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Pten loss in the bone marrow leads to G-CSF–mediated HSC mobilization

Tesio, Melania, Oser, Gabriela M., Baccelli, Irène, Blanco-Bose, William, Wu, Hong, Göthert, Joachim R., Kogan, Scott C., Trumpp, Andreas·2013·Journal of Experimental Medicine
DOI 10.1084/jem.20122768PMC PMC3804947
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Abstract

The phosphatase and tumor suppressor PTEN inhibits the phosphoinositol-3-kinase (PI3K) signaling pathway and plays a key role in cell growth, proliferation, survival, and migration. Pten conditional deletion using MxCre or Scl-CreERT leads to splenomegaly and leukemia formation, which occurs after the relocation of normal hematopoietic stem cells (HSCs) from the bone marrow to the spleen. Unexpectedly, dormant HSCs in the bone marrow do not enter the cell cycle upon Pten loss, they do not lose self-renewal activity, and they are not exhausted. Instead, Pten deficiency causes an up-regulation of the PI3K pathway in myeloid cells, but not in HSCs. Strikingly, myeloid cells secrete high levels of G-CSF upon Pten loss, leading to the mobilization of HSCs from the bone marrow and accumulation in the spleen. After deletion of Pten in mice lacking G-CSF, the splenomegaly, myeloproliferative disease, and splenic HSC accumulation are rescued. Our data show that although PTEN has little if any role in normal HSCs, it is essential to prevent overt G-CSF production by myeloid and stromal cells which otherwise causes HSCs to relocate to the spleen followed by lethal leukemia initiation.

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Figures

Figure 1. Conditional elimination of the ptenflox allele in the hematopoietic system using SCL-CreERT and Mx-Cre. (A) Schematic diagram of the two conditional KO approaches and description about the tissue-specific recombination efficiency (right); +, >90%; ○, <50%. (B) Western blot showing the efficiency of Pten elimination in BM and spleen. (C) Analysis of PTEN expression in sections of bone and spleen using immunohistochemistry. Representative figures (bone, 1 cm = 250 µM; spleen, 1 cm = 500 µM) are shown. The data presented are representative of least three different independent experiments.
Figure 1. Conditional elimination of the ptenflox allele in the hematopoietic system using SCL-CreERT and Mx-Cre. (A) Schematic diagram of the two conditional KO approaches and description about the tissue-specific recombination efficiency (right); +, >90%; ○, <50%. (B) Western blot showing the efficiency of Pten elimination in BM and spleen. (C) Analysis of PTEN expression in sections of bone and spleen using immunohistochemistry. Representative figures (bone, 1 cm = 250 µM; spleen, 1 cm = 500 µM) are shown. The data presented are representative of least three different independent experiments.CC BY-NC-SA · PubMed Central
Figure 2. Elimination of Pten using SCL-CreERT causes premature lethality. (A) Kaplan-Meyer analysis showing lethality upon Pten deletion in PtenΔMx and PtenΔScl mice. P < 0.05. n = 6 mice each group. (B) Hematoxylin & Eosin (H&E)–stained histological sections of bone and spleen showing MPD in the spleen and granulocytic hyperplasia in the bone. R, red pulp; W, white pulp. Bars: (spleen) 200 µm; (bone) 20 µm. (C) Splenomegaly in PtenΔMx and PtenΔScl mice 4 and 7 wk after deletion, respectively. (D) Splenic CD11b+Gr-1+ cells in control or PtenΔScl mice. Three independent experiments, n = 7 controls and n = 6 mutants. ** indicates statistically significant change, P = 0.001. (E) Splenic CD11b+Gr-1+ cells in control or PtenΔMx mice. Three independent experiments, n = 8 each group. P = 0.029. (F–H) Pten, pAktTh308, pAktSer473, and pGSK3βSer9 levels in BM (top) and splenic (bottom) CD11b+Gr-1+ cells of PtenΔMx and control counterparts pI-pC injected for 15 d. Data were obtained using a detergent-based protocol (Cytofix/Cytoperm; BD). A representative FACS plot (F) and the fold change in the expression levels (G and H) are shown. Three independent experiments, n = 6 controls and n = 4 mutants. P < 0.05 for all stainings of BM and spleen. (I–K) Pten, pAktTh308, pAktSer473, and pGSK3βSer9 levels in BM (top) and splenic (bottom) CD11b+Gr-1+ cells of PtenΔScl and control counterparts fed with Tx diet for 28 d. Data were obtained using a detergent-based protocol (Cytofix/Cytoperm). A representative FACS plot (I) and the fold change in the expression levels (J and K) are shown. Three independent experiments, n = 6 each group. P < 0.05 for all stainings of BM and spleen. Data are provided as mean ± SE. Unless otherwise indicated, * indicates statistically significant change with P < 0.05.
