Megakaryocyte progenitor cell function is enhanced upon aging despite the functional decline of aged hematopoietic stem cells.
Megakaryocyte progenitor cell function is enhanced upon aging despite the functional decline of aged hematopoietic stem cells.
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DOI：
10.1016/j.stemcr.2021.04.016
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发表时间：
2021-06-08
影响因子：
5.9
通讯作者：
Forsberg EC
中科院分区：
文献类型：
--
作者：
Poscablo DM;Worthington AK;Smith-Berdan S;Forsberg EC
与年龄相关的发病率与造血干细胞(HSC)功能下降有关，但HSC老化的机制尚不清楚。我们进行了异种时间的HSC移植，随后进行了细胞重建的定量分析。尽管在年轻受者中，年轻的HSC表现优于老年HSC，但年轻的HSC出人意料地未能超过老年受者的老年HSC。有趣的是，尽管大量巨核细胞祖细胞(MKPs)在老年小鼠体内大量丰富，并有报道称随着年龄的增长，血小板(Plt)被激活，但移植的老年HSC在包括MKPs和Plts在内的所有谱系的重建方面都存在缺陷。因此，我们对年轻的和老年的MKP进行了功能分析。令人惊讶的是，与年轻的MKP相比，老年MKP显示出明显更强的再生能力。转录组分析揭示了旧的MKP扩增的可能分子调控因素。总而言之，这些数据表明，衰老以根本不同的方式影响造血干细胞和巨核细胞的生成：尽管旧的造血干细胞功能衰退，但MKP在衰老后获得了扩张能力。通过嵌合体和绝对细胞数观察到老年HSC的重建缺陷年轻HSCs在老年受体小鼠中并不优于常驻HSCs老年MKP显示出显著的植入、扩增和重建血小板的能力衰老与MKP全基因组表达签名的变化有关。探讨与年龄相关的造血干细胞和巨核系祖细胞(MKP)功能的变化。他们发现，随着年龄的增长，MKPS的体外扩张和体内重建潜力有了意想不到的增长。伴随着这些功能变化的是年轻和老年MKP之间的转录组差异，这表明祖细胞机制有助于造血衰老。
Age-related morbidity is associated with a decline in hematopoietic stem cell (HSC) function, but the mechanisms of HSC aging remain unclear. We performed heterochronic HSC transplants followed by quantitative analysis of cell reconstitution. Although young HSCs outperformed old HSCs in young recipients, young HSCs unexpectedly failed to outcompete the old HSCs of aged recipients. Interestingly, despite substantial enrichment of megakaryocyte progenitors (MkPs) in old mice in situ and reported platelet (Plt) priming with age, transplanted old HSCs were deficient in reconstitution of all lineages, including MkPs and Plts. We therefore performed functional analysis of young and old MkPs. Surprisingly, old MkPs displayed unmistakably greater regenerative capacity compared with young MkPs. Transcriptome analysis revealed putative molecular regulators of old MkP expansion. Collectively, these data demonstrated that aging affects HSCs and megakaryopoiesis in fundamentally different ways: whereas old HSCs functionally decline, MkPs gain expansion capacity upon aging. Reconstitution deficit by old HSCs was observed by chimerism and absolute cell numbers Young HSCs did not outcompete resident HSCs in aged recipient mice Old MkPs display remarkable capacity to engraft, expand, and reconstitute platelets Aging is associated with changes in MkP genome-wide expression signatures Poscablo et al. explored age-related changes to hematopoietic stem cell and megakaryocyte progenitor (MkP) function. They found an unexpected gain of in vitro expansion and in vivo reconstitution potential of MkPs upon aging. These functional changes were accompanied by differences in transcriptome profiles between young and old MkPs, suggesting progenitor cell mechanisms contributing to hematopoietic aging.
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影响因子：
16.6
作者：
Grover A;Sanjuan-Pla A;Thongjuea S;Carrelha J;Giustacchini A;Gambardella A;Macaulay I;Mancini E;Luis TC;Mead A;Jacobsen SE;Nerlov C
通讯作者：
Nerlov C
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.8
作者：
DESAUVAGE, FJ;HASS, PE;EATON, DL
通讯作者：
EATON, DL
DOI：
10.1084/jem.20111490
发表时间：
2011-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dykstra B;Olthof S;Schreuder J;Ritsema M;de Haan G
通讯作者：
de Haan G
影响因子：
16.6
作者：
Byrne A;Beaudin AE;Olsen HE;Jain M;Cole C;Palmer T;DuBois RM;Forsberg EC;Akeson M;Vollmers C
通讯作者：
Vollmers C