LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells

doi:10.1186/s13059-018-1557-3

. 2018 Nov 7;19(1):189.

doi: 10.1186/s13059-018-1557-3.

LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells

Ani Grigoryan¹, Novella Guidi¹, Katharina Senger¹, Thomas Liehr², Karin Soller¹, Gina Marka¹, Angelika Vollmer¹, Yolanda Markaki³, Heinrich Leonhardt³, Christian Buske⁴, Daniel B Lipka^{5

6}, Christoph Plass⁶, Yi Zheng⁷, Medhanie A Mulaw⁴, Hartmut Geiger^{1

7}, Maria Carolina Florian^{8

9}

Affiliations

¹ Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Albert-Einstein-Allee 11c, 89081, Ulm, Germany.
² Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Kollegiengasse 10, 07743, Jena, Germany.
³ Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig Maximilians University Munich, Großhaderner Strasse 2, 82152, Planegg-Martinsried, Germany.
⁴ Institute of Experimental Cancer Research, Comprehensive Cancer Center Ulm, University Hospital Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
⁵ Regulation of Cellular Differentiation Group, INF280, 69120, Heidelberg, Germany.
⁶ Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF280, 69120, Heidelberg, Germany.
⁷ Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH, USA.
⁸ Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Albert-Einstein-Allee 11c, 89081, Ulm, Germany. carolina.florian@uni-ulm.de.
⁹ Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Gran Via de l'Hospitalet, 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain. carolina.florian@uni-ulm.de.

PMID: 30404662
PMCID: PMC6223039
DOI: 10.1186/s13059-018-1557-3

LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells

Ani Grigoryan et al. Genome Biol. 2018.

. 2018 Nov 7;19(1):189.

doi: 10.1186/s13059-018-1557-3.

Authors

Affiliations

¹ Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Albert-Einstein-Allee 11c, 89081, Ulm, Germany.
² Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Kollegiengasse 10, 07743, Jena, Germany.
³ Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig Maximilians University Munich, Großhaderner Strasse 2, 82152, Planegg-Martinsried, Germany.
⁴ Institute of Experimental Cancer Research, Comprehensive Cancer Center Ulm, University Hospital Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
⁵ Regulation of Cellular Differentiation Group, INF280, 69120, Heidelberg, Germany.
⁶ Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF280, 69120, Heidelberg, Germany.
⁷ Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH, USA.
⁸ Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Albert-Einstein-Allee 11c, 89081, Ulm, Germany. carolina.florian@uni-ulm.de.
⁹ Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Gran Via de l'Hospitalet, 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain. carolina.florian@uni-ulm.de.

PMID: 30404662
PMCID: PMC6223039
DOI: 10.1186/s13059-018-1557-3

Abstract

Background: The decline of hematopoietic stem cell (HSC) function upon aging contributes to aging-associated immune remodeling and leukemia pathogenesis. Aged HSCs show changes to their epigenome, such as alterations in DNA methylation and histone methylation and acetylation landscapes. We previously showed a correlation between high Cdc42 activity in aged HSCs and the loss of intranuclear epigenetic polarity, or epipolarity, as indicated by the specific distribution of H4K16ac.

Results: Here, we show that not all histone modifications display a polar localization and that a reduction in H4K16ac amount and loss of epipolarity are specific to aged HSCs. Increasing the levels of H4K16ac is not sufficient to restore polarity in aged HSCs and the restoration of HSC function. The changes in H4K16ac upon aging and rejuvenation of HSCs are correlated with a change in chromosome 11 architecture and alterations in nuclear volume and shape. Surprisingly, by taking advantage of knockout mouse models, we demonstrate that increased Cdc42 activity levels correlate with the repression of the nuclear envelope protein LaminA/C, which controls chromosome 11 distribution, H4K16ac polarity, and nuclear volume and shape in aged HSCs.

Conclusions: Collectively, our data show that chromatin architecture changes in aged stem cells are reversible by decreasing the levels of Cdc42 activity, revealing an unanticipated way to pharmacologically target LaminA/C expression and revert alterations of the epigenetic architecture in aged HSCs.

Keywords: Aging; Chromatin architecture; Chromosome 11; Hematopoietic stem cell (HSC); LaminA/C.