Figure 2. Elimination of Pten using SCL-CreERT causes premature lethality. (A) Kaplan-Meyer analysis showing lethality upon Pten deletion in PtenΔMx and PtenΔScl mice. P < 0.05. n = 6 mice each group. (B) Hematoxylin & Eosin (H&E)–stained histological sections of bone and spleen showing MPD in the spleen and granulocytic hyperplasia in the bone. R, red pulp; W, white pulp. Bars: (spleen) 200 µm; (bone) 20 µm. (C) Splenomegaly in PtenΔMx and PtenΔScl mice 4 and 7 wk after deletion, respectively. (D) Splenic CD11b+Gr-1+ cells in control or PtenΔScl mice. Three independent experiments, n = 7 controls and n = 6 mutants. ** indicates statistically significant change, P = 0.001. (E) Splenic CD11b+Gr-1+ cells in control or PtenΔMx mice. Three independent experiments, n = 8 each group. P = 0.029. (F–H) Pten, pAktTh308, pAktSer473, and pGSK3βSer9 levels in BM (top) and splenic (bottom) CD11b+Gr-1+ cells of PtenΔMx and control counterparts pI-pC injected for 15 d. Data were obtained using a detergent-based protocol (Cytofix/Cytoperm; BD). A representative FACS plot (F) and the fold change in the expression levels (G and H) are shown. Three independent experiments, n = 6 controls and n = 4 mutants. P < 0.05 for all stainings of BM and spleen. (I–K) Pten, pAktTh308, pAktSer473, and pGSK3βSer9 levels in BM (top) and splenic (bottom) CD11b+Gr-1+ cells of PtenΔScl and control counterparts fed with Tx diet for 28 d. Data were obtained using a detergent-based protocol (Cytofix/Cytoperm). A representative FACS plot (I) and the fold change in the expression levels (J and K) are shown. Three independent experiments, n = 6 each group. P < 0.05 for all stainings of BM and spleen. Data are provided as mean ± SE. Unless otherwise indicated, * indicates statistically significant change with P < 0.05.CC BY-NC-SA · PubMed Central
Figure 3. Elimination of Pten using SCL-CreERT induces leukemia. (A) H&E-stained histological sections of livers from PtenΔMx, PtenΔScl, or control mice. (B) Frequency of tumors in NOD/SCID mice after transplantation of 106 BM cells of sick PtenΔScl mice and PtenΔMx, n = 5 and n = 11, respectively. Data are provided as mean ± SE. (C) FACS profile showing CD4 and CD8 expression in the BM of a control NOD/SCID mouse (left) and a PtenΔScl transplanted NOD/SCID mouse (right). (D) H&E-stained histological sections of bone, spleen, and liver of a typical PtenΔScl mouse showing T-ALL.
