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p19 INK4d controls hematopoietic stem cells in a cell-autonomous manner during genotoxic stress and through the microenvironment during aging.

Hilpert M, Legrand C, Bluteau D, Balayn N, Betems A, Bluteau O, Villeval JL, Louache F, Gonin P, Debili N, Plo I, Vainchenker W, Gilles L, Raslova H - Stem Cell Reports (2014)

Bottom Line: We demonstrate that p19(INK4d) is involved in the regulation of HSC quiescence by inhibition of the G0/G1 cell cycle transition.Deletion of p19(INK4d) results in megakaryocyte hyperproliferation and increased transforming growth factor β1 secretion.This leads to fibrosis in the bone marrow and spleen, followed by loss of HSCs during aging.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France; University Paris Diderot, 5 rue Thomas-Mann, 75205 Paris, France.

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p19INK4d−/− Mice Exhibit a Defect in the HSC Compartment(A) mRNA expression level of p19INK4d in different populations of C57BL/6 and C57BL/6-Sv129j mice: SLAM (Lin−SCA1+C-KIT+CD48−CD150+), LSK, myeloid progenitors (Lin−SCA1−C-KIT+), CLP (Lin−SCA1lowC-KITlowCD127+THY-1−), CMP (Lin−SCA1−C-KIT+FCγR−CD34+), GMP (Lin−SCA1−C-KITt+FCγR+CD34+), and MEP (Lin−SCA1−C-KIT+FCγR−CD34−). Each population represents a pool derived from 10 mice. Data are normalized to HPRT transcript levels and represent the mean ± SEM of triplicates.(B) BM cellularity (n = 10).(C–E) Immunophenotype (C) and number of LSK (D) and SLAM (E) cells (n = 8).(F–I) Immunophenotype (F) and number of total SP (G), lymphoid SP (H), and myeloid SP (I) populations (n = 4).Mice that were 8 to 10 weeks old were used. KO, p19INK4d−/−. Data represent mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, unpaired t test. See also Figure S1.
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fig1: p19INK4d−/− Mice Exhibit a Defect in the HSC Compartment(A) mRNA expression level of p19INK4d in different populations of C57BL/6 and C57BL/6-Sv129j mice: SLAM (Lin−SCA1+C-KIT+CD48−CD150+), LSK, myeloid progenitors (Lin−SCA1−C-KIT+), CLP (Lin−SCA1lowC-KITlowCD127+THY-1−), CMP (Lin−SCA1−C-KIT+FCγR−CD34+), GMP (Lin−SCA1−C-KITt+FCγR+CD34+), and MEP (Lin−SCA1−C-KIT+FCγR−CD34−). Each population represents a pool derived from 10 mice. Data are normalized to HPRT transcript levels and represent the mean ± SEM of triplicates.(B) BM cellularity (n = 10).(C–E) Immunophenotype (C) and number of LSK (D) and SLAM (E) cells (n = 8).(F–I) Immunophenotype (F) and number of total SP (G), lymphoid SP (H), and myeloid SP (I) populations (n = 4).Mice that were 8 to 10 weeks old were used. KO, p19INK4d−/−. Data represent mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, unpaired t test. See also Figure S1.

Mentions: The expression profile of different CDKIs has previously been reported in C57BL/6 mice (Passegué et al., 2005). Since the p19INK4d−/− mice in this study are in a mixed C57BL/6 × Sv129j genetic background, we first compared the expression level of all CDKIs in mice with a mixed genetic background with that of pure C57BL/6 mice. In long-term (LT) HSCs, purified as the CD48−CD150+ (SLAM) cell subpopulation of primitive Lin−SCA1+C-KIT+ (LSK) BM cells, p19INK4d transcript levels were similar in both genetic backgrounds. Slight differences in transcript levels were observed in both the immature and more mature progenitor populations (Figure 1A). The levels of other CDKIs expressed during hematopoiesis were similar between C57BL/6 and C57BL/6 × Sv129j mice (Figures S1A–S1D available online). We observed relatively high levels of p27Kip1 and p19INK4d transcripts in SLAM cells compared with p18INK4c, p21Cip1 and p57Kip2, suggesting that p27Kip1 and p19INK4d have important roles in quiescent HSCs.


p19 INK4d controls hematopoietic stem cells in a cell-autonomous manner during genotoxic stress and through the microenvironment during aging.