PubMed Disclaimer

Conflict of interest statement

Ethics approval

All mice were housed in the animal barrier facility under pathogen-free conditions either at the Ulm University or at CCHMC. All mouse experiments were performed in compliance with the German Law for Welfare of Laboratory Animals and were approved by the Institutional Review Board of the Ulm University as well as by the Regierungspraesidium Tuebingen (state government of Baden-Württemberg) or by the IACUC of CCHMC respectively.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
The change in the spatial distribution of H4K16ac upon aging is linked to a change in HSC function. a Aging of HSCs. Cartoon scheme of the main previous findings [16]. b Representative FACS dot plots of HSCs (Lin-c-kit+Sca-1+Flk2-CD34-), ST-HSCs (Lin-c-kit+Sca-1+Flk2-CD34+), LMPPs (Lin-c-kit+Sca-1+Flk2+CD34+), and LSKs (Lin-c-kit+Sca-1+) gating strategy of young and aged lineage-depleted BM cells. c Percentage of young and aged HSCs with a polar distribution of H4K16ac, H4K8ac, H4K5ac, H3K27ac, H3K4me1, and H3K4me3; n = 3–4 biological repeats; ~ 150–200 single HSCs scored per sample in total; *p < 0.001. d Representative FACS histograms of an isotype control stained sample. Gates for LT-HSCs and ST-HSCs. Representative FACS histograms of H3K5ac (e), H3K4me3 (f), and H4K16ac (g) of young and aged samples. LT-HSCs and ST-HSCs gates are shown. Median fluorescence intensity of H3K5ac (h), H3K4me3 (i), and H4K16ac (j) plotted as a percentage of young control in young and aged HSCs, ST-HSCs, and LMPPs. Shown are mean values + 1 SE; n = 4–7 biological repeats; *p < 0.05. k Median fluorescence intensity of H4K16ac, H4K8ac, and H4K5ac plotted as a percentage of young control in young, aged, aged CASIN-treated (5 μM, 16 h), and aged NaB-treated (5 mM, 16 h) HSCs. Shown are mean values + 1 SE; n = 4 biological repeats; *p < 0.05. l Representative distribution of H4K16ac in young, aged, aged CASIN-treated (5 μM, 16 h), and aged NaB-treated (5 mM, 16 h) HSCs. Bar = 2 μm. Panels show DAPI (nucleus, blue), H4K16ac (red). m Percentage of young, aged, aged CASIN-treated (5 μM, 16 h), and aged NaB-treated (5 mM, 16 h) HSCs with a polar distribution of H4K16ac; n = 3–4 biological repeats; ~ 150–200 single HSCs scored per sample in total; *p < 0.05. n Schematic representation of the experimental setup for HSC transplantation. Percentage of B220⁺ (o), myeloid (Gr1⁺, Mac1⁺, and Gr1⁺Mac1⁺) (p), and CD3⁺ (q) cells among Ly5.2⁺ donor-derived cells in peripheral blood (PB) of recipient Ly5.1⁺ mice; *p < 0.05, **p < 0.01; n = 12–19. r Percentage of HSCs among donor-derived Ly5.2⁺ LSKs in BM of recipient Ly5.1⁺ mice; *p < 0.05, **p < 0.01; n = 12–19. s Representative distribution of H4K16ac in donor-derived Ly5.2⁺ HSCs sorted from mice after 24 weeks from transplant with young, aged, aged CASIN-treated (5 μM, 16 h), and aged NaB-treated (5 mM, 16 h) HSCs. Bar = 2 μm. Panels show DAPI (nucleus, blue), H4K16ac (red). t Percentage of H4K16ac-polarized donor-derived Ly5.2⁺ HSCs sorted from mice after 24 weeks from transplant with young, aged, aged+CASIN 5 μM, and aged+NaB 5 mM HSCs; n = 3 biological repeats; ~ 100–150 single HSCs scored per sample in total; *p < 0.05, **p < 0.01