Figure 3. Elimination of Pten using SCL-CreERT induces leukemia. (A) H&E-stained histological sections of livers from PtenΔMx, PtenΔScl, or control mice. (B) Frequency of tumors in NOD/SCID mice after transplantation of 106 BM cells of sick PtenΔScl mice and PtenΔMx, n = 5 and n = 11, respectively. Data are provided as mean ± SE. (C) FACS profile showing CD4 and CD8 expression in the BM of a control NOD/SCID mouse (left) and a PtenΔScl transplanted NOD/SCID mouse (right). (D) H&E-stained histological sections of bone, spleen, and liver of a typical PtenΔScl mouse showing T-ALL.CC BY-NC-SA · PubMed Central
Figure 4. Phenotypic and functional analysis of Pten-deficient HSCs. (A) Kinetic analysis of the relative change of LSKCD34−CD135− cells in the BM of PtenΔMx and PtenΔScl mice compared with controls (set to 100%). The asterisk indicates statistical significant change (P < 0.05). The cross indicates that the majority of mice do not survive beyond this time point. Each dot represents the mean value obtained from three to four mice. (B) FACS plots (top) and bar graph (bottom) showing the percentage of BrdU+ cells within the LSKCD135− population in BM and spleen after 90 min and in BM after 18 h of BrdU labeling. P = 0.99, P = 0.19, and P = 0.75, respectively. (C) Percentage of BrdU LRCs within the LSKCD34−CD135−population. Mice were initially labeled for 10 d with BrdU, followed by simultaneous induction of SCL-CreERT with Tx and 70 d of a BrdU free chase period. P = 0.02. Each dot represents a single mouse. Horizontal bars indicate mean values. (D) Kaplan-Meyer curve showing the survival of PtenΔMx and PtenΔScl mice (15 d [Mx] or 21 d [Scl] after deletion) during weekly 5-FU administration. n = 7 PtenΔMxmice, n = 4 PtenΔScl mice, n = 4 of each control group. (E) Analysis of intracellular Ki67 expression in LSKCD135− cells from BM (top, P = 0.43) and spleen (bottom, P = 0.81) of ptenΔMx mice. (F) Kinetic analysis of the relative change of LSKCD34−CD135− cells in the spleen of PtenΔMx and PtenΔScl mice compared with controls (set to 100%). The asterisk indicates statistically significant change (P < 0.05). The cross indicates that the majority of mice do not survive beyond this time point. Each dot represents the mean value obtained from three to four mice. (G) Bar graph showing CD45.2 donor contribution 5, 7, and 9 wk after transplantation of 0.4% of total BM and 1.6% of total splenocytes of control and PtenΔMx mice into CD45.1 hosts. n = 4 each group. (H) Limiting dilution analysis of BM cells (top) and splenocytes (bottom) of ptenΔMx (KO) and control (wt) mice. Values represent reconstituted mice (chimerism > 0.5%) versus total mice transplanted. CRUs were calculated using the method of maximum likelihood. The number of mice per group is indicated. (I) Percentage of CD45.2 donor contribution 12 wk after transplantation of 2500 LSK cells of control and PtenΔMx mice into CD45.1 hosts. (J and K) Multilineage reconstitution after transplantation of 2500 BM (J) or splenic (K) LSK cells from ptenΔMx mice. n = 2 controls, n = 3 mutants. (L) PCR analysis of DNA from FACS-sorted donor (CD45.2) splenocytes 12 wk after transplantation showing the absence of the Ptenflox but presence of the PtenΔ allele. (M–O) Pten, pAktTh308, pAktSer473, and pGSK3βSer9 levels in BM LSKCD135−CD34− (top) or splenic LSK cells (bottom) of PtenΔMx and controls (pI-pC treated). A representative FACS plot (M) and the fold change in the expression levels (N and O) are shown. Three independent experiments, n = 6 for each group. BM: P = 0.01 Pten, P > 0.05 pAktTh308, pAktSer473, and pGSK3βSer9. Spleen: P = 0.04 Pten, P > 0.05 pAktTh308, pAktSer473, and pGSK3βSer9. Unless otherwise indicated, the data presented in this figure refer to at least three independent experiments using at least three mice per group. Data are provided as mean ± SE.