Hilpert M, Legrand C, Bluteau D, Balayn N, Betems A, Bluteau O, Villeval JL, Louache F, Gonin P, Debili N, Plo I, Vainchenker W, Gilles L, Raslova H - Stem Cell Reports (2014)

p19INK4d−/− Mice Exhibit a Defect in the HSC Compartment(A) mRNA expression level of p19INK4d in different populations of C57BL/6 and C57BL/6-Sv129j mice: SLAM (Lin−SCA1+C-KIT+CD48−CD150+), LSK, myeloid progenitors (Lin−SCA1−C-KIT+), CLP (Lin−SCA1lowC-KITlowCD127+THY-1−), CMP (Lin−SCA1−C-KIT+FCγR−CD34+), GMP (Lin−SCA1−C-KITt+FCγR+CD34+), and MEP (Lin−SCA1−C-KIT+FCγR−CD34−). Each population represents a pool derived from 10 mice. Data are normalized to HPRT transcript levels and represent the mean ± SEM of triplicates.(B) BM cellularity (n = 10).(C–E) Immunophenotype (C) and number of LSK (D) and SLAM (E) cells (n = 8).(F–I) Immunophenotype (F) and number of total SP (G), lymphoid SP (H), and myeloid SP (I) populations (n = 4).Mice that were 8 to 10 weeks old were used. KO, p19INK4d−/−. Data represent mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, unpaired t test. See also Figure S1.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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fig1: p19INK4d−/− Mice Exhibit a Defect in the HSC Compartment(A) mRNA expression level of p19INK4d in different populations of C57BL/6 and C57BL/6-Sv129j mice: SLAM (Lin−SCA1+C-KIT+CD48−CD150+), LSK, myeloid progenitors (Lin−SCA1−C-KIT+), CLP (Lin−SCA1lowC-KITlowCD127+THY-1−), CMP (Lin−SCA1−C-KIT+FCγR−CD34+), GMP (Lin−SCA1−C-KITt+FCγR+CD34+), and MEP (Lin−SCA1−C-KIT+FCγR−CD34−). Each population represents a pool derived from 10 mice. Data are normalized to HPRT transcript levels and represent the mean ± SEM of triplicates.(B) BM cellularity (n = 10).(C–E) Immunophenotype (C) and number of LSK (D) and SLAM (E) cells (n = 8).(F–I) Immunophenotype (F) and number of total SP (G), lymphoid SP (H), and myeloid SP (I) populations (n = 4).Mice that were 8 to 10 weeks old were used. KO, p19INK4d−/−. Data represent mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, unpaired t test. See also Figure S1.
Mentions: The expression profile of different CDKIs has previously been reported in C57BL/6 mice (Passegué et al., 2005). Since the p19INK4d−/− mice in this study are in a mixed C57BL/6 × Sv129j genetic background, we first compared the expression level of all CDKIs in mice with a mixed genetic background with that of pure C57BL/6 mice. In long-term (LT) HSCs, purified as the CD48−CD150+ (SLAM) cell subpopulation of primitive Lin−SCA1+C-KIT+ (LSK) BM cells, p19INK4d transcript levels were similar in both genetic backgrounds. Slight differences in transcript levels were observed in both the immature and more mature progenitor populations (Figure 1A). The levels of other CDKIs expressed during hematopoiesis were similar between C57BL/6 and C57BL/6 × Sv129j mice (Figures S1A–S1D available online). We observed relatively high levels of p27Kip1 and p19INK4d transcripts in SLAM cells compared with p18INK4c, p21Cip1 and p57Kip2, suggesting that p27Kip1 and p19INK4d have important roles in quiescent HSCs.

Bottom Line: We demonstrate that p19(INK4d) is involved in the regulation of HSC quiescence by inhibition of the G0/G1 cell cycle transition.Deletion of p19(INK4d) results in megakaryocyte hyperproliferation and increased transforming growth factor β1 secretion.This leads to fibrosis in the bone marrow and spleen, followed by loss of HSCs during aging.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale, U1009, Equipe labellisée Ligue Nationale contre le Cancer, 114 rue Edouard Vaillant, 94805 Villejuif, France; University Paris Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France; Gustave Roussy, IFR54, 114, rue Edouard Vaillant, 94805 Villejuif, France; University Paris Diderot, 5 rue Thomas-Mann, 75205 Paris, France.

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Related in: MedlinePlus