Caspase-3/NLRP3 Signaling in the Mesenchymal Stromal Niche Regulates Myeloid-biased Hematopoiesis

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2021 Nov 21

PMID 34801085

Citations 8

Authors

Jing Zhang

Yaozhen Chen

Dandan Yin

Fan Feng

Qunxing An

Zhixin Liu

Ning An

Jinmei Xu

Jing Yi

Shunli Gu

Wen Yin

Yazhou Wang

Xingbin Hu

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Citing Articles

Inflammasomes: potential therapeutic targets in hematopoietic stem cell transplantation.

Luo J, Zhou Y, Wang M, Zhang J, Jiang E Cell Commun Signal. 2024; 22(1):596.

PMID: 39695742 PMC: 11657697. DOI: 10.1186/s12964-024-01974-3.

Loss of PADI2 and PADI4 ameliorates sepsis-induced acute lung injury by suppressing NLRP3+ macrophages.

Yu X, Song Y, Dong T, Ouyang W, Shao L, Quan C JCI Insight. 2024; 9(22).

PMID: 39405117 PMC: 11601939. DOI: 10.1172/jci.insight.181686.

Clodronate liposomes may biases MSC differentiation toward adipogenesis through activation of NLRP3.

Ding S, Wang Y, Liu Z, Du Y, Zhou Y, Liu Y Regen Ther. 2023; 24:54-63.

PMID: 37868719 PMC: 10584668. DOI: 10.1016/j.reth.2023.05.001.

NLRP3 inflammasome inhibition of OP9 cells enhance therapy for inflammatory bowel disease.

Chen Y, Meng W, Ren G, An N, Zhang J, Liu Z Heliyon. 2023; 9(7):e18038.

PMID: 37483815 PMC: 10362138. DOI: 10.1016/j.heliyon.2023.e18038.

Mechanism of NLRP3 inflammasome intervention for synovitis in knee osteoarthritis: A review of TCM intervention.

Han X, Lin D, Huang W, Li D, Li N, Xie X Front Genet. 2023; 14:1159167.

PMID: 37065495 PMC: 10090545. DOI: 10.3389/fgene.2023.1159167.

References

Kaushansky K, Zhan H . The marrow stem cell niche in normal and malignant hematopoiesis. Ann N Y Acad Sci. 2019; 1466(1):17-23. PMC: 6814507. DOI: 10.1111/nyas.14028. View

Paugh S, Bonten E, Savic D, Ramsey L, Thierfelder W, Gurung P . NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nat Genet. 2015; 47(6):607-14. PMC: 4449308. DOI: 10.1038/ng.3283. View

Morrison S, Scadden D . The bone marrow niche for haematopoietic stem cells. Nature. 2014; 505(7483):327-34. PMC: 4514480. DOI: 10.1038/nature12984. View

Hurwitz S, Jung S, Kurre P . Hematopoietic stem and progenitor cell signaling in the niche. Leukemia. 2020; 34(12):3136-3148. DOI: 10.1038/s41375-020-01062-8. View

Anthony B, Link D . Regulation of hematopoietic stem cells by bone marrow stromal cells. Trends Immunol. 2013; 35(1):32-7. PMC: 3947365. DOI: 10.1016/j.it.2013.10.002. View

Fajardo-Orduna G, Mayani H, Montesinos J . Hematopoietic Support Capacity of Mesenchymal Stem Cells: Biology and Clinical Potential. Arch Med Res. 2015; 46(8):589-96. DOI: 10.1016/j.arcmed.2015.10.001. View

Sanchez-Aguilera A, Mendez-Ferrer S . The hematopoietic stem-cell niche in health and leukemia. Cell Mol Life Sci. 2016; 74(4):579-590. PMC: 5272896. DOI: 10.1007/s00018-016-2306-y. View

Kuida K, Zheng T, Na S, Kuan C, Yang D, Karasuyama H . Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature. 1996; 384(6607):368-72. DOI: 10.1038/384368a0. View

Crane G, Jeffery E, Morrison S . Adult haematopoietic stem cell niches. Nat Rev Immunol. 2017; 17(9):573-590. DOI: 10.1038/nri.2017.53. View

10.

Lu Y, Xu S, Chen H, He M, Deng Y, Cao Z . CdSe/ZnS quantum dots induce hepatocyte pyroptosis and liver inflammation via NLRP3 inflammasome activation. Biomaterials. 2016; 90:27-39. DOI: 10.1016/j.biomaterials.2016.03.003. View

11.

Kelley N, Jeltema D, Duan Y, He Y . The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int J Mol Sci. 2019; 20(13). PMC: 6651423. DOI: 10.3390/ijms20133328. View

12.

Basiorka A, McGraw K, Eksioglu E, Chen X, Johnson J, Zhang L . The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016; 128(25):2960-2975. PMC: 5179338. DOI: 10.1182/blood-2016-07-730556. View

13.

Wang Y, Gao W, Shi X, Ding J, Liu W, He H . Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017; 547(7661):99-103. DOI: 10.1038/nature22393. View

14.

Liu D, Kou X, Chen C, Liu S, Liu Y, Yu W . Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors. Cell Res. 2018; 28(9):918-933. PMC: 6123409. DOI: 10.1038/s41422-018-0070-2. View

15.

Carlile G, Smith D, Wiedmann M . Caspase-3 has a nonapoptotic function in erythroid maturation. Blood. 2004; 103(11):4310-6. DOI: 10.1182/blood-2003-09-3362. View

16.

Chen Y, Qin X, An Q, Yi J, Feng F, Yin D . Mesenchymal Stromal Cells Directly Promote Inflammation by Canonical NLRP3 and Non-canonical Caspase-11 Inflammasomes. EBioMedicine. 2018; 32:31-42. PMC: 6020748. DOI: 10.1016/j.ebiom.2018.05.023. View

17.

Chen H, Yang D, Han F, Tan J, Zhang L, Xiao J . The Bacterial T6SS Effector EvpP Prevents NLRP3 Inflammasome Activation by Inhibiting the Ca-Dependent MAPK-Jnk Pathway. Cell Host Microbe. 2017; 21(1):47-58. DOI: 10.1016/j.chom.2016.12.004. View

18.

Zhang Y, Gao S, Xia J, Liu F . Hematopoietic Hierarchy - An Updated Roadmap. Trends Cell Biol. 2018; 28(12):976-986. DOI: 10.1016/j.tcb.2018.06.001. View

19.

Schroder K, Tschopp J . The inflammasomes. Cell. 2010; 140(6):821-32. DOI: 10.1016/j.cell.2010.01.040. View

20.

Boettcher S, Manz M . Regulation of Inflammation- and Infection-Driven Hematopoiesis. Trends Immunol. 2017; 38(5):345-357. DOI: 10.1016/j.it.2017.01.004. View