Figure 4. Phenotypic and functional analysis of Pten-deficient HSCs. (A) Kinetic analysis of the relative change of LSKCD34−CD135− cells in the BM of PtenΔMx and PtenΔScl mice compared with controls (set to 100%). The asterisk indicates statistical significant change (P < 0.05). The cross indicates that the majority of mice do not survive beyond this time point. Each dot represents the mean value obtained from three to four mice. (B) FACS plots (top) and bar graph (bottom) showing the percentage of BrdU+ cells within the LSKCD135− population in BM and spleen after 90 min and in BM after 18 h of BrdU labeling. P = 0.99, P = 0.19, and P = 0.75, respectively. (C) Percentage of BrdU LRCs within the LSKCD34−CD135−population. Mice were initially labeled for 10 d with BrdU, followed by simultaneous induction of SCL-CreERT with Tx and 70 d of a BrdU free chase period. P = 0.02. Each dot represents a single mouse. Horizontal bars indicate mean values. (D) Kaplan-Meyer curve showing the survival of PtenΔMx and PtenΔScl mice (15 d [Mx] or 21 d [Scl] after deletion) during weekly 5-FU administration. n = 7 PtenΔMxmice, n = 4 PtenΔScl mice, n = 4 of each control group. (E) Analysis of intracellular Ki67 expression in LSKCD135− cells from BM (top, P = 0.43) and spleen (bottom, P = 0.81) of ptenΔMx mice. (F) Kinetic analysis of the relative change of LSKCD34−CD135− cells in the spleen of PtenΔMx and PtenΔScl mice compared with controls (set to 100%). The asterisk indicates statistically significant change (P < 0.05). The cross indicates that the majority of mice do not survive beyond this time point. Each dot represents the mean value obtained from three to four mice. (G) Bar graph showing CD45.2 donor contribution 5, 7, and 9 wk after transplantation of 0.4% of total BM and 1.6% of total splenocytes of control and PtenΔMx mice into CD45.1 hosts. n = 4 each group. (H) Limiting dilution analysis of BM cells (top) and splenocytes (bottom) of ptenΔMx (KO) and control (wt) mice. Values represent reconstituted mice (chimerism > 0.5%) versus total mice transplanted. CRUs were calculated using the method of maximum likelihood. The number of mice per group is indicated. (I) Percentage of CD45.2 donor contribution 12 wk after transplantation of 2500 LSK cells of control and PtenΔMx mice into CD45.1 hosts. (J and K) Multilineage reconstitution after transplantation of 2500 BM (J) or splenic (K) LSK cells from ptenΔMx mice. n = 2 controls, n = 3 mutants. (L) PCR analysis of DNA from FACS-sorted donor (CD45.2) splenocytes 12 wk after transplantation showing the absence of the Ptenflox but presence of the PtenΔ allele. (M–O) Pten, pAktTh308, pAktSer473, and pGSK3βSer9 levels in BM LSKCD135−CD34− (top) or splenic LSK cells (bottom) of PtenΔMx and controls (pI-pC treated). A representative FACS plot (M) and the fold change in the expression levels (N and O) are shown. Three independent experiments, n = 6 for each group. BM: P = 0.01 Pten, P > 0.05 pAktTh308, pAktSer473, and pGSK3βSer9. Spleen: P = 0.04 Pten, P > 0.05 pAktTh308, pAktSer473, and pGSK3βSer9. Unless otherwise indicated, the data presented in this figure refer to at least three independent experiments using at least three mice per group. Data are provided as mean ± SE.CC BY-NC-SA · PubMed Central
Figure 5. Pten loss mobilizes HSCs in a hematopietic cell–autonomous manner. (A) Experimental setup used to generate reverse chimeras. (B) PTEN expression in BM stromal cells by Western blot. (C) Percentage of donor-derived wild-type LSK cells isolated from control and MxCre;ptenΔ hosts. black, co-host; blue, MxCre;ptenΔ host. P > 0.05. n = 3 MxCre;ptenΔ, n = 3 control mice. (D) Percentages of donor-derived wild-type mature granulocytes, B cells, and CD4 T cells in spleens isolated from control and MxCre;ptenΔ hosts. P > 0.05. n = 3 MxCre;ptenΔ, n = 3 control mice. Data are provided as mean ± SE.
