Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Stem Cell Res Ther. 2021 Nov 20;12(1):579. doi: 10.1186/s13287-021-02640-y.
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.
造血干细胞（HSCs）的命运由一个复杂的调控网络决定，包括内在和外在信号。在过去的几十年中，许多 HSCs 的内在关键分子已被证明可以控制造血稳态。非造血龛细胞也有助于 HSCs 的自我更新、静止和分化。间充质基质细胞（MSCs）已被确定为龛的重要组成部分。然而，MSCs 在造血中的调节作用尚未完全理解。
分别生成 Caspase-3 和 NLRP3 基因敲除小鼠，并通过流式细胞术、集落形成实验和骨髓移植评估外周循环和骨髓中的造血发育。然后从基因敲除小鼠中分离出与骨相关的 MSCs（BA-MSCs），并在体内和体外探索 Caspase-3/NLRP3 缺陷的 BA-MSCs 对造血调节的影响。
我们报告 Caspase-3 缺陷小鼠表现出增加的髓系生成和异常的 HSC 池。BA-MSCs 中 Caspase-3 的缺失通过改变造血保留细胞因子（包括 SCF 和 CXCL12）的表达来调节髓系细胞的扩增。有趣的是，NLRP3 基因敲除小鼠与 Caspase-3 缺陷小鼠具有相似的表型。此外，我们发现 NLRP3 可能通过影响造血祖细胞的细胞周期和凋亡来影响髓系发育。
我们的数据表明 Caspase-3/NLRP3 信号作为生理造血中的一个重要调节剂发挥作用，这为影响骨髓中造血调节的龛信号提供了新的见解。
