Caspase-3/NLRP3 signaling in the mesenchymal stromal niche regulates myeloid-biased hematopoiesis.
Caspase-3/NLRP3 signaling in the mesenchymal stromal niche regulates myeloid-biased hematopoiesis.
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间充质基质微环境中的 Caspase-3/NLRP3 信号传导调节骨髓偏向的造血作用。
DOI：
10.1186/s13287-021-02640-y
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发表时间：
2021-11-20
影响因子：
7.5
通讯作者：
Hu X
中科院分区：
文献类型：
--
作者：
Zhang J;Chen Y;Yin D;Feng F;An Q;Liu Z;An N;Xu J;Yi J;Gu S;Yin W;Wang Y;Hu X
造血干细胞（HSC）的命运是由一个复杂的调控网络，包括内在和外在的信号。在过去的几十年里，许多内在的关键分子的造血干细胞已被证明是控制造血稳态。非造血小生境细胞也有助于HSC的自我更新、静止和分化。间充质基质细胞（MSC）已被确定为生态位的重要组成部分。然而，MSC在造血中的调节作用尚未完全了解。分别建立Caspase-3和NLRP 3基因敲除小鼠模型，通过流式细胞术、集落形成试验和骨髓移植评价外周血和骨髓造血发育。然后从基因敲除小鼠中分离骨相关MSC（BA-MSC），并在体内和离体探索Caspase-3/NLRP 3缺陷的BA-MSC对造血调节的影响。我们报告，Caspase-3缺陷小鼠表现出增加骨髓造血和异常的HSC池。BA-MSC中Caspase-3的消融通过改变造血保留细胞因子（包括SCF和CXCL 12）的表达来调节骨髓谱系扩增。有趣的是，NLRP 3基因敲除小鼠与Caspase-3缺陷小鼠具有表型相似性。此外，我们发现NLRP 3可能通过影响造血祖细胞的细胞周期和凋亡在骨髓发育中发挥作用。我们的数据表明，Caspase-3/NLRP 3信号作为一个重要的调节生理造血功能，这提供了新的见解有关的利基信号，影响骨髓造血调控。在线版本包含补充材料，可通过10.1186/s13287-021-02640-y获得。
The fate of hematopoietic stem cells (HSCs) is determined by a complex regulatory network that includes both intrinsic and extrinsic signals. In the past decades, many intrinsic key molecules of HSCs have been shown to control hematopoiesis homeostasis. Non-hematopoietic niche cells also contribute to the self-renewal, quiescence, and differentiation of HSCs. Mesenchymal stromal cells (MSCs) have been identified as important components of the niche. However, the regulatory role of MSCs in hematopoiesis has not been fully understood. Caspase-3 and NLRP3 gene knockout mice were generated respectively, and hematopoietic development was evaluated in the peripheral circulation and bone marrow by flow cytometry, colony formation assay, and bone marrow transplantation. Bone-associated MSCs (BA-MSCs) were then isolated from gene knockout mice, and the effect of Caspase-3/NLRP3 deficient BA-MSCs on hematopoiesis regulation was explored in vivo and ex vivo. We report that Caspase-3 deficient mice exhibit increased myelopoiesis and an aberrant HSC pool. Ablation of Caspase-3 in BA-MSCs regulates myeloid lineage expansion by altering the expression of hematopoietic retention cytokines, including SCF and CXCL12. Interestingly, NLRP3 gene knockout mice share phenotypic similarities with Caspase-3 deficient mice. Additionally, we found that NLRP3 may play a role in myeloid development by affecting the cell cycle and apoptosis of hematopoietic progenitors. Our data demonstrate that the Caspase-3/NLRP3 signaling functions as an important regulator in physiological hematopoiesis, which provides new insights regarding niche signals that influence hematopoiesis regulation in the bone marrow. The online version contains supplementary material available at 10.1186/s13287-021-02640-y.
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影响因子：
21.3
作者：
Asada N;Kunisaki Y;Pierce H;Wang Z;Fernandez NF;Birbrair A;Ma'ayan A;Frenette PS
通讯作者：
Frenette PS
影响因子：
32.4
作者：
Omatsu, Yoshiki;Sugiyama, Tatsuki;Nagasawa, Takashi
通讯作者：
Nagasawa, Takashi
影响因子：
30.8
作者：
Paugh, Steven W.;Bonten, Erik J.;Savic, Daniel;Ramsey, Laura B.;Thierfelder, William E.;Gurung, Prajwal;Malireddi, R. K. Subbarao;Actis, Marcelo;Mayasundari, Anand;Min, Jaeki;Coss, David R.;Laudermilk, Lucas T.;Panetta, John C.;McCorkle, J. Robert;Fan, Yiping;Crews, Kristine R.;Stocco, Gabriele;Wilkinson, Mark R.;Ferreira, Antonio M.;Cheng, Cheng;Yang, Wenjian;Karol, Seth E.;Fernandez, Christian A.;Diouf, Barthelemy;Smith, Colton;Hicks, J. Kevin;Zanut, Alessandra;Giordanengo, Audrey;Crona, Daniel;Bianchi, Joy J.;Holmfeldt, Linda;Mullighan, Charles G.;den Boer, Monique L.;Pieters, Rob;Jeha, Sima;Dunwell, Thomas L.;Latif, Farida;Bhojwani, Deepa;Carroll, William L.;Pui, Ching-Hon;Myers, Richard M.;Guy, R. Kiplin;Kanneganti, Thirumala-Devi;Relling, Mary V.;Evans, William E.
通讯作者：
Evans, William E.
影响因子：
5.6
作者：
Kilroy, Gail E.;Foster, Sandra J.;Gimble, Jeffrey M.
通讯作者：
Gimble, Jeffrey M.
影响因子：
15.9
作者：
Miura, M;Chen, XD;Shi, ST
通讯作者：
Shi, ST