Unique molecular and functional features of extramedullary hematopoietic stem and progenitor cell reservoirs in humans.
Unique molecular and functional features of extramedullary hematopoietic stem and progenitor cell reservoirs in humans.
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DOI：
10.1182/blood.2021013450
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发表时间：
2022-06-09
期刊：
影响因子：
20.3
通讯作者：
Laurenti E
中科院分区：
文献类型：
--
作者：
Mende N;Bastos HP;Santoro A;Mahbubani KT;Ciaurro V;Calderbank EF;Quiroga Londoño M;Sham K;Mantica G;Morishima T;Mitchell E;Lidonnici MR;Meier-Abt F;Hayler D;Jardine L;Curd A;Haniffa M;Ferrari G;Takizawa H;Wilson NK;Göttgens B;Saeb-Parsy K;Frontini M;Laurenti E
骨髓（BM）外的罕见造血干细胞和祖细胞（HSPC）池有助于应激和疾病中的造血，但仍不明确。尽管常规采集非动员外周血（PB）用于临床管理，但PB HSPC的诊断和监测潜力仍未开发，因为尚未报告健康PB HSPC基线。在这里，我们使用单细胞RNA-seq和/或功能测定法，比较脾、PB和动员PB（mPB）与BM，全面描绘人髓外HSPC隔室。我们发现了髓外组织和PB特有的其他组织所共有的HSPC特征。首先，与活跃分裂的BM HSPC相反，我们没有发现在稳态下髓外组织中大量持续造血的证据，但报告了应激红细胞生成期间脾HSPC增殖输出增加。第二，来自脾、PB和mPB的髓外干细胞/多能祖细胞（HSC/MPP）与BM相比共享共同的转录特征和增加的谱系引发的子集丰度。第三，健康的PB HSPC显示出对红系-巨核细胞分化的独特偏好。在HSC/MPP水平，这在功能上由表型CD 71 + HSC/MPP的子集赋予，专门产生红细胞和巨核细胞，在PB中高度丰富，但在其他成人组织中罕见。最后，在原发性血小板增多症和β-地中海贫血中，PB独特的红细胞-巨核细胞-偏斜随年龄而改变。总的来说，我们确定了髓外谱系引发的HSPC水库是非增殖性原位和报告参与脾HSPC在需求适应性造血。我们的数据还确定了循环HSPC的异常组成和功能作为BM功能障碍的潜在临床指标。
Rare hematopoietic stem and progenitor cell (HSPC) pools outside the bone marrow (BM) contribute to blood production in stress and disease but remain ill-defined. Although non-mobilized peripheral blood (PB) is routinely sampled for clinical management, the diagnosis and monitoring potential of PB HSPCs remains untapped, as no healthy PB HSPC baseline has been reported. Here we comprehensively delineate human extramedullary HSPC compartments comparing spleen, PB and mobilized PB (mPB) to BM using single-cell RNA-seq and/or functional assays. We uncover HSPC features shared by extramedullary tissues and others unique to PB. First, in contrast to actively dividing BM HSPCs, we find no evidence of substantial ongoing hematopoiesis in extramedullary tissues at steady state, but report increased splenic HSPC proliferative output during stress erythropoiesis. Second, extramedullary stem cells/multipotent progenitors (HSC/MPPs) from spleen, PB and mPB share a common transcriptional signature and increased abundance of lineage-primed subsets compared to BM. Third, healthy PB HSPCs display a unique bias towards erythroid-megakaryocytic differentiation. At HSC/MPP level, this is functionally imparted by a subset of phenotypic CD71+ HSC/MPPs, exclusively producing erythrocytes and megakaryocytes, highly abundant in PB but rare in other adult tissues. Finally, the unique erythroid-megakaryocytic-skewing of PB is perturbed with age, in essential thrombocythemia and in beta-thalassemia. Collectively, we identify extramedullary lineage-primed HSPC reservoirs that are non-proliferative in situ and report involvement of splenic HSPCs during demand-adapted hematopoiesis. Our data also establish aberrant composition and function of circulating HSPCs as potential clinical indicators of BM dysfunction.
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影响因子：
30.5
作者：
Laurenti E;Doulatov S;Zandi S;Plumb I;Chen J;April C;Fan JB;Dick JE
通讯作者：
Dick JE
影响因子：
64.8
作者：
Inra CN;Zhou BO;Acar M;Murphy MM;Richardson J;Zhao Z;Morrison SJ
通讯作者：
Morrison SJ
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：
23.9
作者：
Florian, Maria Carolina;Doerr, Karin;Niebel, Anja;Daria, Deidre;Schrezenmeier, Hubert;Rojewski, Markus;Filippi, Marie-Dominique;Hasenberg, Anja;Gunzer, Matthias;Scharffetter-Kochanek, Karin;Zheng, Yi;Geiger, Hartmut
通讯作者：
Geiger, Hartmut
影响因子：
2.6
作者：
Hay SB;Ferchen K;Chetal K;Grimes HL;Salomonis N
通讯作者：
Salomonis N