Figure 5. Pten loss mobilizes HSCs in a hematopietic cell–autonomous manner. (A) Experimental setup used to generate reverse chimeras. (B) PTEN expression in BM stromal cells by Western blot. (C) Percentage of donor-derived wild-type LSK cells isolated from control and MxCre;ptenΔ hosts. black, co-host; blue, MxCre;ptenΔ host. P > 0.05. n = 3 MxCre;ptenΔ, n = 3 control mice. (D) Percentages of donor-derived wild-type mature granulocytes, B cells, and CD4 T cells in spleens isolated from control and MxCre;ptenΔ hosts. P > 0.05. n = 3 MxCre;ptenΔ, n = 3 control mice. Data are provided as mean ± SE.CC BY-NC-SA · PubMed Central
Figure 6. Increased level of mobilizing cytokines in ptenΔMx and ptenΔScl mice. (A and B) FACS plot (A) and histogram showing GCSF expression in BM CD11b+Gr-1+ cells of control and PtenΔMx mice. Two independent experiments were done for controls (n = 7) and mutants (n = 8; *** indicates statistically significant change, P = 0.0008). (C) Cytokine array screen showing serum levels of indicated cytokines 15 d (PtenΔMx) or 28 d (PtenΔScl) after deletion. This screen has been performed once with n = 2 per group. (D) MCP-5 and IL-9 levels in splenic Gr-1high/CD115− and CD4+CD8+ cells or BM CD11b+Gr-1+ and CD4+CD8+ cells of PtenΔScl mice and control counterparts. Data are shown as fold change as compared with control levels. P = 0.01, MCP-5 in Gr-1high/CD115− cells. P = 0.007, MCP-5 in CD4+CD8+ cells. P = 0.03, IL-9 in BM CD4+CD8+ cells. P = 0.04, IL-9 in BM CD11b+Gr-1+ cells. Three independent experiments were performed, n = 11 controls and n = 6 mutants. (E) CXCL-12 levels observed in osteoblasts (CD45−CD31−Ter119−CD51+Sca-1− cells) and endothelial cells (CD45−Ter119−CD31+) of PtenΔMx mice and controls. Data are shown as fold change as compared with control levels. Two independent experiments (5 controls and 10 mutants) were performed. P < 0.01, osteoblasts, P < 0.05 endothelial cells. Data are provided as mean ± SE. Unless otherwise indicated, * indicates statistically significant change with P < 0.05.
Figure 6. Increased level of mobilizing cytokines in ptenΔMx and ptenΔScl mice. (A and B) FACS plot (A) and histogram showing GCSF expression in BM CD11b+Gr-1+ cells of control and PtenΔMx mice. Two independent experiments were done for controls (n = 7) and mutants (n = 8; *** indicates statistically significant change, P = 0.0008). (C) Cytokine array screen showing serum levels of indicated cytokines 15 d (PtenΔMx) or 28 d (PtenΔScl) after deletion. This screen has been performed once with n = 2 per group. (D) MCP-5 and IL-9 levels in splenic Gr-1high/CD115− and CD4+CD8+ cells or BM CD11b+Gr-1+ and CD4+CD8+ cells of PtenΔScl mice and control counterparts. Data are shown as fold change as compared with control levels. P = 0.01, MCP-5 in Gr-1high/CD115− cells. P = 0.007, MCP-5 in CD4+CD8+ cells. P = 0.03, IL-9 in BM CD4+CD8+ cells. P = 0.04, IL-9 in BM CD11b+Gr-1+ cells. Three independent experiments were performed, n = 11 