**Fig. 2**
Changes in H4K16ac epipolarity are linked to changes in chromosome 11 homolog distribution. a Schematic representation of the experimental setup. Heatmaps and profiles show input-corrected H4K16ac signals ± 1.5 kb from TSS (b) and at H4K16ac peaks ± 1.0 kb (c). TSS and peak regions were ranked by the signal intensity in young HSCs. Summary profile of n = 3 biological repeats. Each sample was generated by pooling 50,000 sorted HSCs that were incubated 16 h in HBSS+ 10% FBS+P/S±CASIN 5 μM at 3% O₂. d Pie chart showing genomic annotations of the total 34,019 H4K16ac peaks in young, aged HSCs, and aged+CASIN 5 μM HSCs. ChIP-seq data are available at GEO Series accession number GSE120232. e Venn diagram showing results of the cross-analysis of differentially bound H4K16ac peaks between young and aged HSCs (1358 peaks), aged+CASIN 5 μM, and aged HSCs (1135 peaks). Two hundred eleven differentially bound peaks were overlapping, and of these, 118 showed the same direction of change. f Gene Set Enrichment Analysis (GSEA) for the 211 differentially bound H4K16ac peaks overlapping between young and CASIN HSCs as compared to aged HSCs in both young vs aged and CASIN vs aged RNA-seq dataset. RNA-seq data are available at GEO Series accession number GSE119466. g–h UCSC browser track showing H4K16ac signal at the *Cbx4* locus and real-time PCR transcript level for *Cbx4* in young, aged, and aged+CASIN 5 μM HSCs: n = 3 biological repeats, *p < 0.0001

**Fig. 3**
Changes in H4K16ac epipolarity are linked to the changes in chromosome 11 homologs distribution. a Comparison of the observed peak count and expected peak count relative to the chromosome size for the 118 peaks identified as described in panel M. Goodness of fit test was used, and it revealed that these 118 differentially bound H4K16ac peaks are not randomly distributed and chromosome 11 presented with the highest enrichment score. b Representative confocal 3D reconstruction of the nucleus (stained with DAPI, blue) and of chromosomes 3 (red), 7 (green), and 16 (green) by FISH stained with full-paint probe in young and aged HSCs. Bar = 2 μm. c Measurements of the distances between chromosomes 3 (n = 3 biological repeats, 28 cells for young, 21 cells for aged in total), 7 (n = 3 biological repeats, 25 cells for young, 26 cells for aged in total), and 16 (n = 3 biological repeats, 30 cells for young, 18 cells for aged in total) homologs in young and aged HSCs by Volocity 3D Image Analysis Software. d Percentage of young and aged HSCs with chromosome homolog proximity for chromosomes 3, 7, and 16, n = 3 biological repeats. e Representative confocal 3D reconstruction of the nucleus (stained with DAPI, blue) and of chromosome11 (red, FISH stained with a full-paint probe) in young, aged, and aged+CASIN 5 μM HSCs. Bar = 2 μm. f 3D reconstruction of the chromosome 11 homologs (red and green) and the distance measurement between them by Volocity 3D Image Analysis. In young HSCs, green color for two homologs shows that they are distributed very close to each other and are not recognized as two objects by the software. While in aged and aged+CASIN 5 μM HSCs, they are marked as two objects in green and red. Bar = 2 μm. g Measurements of the distances between chromosome 11 homologs by Volocity 3D Image Analysis. Shown are mean values + 1 SE; *p < 0.01; n = 6 biological repeats, 64 cells for young, 58 cells for aged, and 55 cells for aged+CASIN in total. h Percentage of young, aged, and aged+CASIN 5 μM HSCs with homolog proximity for chromosome11; **p < 0.01. i Representative confocal 3D reconstruction of young, aged, and aged+CASIN 5 μM HSCs after DNA-FISH+IF. H4K16ac (green), chromosome 11 (red), the nucleus is stained with DAPI (blue). Bar = 2 μm. j Volume measurement of the co-localized area between H4K16ac and chromosomes 11 and 16 by Volocity 3D Image Analysis; *p < 0.05, n = 3 biological repeats, 33 cells for young, 33 cells for aged, and 28 cells for aged+CASIN in total for chromosome 11 and 32 cells for young, 26 cells for aged, and 19 cells for aged+CASIN in total for chromosome 16

