Cdc42 活性调节造血干细胞衰老和更新。
Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation.
机构信息
Department of Dermatology and Allergic Diseases, University of Ulm, 89091 Ulm, Germany.
出版信息
Cell Stem Cell. 2012 May 4;10(5):520-30. doi: 10.1016/j.stem.2012.04.007.
Abstract
The decline in hematopoietic function seen during aging involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, and has been linked to aging of hematopoietic stem cells (HSCs). The molecular mechanisms underlying HSC aging remain unclear. Here we demonstrate that elevated activity of the small RhoGTPase Cdc42 in aged HSCs is causally linked to HSC aging and correlates with a loss of polarity in aged HSCs. Pharmacological inhibition of Cdc42 activity functionally rejuvenates aged HSCs, increases the percentage of polarized cells in an aged HSC population, and restores the level and spatial distribution of histone H4 lysine 16 acetylation to a status similar to that seen in young HSCs. Our data therefore suggest a mechanistic role for Cdc42 activity in HSC biology and epigenetic regulation, and identify Cdc42 activity as a pharmacological target for ameliorating stem cell aging.
摘要
衰老过程中造血功能的下降涉及免疫反应的逐渐减弱和髓系恶性肿瘤发病率的增加，这与造血干细胞（HSCs）的衰老有关。HSC 衰老的分子机制尚不清楚。在这里，我们证明了衰老 HSCs 中小 RhoGTPase Cdc42 的活性升高与 HSC 衰老有关，并与衰老 HSCs 中极性的丧失相关。Cdc42 活性的药理学抑制可使衰老 HSCs 功能上恢复活力，增加衰老 HSC 群体中极化细胞的百分比，并恢复组蛋白 H4 赖氨酸 16 乙酰化的水平和空间分布，使其状态类似于年轻 HSCs。因此，我们的数据表明 Cdc42 活性在 HSC 生物学和表观遗传调控中具有机制作用，并将 Cdc42 活性确定为改善干细胞衰老的药理学靶标。
相似文献
1
Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation.Cdc42 活性调节造血干细胞衰老和更新。
Cell Stem Cell. 2012 May 4;10(5):520-30. doi: 10.1016/j.stem.2012.04.007.
2
Cdc42 and aging of hematopoietic stem cells.Cdc42 与造血干细胞衰老。
Curr Opin Hematol. 2013 Jul;20(4):295-300. doi: 10.1097/MOH.0b013e3283615aba.
3
LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells.核层蛋白 A/C 在造血干细胞衰老过程中调节表观遗传和染色质结构的变化。
Genome Biol. 2018 Nov 7;19(1):189. doi: 10.1186/s13059-018-1557-3.
4
Regulation of hematopoietic stem cell aging by the small RhoGTPase Cdc42.小RhoGTP酶Cdc42对造血干细胞衰老的调控
Exp Cell Res. 2014 Dec 10;329(2):214-9. doi: 10.1016/j.yexcr.2014.09.001. Epub 2014 Sep 16.
5
Aging alters the epigenetic asymmetry of HSC division.衰老改变造血干细胞分裂的表观遗传不对称性。
PLoS Biol. 2018 Sep 20;16(9):e2003389. doi: 10.1371/journal.pbio.2003389. eCollection 2018 Sep.
6
Stem cells, aging, niche, adhesion and Cdc42: a model for changes in cell-cell interactions and hematopoietic stem cell aging.干细胞、衰老、微环境、黏附与Cdc42：细胞间相互作用及造血干细胞衰老变化的模型
Cell Cycle. 2007 Apr 15;6(8):884-7. doi: 10.4161/cc.6.8.4131. Epub 2007 Apr 7.
7
A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing.造血干细胞衰老过程中经典 Wnt 信号与非经典 Wnt 信号的转换。
Nature. 2013 Nov 21;503(7476):392-6. doi: 10.1038/nature12631. Epub 2013 Oct 20.
8
Mechanisms and rejuvenation strategies for aged hematopoietic stem cells.衰老造血干细胞的机制和 rejuvenation 策略。
J Hematol Oncol. 2020 Apr 6;13(1):31. doi: 10.1186/s13045-020-00864-8.
9
Aged murine hematopoietic stem cells drive aging-associated immune remodeling.衰老的鼠造血干细胞驱动与衰老相关的免疫重塑。
Blood. 2018 Aug 9;132(6):565-576. doi: 10.1182/blood-2018-02-831065. Epub 2018 Jun 11.
10
Mechanisms involved in hematopoietic stem cell aging.造血干细胞衰老涉及的机制。
Cell Mol Life Sci. 2022 Aug 8;79(9):473. doi: 10.1007/s00018-022-04356-5.
引用本文的文献
1
Control of stress-activated Cdc42 dynamics by the MAP kinase Sty1-NDR kinase Orb6 regulatory axis.通过丝裂原活化蛋白激酶Sty1-NDR激酶Orb6调控轴控制应激激活的Cdc42动力学
iScience. 2025 Aug 5;28(9):113298. doi: 10.1016/j.isci.2025.113298. eCollection 2025 Sep 19.