controls and n = 6 mutants. (E) CXCL-12 levels observed in osteoblasts (CD45−CD31−Ter119−CD51+Sca-1− cells) and endothelial cells (CD45−Ter119−CD31+) of PtenΔMx mice and controls. Data are shown as fold change as compared with control levels. Two independent experiments (5 controls and 10 mutants) were performed. P < 0.01, osteoblasts, P < 0.05 endothelial cells. Data are provided as mean ± SE. Unless otherwise indicated, * indicates statistically significant change with P < 0.05.CC BY-NC-SA · PubMed Central
Figure 7. In the absence of G-CSF, the Pten mutant phenotype is rescued. (A) Spleens of Ptenfl/fl, Ptenfl/fl;G-CSF−/−, PtenΔMx;G-CSF−/−, or PtenΔMx;G-CSF+/+ 15 d after deletion. (B) Splenic cellularity of Ptenfl/fl, Ptenfl/fl;G-CSF−/−, PtenΔMx;G-CSF−/−, or PtenΔMx;G-CSF+/+ 15 d after deletion. Ptenfl/fl versus PtenΔMx;G-CSF+/+, P = 0.02. PtenΔMx;G-CSF+/+ versus PtenΔMx;G-CSF−/−, P = 0.04. Ptenfl/fl versus Ptenfl/fl G-CSF−/−, P = 0.36. (B–E) Four independent experiments, n = 7 each group. (C and D) Percentages of CD11b+Gr-1+ cells in the spleens of Ptenfl/fl, Ptenfl/fl;G-CSF−/−, PtenΔMx;G-CSF−/−, or PtenΔMx;G-CSF+/+ 15 d after deletion. Ptenfl/fl versus PtenΔMx;G-CSF+/+, P = 0.01. PtenΔMx;G-CSF+/+ versus PtenΔMx;G-CSF−/−, P = 0.01. Ptenfl/fl versus Ptenfl/fl G-CSF−/−, P = 0.29. (E) Relative changes in splenic LSKCD34−CD135− levels. Ptenfl/fl versus PtenΔMx;G-CSF+/+, P = 0.04. PtenΔMx;G-CSF+/+ versus PtenΔMx;G-CSF−/−, P = 0.04. Ptenfl/fl versus Ptenfl/fl G-CSF−/−, P = 0.07. (F) Spleens of PtenΔMx;G-CSF−/− or PtenΔScl;G-CSF+/+ mice or their control counterpart Ptenfl/fl and or Ptenfl/fl;G-CSF−/− after 28 d of Tx diet. (G) Splenic cellularity of PtenΔMx;G-CSF−/− or PtenΔScl;G-CSF+/+ mice or their control counterpart Ptenfl/fl and or Ptenfl/fl;G-CSF−/− after 28 d of Tx diet. Ptenfl/fl versus PtenΔscl;G-CSF+/+, P = 0.026. PtenΔScl;G-CSF+/+ versus PtenΔScl;G-CSF−/−, P = 0.047. Five independent experiments, n = 10 each group. (H and I) CD11b+Gr-1+ cells in the spleens of PtenΔScl;G-CSF−/−, PtenΔScl;G-CSF+/+, Ptenfl/fl, or Ptenfl/fl;G-CSF−/− mice which were fed with Tx for 28 d. A representative FACS plot and a histogram are shown in E and G, respectively. Ptenfl/fl versus PtenΔscl;G-CSF+/+, P = 0.029. PtenΔScl;G-CSF+/+ versus PtenΔScl;G-CSF−/−, P = 0.002. Three independent experiments are shown, n = 7 each group (H and K). (J) Relative changes in the levels of LSKCD34−CD135− in the BM and spleen of PtenΔScl;G-CSF−/−, PtenΔScl;G-CSF+/+, Ptenfl/fl, or Ptenfl/fl;G-CSF−/− mice. Ptenfl/fl versus PtenΔscl;G-CSF+/+, P = 0.036. PtenΔScl;G-CSF+/+ versus PtenΔScl;G-CSF−/−, P = 0.042. (K) Relative changes in the levels of LSKCD34−CD135− in the BM and spleen of PtenΔScl;G-CSF−/−, PtenΔScl;G-CSF+/+, Ptenfl/fl, or Ptenfl/fl;G-CSF−/− mice. Ptenfl/fl versus PtenΔscl;G-CSF+/+, P = 0.037. PtenΔScl;G-CSF+/+ versus PtenΔScl;G-CSF−/−, P = 0.16. Data are provided as mean ± SE. Unless otherwise indicated, * indicates statistically significant change with P < 0.05.