**Fig. 4**
Nuclear volume and nuclear shape are altered upon aging of HSCs. a Representative confocal 3D reconstruction of the nucleus (stained with DAPI, blue) of young, aged, and aged+CASIN 5 μM HSCs. The arrowheads indicate the nuclear invagination normally observed in young and aged+CASIN HSCs. Bar = 2 μm. b Nuclear volume measurements by 3D-structured illumination (SIM) analysis (based on DAPI staining). ***p < 0.001; n = 3 biological repeats, 47 cells for young, 44 cells for aged, and 70 cells for aged+CASIN 5 μM in total. c Nuclear shape factor (NSF) measurements by Volocity 3D Image Analysis. The NSF scores the 3D shape of an object: 1 corresponds to a perfect sphere. *p < 0.05, ***p < 0.001; n = 6 biological repeats, 62 cells for young, 64 cells for aged, and 61 cells for aged+CASIN 5 μM in total. d Cartoon scheme summarizing premature aging-like phenotypes of Cdc42 GAP knockout (Cdc42GAP^−/−) mice. e Representative confocal 3D reconstruction of the nucleus (stained with DAPI, blue) of Cdc42GAP^+/+ and Cdc42GAP^−/− HSCs. The arrowheads indicate the nuclear invagination observed in Cdc42GAP^+/+ HSCs. Bar = 2 μm. f Nuclear volume measurements by Volocity 3D Image Analysis (based on DAPI staining). ****p < 0.0001; n = 4 biological repeats, 119 cells for Cdc42GAP^+/+, and 102 cells for Cdc42GAP^−/− mice in total. g Nuclear shape factor (NSF) measurements by Volocity 3D Image Analysis. The NSF scores the 3D shape of an object: 1 corresponds to a perfect sphere. **p < 0.01, n = 4 biological repeats, 118 cells for Cdc42GAP^+/+, and 101 cells for Cdc42GAP^−/− mice in total. h Representative confocal 3D reconstruction of the nucleus (stained with DAPI, blue) and of LaminA/C (green) of Cdc42GAP^+/+ and Cdc42GAP^−/− HSCs. Bar = 2 μm. i LaminA/C volume measurements by Volocity 3D Image Analysis (based on LaminA/C staining). **p < 0.01; n = 3 biological repeats, 50 cells for Cdc42GAP^+/+, and 50 cells for Cdc42GAP^−/− mice in total

**Fig. 5**
LaminA/C expression in the hematopoietic system is specific to HSCs and is decreased upon aging. a Representative confocal 3D reconstruction of the nucleus (stained with DAPI, blue) and LaminB (green) of young, aged, and aged+CASIN 5 μM HSCs. Bar = 2 μm. b Representative confocal 3D reconstruction of the nucleus (stained with DAPI, blue) and of LaminA/C (green) of young, aged, aged+CASIN 5 μM HSCs, and young ST-HSCs. Bar = 2 μm. c *Lmna* transcript levels in young, aged, aged+CASIN 5 μM HSCs, and in young ST-HSCs. Shown are mean values + 1 SE; n = 3 biological repeats; ****p < 0.0001. d Representative distribution of LaminA/C (green) in young HSCs. Bar = 2 μm. The arrow indicates LaminA/C distribution in the deep invagination of young HSCs nuclei. e Percentage of young HSCs with invaginated nuclei, n = 4 biological repeats, 45 single HSCs in total. f Percentage of young HSCs which have LaminA/C distribution in the invagination site of HSCs nuclei out of invaginated HSCs, n = 4 biological repeats, 45 single HSCs in total. g Representative confocal 3D reconstruction of the distribution of H3K9me2 in young, aged, and aged CASIN-treated LT-HSCs. Bar = 2 μm. h Percentage of young, aged, and aged+CASIN 5 μM HSCs presenting with peripheral heterochromatin localization of H3K9me2, n = 3 biological repeats, ~ 150 single HSCs for young and aged, 20 single HSCs for aged+CASIN 5 μM in total; *p < 0.05. i Representative FACS dot plots of B220⁺, CD3⁺, and myeloid (Gr1⁺, Mac1⁺, and Gr1⁺Mac1⁺) cells in control Lmna^fl/fl and Lmna^{Δ/Δ/Vav-Cre} PB. j Percentage of B220⁺, CD3⁺, and myeloid (Gr1⁺, Mac1⁺, and Gr1⁺Mac1⁺) cells in PB of control Lmna^fl/fl and Lmna^{Δ/Δ/Vav-Cre} mice; *p < 0.05, n = 4–6 mice. k Hematologic analyses of control Lmna^fl/fl and Lmna^{Δ/Δ/Vav-Cre} mice. *p < 0.05, **p < 0.01; n = 5–6 mice