2
Targeting immunosenescence and inflammaging: advancing longevity research.针对免疫衰老和炎症衰老：推进长寿研究。
Exp Mol Med. 2025 Sep 1. doi: 10.1038/s12276-025-01527-9.
3
Regulation of Tetraspanin CD63 in Chronic Myeloid Leukemia (CML): Single-Cell Analysis of Asymmetric Hematopoietic Stem Cell Division Genes.慢性髓性白血病（CML）中四跨膜蛋白CD63的调控：不对称造血干细胞分裂基因的单细胞分析
Bioengineering (Basel). 2025 Jul 31;12(8):830. doi: 10.3390/bioengineering12080830.
4
Haematopoietic ageing in health and lifespan.健康与寿命中的造血衰老
Nat Cell Biol. 2025 Aug 25. doi: 10.1038/s41556-025-01739-1.
5
Systematic evaluation of GAPs and GEFs identifies a targetable dependency for hematopoietic malignancies.对GAP和GEF的系统评估确定了造血系统恶性肿瘤的一个可靶向依赖因素。
Cancer Discov. 2025 Aug 12. doi: 10.1158/2159-8290.CD-25-0299.
6
Immunosenescence: signaling pathways, diseases and therapeutic targets.免疫衰老：信号通路、疾病与治疗靶点。
Signal Transduct Target Ther. 2025 Aug 6;10(1):250. doi: 10.1038/s41392-025-02371-z.
7
Hypotonic stimuli promote osteocyte dendrite formation by modulating actin dynamics via the TRPV4-CDC42 signaling pathway.低渗刺激通过TRPV4-CDC42信号通路调节肌动蛋白动力学，从而促进骨细胞树突形成。
Mater Today Bio. 2025 Jul 21;34:102120. doi: 10.1016/j.mtbio.2025.102120. eCollection 2025 Oct.
8
Cdc42 Partitioning by Chaperone Ydj1 During Asymmetric Division and Aging in Yeast.伴侣蛋白Ydj1在酵母不对称分裂和衰老过程中对Cdc42的分配
bioRxiv. 2025 Jul 15:2025.07.10.664052. doi: 10.1101/2025.07.10.664052.
9
The aging hematopoietic stem cell niche: a mini review.衰老的造血干细胞微环境：一篇综述
Front Hematol. 2025;4. doi: 10.3389/frhem.2025.1525132. Epub 2025 Feb 6.
10
The transcription factor Bcl11a is essential for B-1a cell maintenance during aging.转录因子Bcl11a对于衰老过程中B-1a细胞的维持至关重要。
Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2501974122. doi: 10.1073/pnas.2501974122. Epub 2025 Jul 3.
本文引用的文献
1
Cdc42 and Rab8a are critical for intestinal stem cell division, survival, and differentiation in mice.Cdc42 和 Rab8a 对于小鼠肠道干细胞的分裂、存活和分化至关重要。
J Clin Invest. 2012 Mar;122(3):1052-65. doi: 10.1172/JCI60282. Epub 2012 Feb 22.
2
Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock.衰老、返老还童和表观遗传重编程：重置衰老时钟。
Cell. 2012 Jan 20;148(1-2):46-57. doi: 10.1016/j.cell.2012.01.003.
3
Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells.克隆分析揭示了衰老的鼠造血干细胞的多种功能缺陷。
J Exp Med. 2011 Dec 19;208(13):2691-703. doi: 10.1084/jem.20111490. Epub 2011 Nov 21.
4
Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans.线虫的跨代表观遗传遗传与长寿。
Nature. 2011 Oct 19;479(7373):365-71. doi: 10.1038/nature10572.
5
Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice.组蛋白 H4 赖氨酸 16 低乙酰化与 Zmpste24 缺陷小鼠中 DNA 修复缺陷和过早衰老有关。
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12325-30. doi: 10.1073/pnas.1102789108. Epub 2011 Jul 11.
6
Atypical protein kinase C (aPKCzeta and aPKClambda) is dispensable for mammalian hematopoietic stem cell activity and blood formation.非典型蛋白激酶 C（aPKCzeta 和 aPKClambda）对于哺乳动物造血干细胞活性和血液形成是可有可无的。
Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9957-62. doi: 10.1073/pnas.1103132108. Epub 2011 Jun 8.
7
Epigenetic regulation of aging stem cells.衰老干细胞的表观遗传调控。
Oncogene. 2011 Jul 14;30(28):3105-26. doi: 10.1038/onc.2011.45. Epub 2011 Mar 28.
8
Concise review: polarity in stem cells, disease, and aging.简明综述：干细胞、疾病和衰老中的极性。
Stem Cells. 2010 Sep;28(9):1623-9. doi: 10.1002/stem.481.
9
Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion.功能不同的造血干细胞通过克隆扩增的机制在衰老过程中调节造血谱系潜能。
Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5465-70. doi: 10.1073/pnas.1000834107. Epub 2010 Mar 18.
10
Mechanisms of hematopoietic stem cell aging.造血干细胞衰老的机制。
Exp Gerontol. 2010 Apr;45(4):286-90. doi: 10.1016/j.exger.2009.12.010. Epub 2009 Dec 23.
Zotero 插件