 4 Meis1 regulates cell cycle of the HSC compartment. (A) Representative flow cytometric profiles showing Annexin V and 7-AAD staining of LSK cells from Mx1-Cre+ Meis1 fl/fl and control mice one week after poly(I:C) treatment. Bar graphs on the right represent the percentages of apoptotic LSK cells (anexin V+ 7-AAD−) cells from poly(I:C)–treated Mx1-Cre + Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 3). (B) Representative flow cytometric profiles showing BrdU incorporation and 7-AAD staining of LSK cells from Mx1-Cre Meis1 fl/fl and control mice one week after poly(I:C) treatment. Bar graphs shown on the right represent the percentages of cells in G0/G1-, S- and G2/M-phase of the cell cycle in the LSK cell population from poly(I:C)–treated Mx1-Cre + Meis1 fl/fl (solid bars) and control Meis1 fl/fl (open bars) mice (mean and SD; n = 3). **p<0.01.CC BY · PubMed Central
Figure 5 Meis1 controls expression of genes involved in HSC cell cycle and maintenance. (A) Alterations of gene expression in LSK cells induced by Meis1 loss were analyzed by quantitative RT-PCR. Histograms show the indicated transcripts in sorted LSK cells from Mx1-Cre+ Meis1 fl/fl mice (open bars) and control Meis1 fl/fl mice (solid bars) one week post poly(I:C) treatment. Data were normalized to Gapdh expression and the level of each transcript in LSK cells from control mice was arbitrarily set to 1. Data are the means and standard deviations of three independent experiments. *p<0.05 and **p<0.01. (B) Models illustrating potential mechanisms of Meis1 function in the maintenance of HSC.
Figure 5 Meis1 controls expression of genes involved in HSC cell cycle and maintenance. (A) Alterations of gene expression in LSK cells induced by Meis1 loss were analyzed by quantitative RT-PCR. Histograms show the indicated transcripts in sorted LSK cells from Mx1-Cre+ Meis1 fl/fl mice (open bars) and control Meis1 fl/fl mice (solid bars) one week post poly(I:C) treatment. Data were normalized to Gapdh expression and the level of each transcript in LSK cells from control mice was arbitrarily set to 1. Data are the means and standard deviations of three independent experiments. *p<0.05 and **p<0.01. (B) Models illustrating potential mechanisms of Meis1 function in the maintenance of HSC.CC BY · PubMed Central

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Citations

Cites

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Metadata

Authors
Ariki, R., Morikawa, S., Mabuchi, Y., Suzuki, S., Nakatake, M., Yoshioka, K., Hidano, S., Nakauchi, H., Matsuzaki, Y., Nakamura, T., & Goitsuka, R.
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-02-03
Volume
9
Issue
2
Pages
e87646
ISSN
1932-6203
DOI
10.1371/journal.pone.0087646
PMC
PMC3911998
Cited by
53
References
5
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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