**Fig. 6**
The decrease of LaminA/C expression in HSCs determines changes in nuclear volume and shape, H4K16ac polarity, and chromosome 11 homolog proximity. a Representative confocal 3D reconstruction of the nucleus (stained with DAPI, blue) of Lmna^fl/fl and Lmna^{Δ/Δ/Vav-Cre} HSCs. Bar = 2 μm. b Nuclear volume measurements by Volocity 3D Image Analysis (based on DAPI staining). **p < 0.01; n = 8 biological repeats; 100 single HSCs for Lmna^fl/fl, 115 single HSCs for Lmna^{Δ/Δ/Vav-Cre} in total. c Nuclear shape factor (NSF) measurements. *p < 0.05; n = 4 biological repeats; 99 HSCs for Lmna^fl/fl, 100 HSCs for Lmna^{Δ/Δ/Vav-Cre} in total. d Representative distribution of H4K16ac in Lmna^fl/fl, Lmna^{Δ/Δ/Vav-Cre}, Lmna^{Δ/Δ/Vav-Cre} + CASIN 5 μM, aged, and aged+CASIN 5 μM HSCs. Bar = 2 μm. Panels show DAPI (nucleus, blue), H4K16ac (red). e Percentage of Lmna^fl/fl, Lmna^{Δ/Δ/Vav-Cre}, Lmna^{Δ/Δ/Vav-Cre} + CASIN 5 μM, aged, and aged+CASIN 5 μM HSCs with a polar distribution of H4K16ac. Shown are mean values + 1 SE; n = 3–5 biological repeats, ~ 30–100 single HSCs scored per sample in total; *p < 0.05, ***p < 0.001. f Representative FACS histograms of an isotype control stained sample and of H4K16ac in Lmna^fl/fl and Lmna^{Δ/Δ7Vav-Cre} samples. HSCs gates are shown. g Median fluorescence intensity of H4K16ac in HSCs of control Lmna^fl/fl and Lmna^{Δ/Δ/Vav-Cre} mice; n = 3 biological repeats. h Measurements of the distances between chromosome 11 homologs in Lmna^fl/fl and Lmna^Δ/ΔVav-Cre HSCs by Volocity 3D Image Analysis; **p < 0.01; n = 3 biological repeats, 27 cells for Lmna^fl/fl, 30 cells for Lmna^{Δ/Δ/Vav-Cre} in total. i Percentage of Lmna^fl/fl and Lmna^{Δ/Δ/Vav-Cre} HSCs with chromosome homologs proximity for chromosome 11; n = 3 biological repeats; *p < 0.05. j Representative confocal 3D reconstruction of the nucleus (stained with DAPI, blue) and of chromosome 11 (red, FISH stained with a full-paint probe) in Lmna^fl/fl and Lmna^{Δ/Δ/Vav-Cre} HSCs. Bar = 2 μm. k 3D reconstruction of the chromosome 11 homologs (red and green) and the distance measurement between them by Volocity 3D Image Analysis. In Lmna^fl/fl HSCs green, color for two homologs shows that they are distributed very close to each other and are not recognized as two objects by the software. While in Lmna^{Δ/Δ/Vav-Cre} HSCs, they are marked as two objects in green and red. Bar = 2 μm. l Summary of premature aging-like phenotypes in the hematopoietic system of LaminA/C conditional knockout mice. m Aging of HSCs compartment. Cartoon scheme integrating the novel main findings. The newly identified HSC aging phenotypes are highlighted in red