Figure 7. In the absence of G-CSF, the Pten mutant phenotype is rescued. (A) Spleens of Ptenfl/fl, Ptenfl/fl;G-CSF−/−, PtenΔMx;G-CSF−/−, or PtenΔMx;G-CSF+/+ 15 d after deletion. (B) Splenic cellularity of Ptenfl/fl, Ptenfl/fl;G-CSF−/−, PtenΔMx;G-CSF−/−, or PtenΔMx;G-CSF+/+ 15 d after deletion. Ptenfl/fl versus PtenΔMx;G-CSF+/+, P = 0.02. PtenΔMx;G-CSF+/+ versus PtenΔMx;G-CSF−/−, P = 0.04. Ptenfl/fl versus Ptenfl/fl G-CSF−/−, P = 0.36. (B–E) Four independent experiments, n = 7 each group. (C and D) Percentages of CD11b+Gr-1+ cells in the spleens of Ptenfl/fl, Ptenfl/fl;G-CSF−/−, PtenΔMx;G-CSF−/−, or PtenΔMx;G-CSF+/+ 15 d after deletion. Ptenfl/fl versus PtenΔMx;G-CSF+/+, P = 0.01. PtenΔMx;G-CSF+/+ versus PtenΔMx;G-CSF−/−, P = 0.01. Ptenfl/fl versus Ptenfl/fl G-CSF−/−, P = 0.29. (E) Relative changes in splenic LSKCD34−CD135− levels. Ptenfl/fl versus PtenΔMx;G-CSF+/+, P = 0.04. PtenΔMx;G-CSF+/+ versus PtenΔMx;G-CSF−/−, P = 0.04. Ptenfl/fl versus Ptenfl/fl G-CSF−/−, P = 0.07. (F) Spleens of PtenΔMx;G-CSF−/− or PtenΔScl;G-CSF+/+ mice or their control counterpart Ptenfl/fl and or Ptenfl/fl;G-CSF−/− after 28 d of Tx diet. (G) Splenic cellularity of PtenΔMx;G-CSF−/− or PtenΔScl;G-CSF+/+ mice or their control counterpart Ptenfl/fl and or Ptenfl/fl;G-CSF−/− after 28 d of Tx diet. Ptenfl/fl versus PtenΔscl;G-CSF+/+, P = 0.026. PtenΔScl;G-CSF+/+ versus PtenΔScl;G-CSF−/−, P = 0.047. Five independent experiments, n = 10 each group. (H and I) CD11b+Gr-1+ cells in the spleens of PtenΔScl;G-CSF−/−, PtenΔScl;G-CSF+/+, Ptenfl/fl, or Ptenfl/fl;G-CSF−/− mice which were fed with Tx for 28 d. A representative FACS plot and a histogram are shown in E and G, respectively. Ptenfl/fl versus PtenΔscl;G-CSF+/+, P = 0.029. PtenΔScl;G-CSF+/+ versus PtenΔScl;G-CSF−/−, P = 0.002. Three independent experiments are shown, n = 7 each group (H and K). (J) Relative changes in the levels of LSKCD34−CD135− in the BM and spleen of PtenΔScl;G-CSF−/−, PtenΔScl;G-CSF+/+, Ptenfl/fl, or Ptenfl/fl;G-CSF−/− mice. Ptenfl/fl versus PtenΔscl;G-CSF+/+, P = 0.036. PtenΔScl;G-CSF+/+ versus PtenΔScl;G-CSF−/−, P = 0.042. (K) Relative changes in the levels of LSKCD34−CD135− in the BM and spleen of PtenΔScl;G-CSF−/−, PtenΔScl;G-CSF+/+, Ptenfl/fl, or Ptenfl/fl;G-CSF−/− mice. Ptenfl/fl versus PtenΔscl;G-CSF+/+, P = 0.037. PtenΔScl;G-CSF+/+ versus PtenΔScl;G-CSF−/−, P = 0.16. Data are provided as mean ± SE. Unless otherwise indicated, * indicates statistically significant change with P < 0.05.CC BY-NC-SA · PubMed Central

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Cited by

See all 35

Metadata

Authors
Tesio, M., Oser, G. M., Baccelli, I., Blanco-Bose, W., Wu, H., Göthert, J. R., Kogan, S. C., & Trumpp, A.
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2013-10-14
Volume
210
Issue
11
Pages
2337-2349
ISSN
  • 1540-9538
  • 0022-1007
DOI
10.1084/jem.20122768
PMC
PMC3804947
Cited by
35
References
11
Language
en

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