See this image and copyright information in PMC

Cited by

Quantifying cell-cycle-dependent chromatin dynamics during interphase by live 3D tracking.
Naor T, Nogin Y, Nehme E, Ferdman B, Weiss LE, Alalouf O, Shechtman Y. Naor T, et al. iScience. 2022 Apr 4;25(5):104197. doi: 10.1016/j.isci.2022.104197. eCollection 2022 May 20. iScience. 2022. PMID: 35494233 Free PMC article.
Mechanisms involved in hematopoietic stem cell aging.
Fujino T, Asada S, Goyama S, Kitamura T. Fujino T, et al. Cell Mol Life Sci. 2022 Aug 8;79(9):473. doi: 10.1007/s00018-022-04356-5. Cell Mol Life Sci. 2022. PMID: 35941268 Free PMC article. Review.
Epigenetic alterations in stem cell ageing-a promising target for age-reversing interventions?
Pouikli A, Tessarz P. Pouikli A, et al. Brief Funct Genomics. 2022 Jan 25;21(1):35-42. doi: 10.1093/bfgp/elab010. Brief Funct Genomics. 2022. PMID: 33738480 Free PMC article. Review.
Dissecting Murine Muscle Stem Cell Aging through Regeneration Using Integrative Genomic Analysis.
Shcherbina A, Larouche J, Fraczek P, Yang BA, Brown LA, Markworth JF, Chung CH, Khaliq M, de Silva K, Choi JJ, Fallahi-Sichani M, Chandrasekaran S, Jang YC, Brooks SV, Aguilar CA. Shcherbina A, et al. Cell Rep. 2020 Jul 28;32(4):107964. doi: 10.1016/j.celrep.2020.107964. Cell Rep. 2020. PMID: 32726628 Free PMC article.
Multiple superovulations alter histone modifications in mouse early embryos.
Tang SB, Yang LL, Zhang TT, Wang Q, Yin S, Luo SM, Shen W, Ge ZJ, Sun QY. Tang SB, et al. Reproduction. 2019 Jun;157(6):511-523. doi: 10.1530/REP-18-0495. Reproduction. 2019. PMID: 30884466 Free PMC article.

See all "Cited by" articles

References

1. Schultz MB, Sinclair DA. When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development. 2016;143:3–14. doi: 10.1242/dev.130633. - DOI - PMC - PubMed
1. Akunuru S, Geiger H. Aging, clonality, and rejuvenation of hematopoietic stem cells. Trends Mol Med. 2016;22:701–712. doi: 10.1016/j.molmed.2016.06.003. - DOI - PMC - PubMed
1. Geiger H, de Haan G, Florian MC. The ageing haematopoietic stem cell compartment. Nat Rev Immunol. 2013;13:376–389. doi: 10.1038/nri3433. - DOI - PubMed
1. Snoeck HW. Aging of the hematopoietic system. Curr Opin Hematol. 2013;20:355–361. doi: 10.1097/MOH.0b013e3283623c77. - DOI - PubMed
1. Beerman I, Maloney WJ, Weissmann IL, Rossi DJ. Stem cells and the aging hematopoietic system. Curr Opin Immunol. 2010;22:500–506. doi: 10.1016/j.coi.2010.06.007. - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases
Miscellaneous
- NCI CPTAC Assay Portal

[1] Schultz MB, Sinclair DA. When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development. 2016;143:3–14. doi: 10.1242/dev.130633. - DOI - PMC - PubMed

[2] Schultz MB, Sinclair DA. When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development. 2016;143:3–14. doi: 10.1242/dev.130633. - DOI - PMC - PubMed

[3] Akunuru S, Geiger H. Aging, clonality, and rejuvenation of hematopoietic stem cells. Trends Mol Med. 2016;22:701–712. doi: 10.1016/j.molmed.2016.06.003. - DOI - PMC - PubMed

[4] Akunuru S, Geiger H. Aging, clonality, and rejuvenation of hematopoietic stem cells. Trends Mol Med. 2016;22:701–712. doi: 10.1016/j.molmed.2016.06.003. - DOI - PMC - PubMed

[5] Geiger H, de Haan G, Florian MC. The ageing haematopoietic stem cell compartment. Nat Rev Immunol. 2013;13:376–389. doi: 10.1038/nri3433. - DOI - PubMed

[6] Geiger H, de Haan G, Florian MC. The ageing haematopoietic stem cell compartment. Nat Rev Immunol. 2013;13:376–389. doi: 10.1038/nri3433. - DOI - PubMed

[7] Snoeck HW. Aging of the hematopoietic system. Curr Opin Hematol. 2013;20:355–361. doi: 10.1097/MOH.0b013e3283623c77. - DOI - PubMed

[8] Snoeck HW. Aging of the hematopoietic system. Curr Opin Hematol. 2013;20:355–361. doi: 10.1097/MOH.0b013e3283623c77. - DOI - PubMed

[9] Beerman I, Maloney WJ, Weissmann IL, Rossi DJ. Stem cells and the aging hematopoietic system. Curr Opin Immunol. 2010;22:500–506. doi: 10.1016/j.coi.2010.06.007. - DOI - PMC - PubMed

[10] Beerman I, Maloney WJ, Weissmann IL, Rossi DJ. Stem cells and the aging hematopoietic system. Curr Opin Immunol. 2010;22:500–506. doi: 10.1016/j.coi.2010.06.007. - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed