Caspase-3/NLRP3 signaling in the mesenchymal stromal niche regulates myeloid-biased hematopoiesis

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.

Bone Marrow Niches and Tumour Cells: Lights and Shadows of a Mutual Relationship

“…A plethora of supportive factors are provided in the niches (Table 1). Recent evidence showed that the key niche factors SCF and CXCL12 can be modulated by the Caspase3/NLRP3 signaling, which extends understanding of regulatory mechanisms influencing haematopoiesis (40). Of note, the same molecular cue presented by diverse cells in BM niches may serve different functions in each compartment.…”

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

“…The NLRP3 inflammasome pathway belongs to the classical inflammasome pyroptosis pathway (Caspase-1 mediated). In addition, there are non-classical inflammasome pyroptosis pathways (Caspase-4, Caspase-5, Caspase-11 mediated) and apoptotic protein Caspase-3 mediated pyroptosis pathway ( Moretti et al, 2022 ; Fu et al, 2021 ; Zhang et al, 2021b ). The role of NLRP3 inflammasome for synovitis in KOA is a hot topic in recent years, many studies have shown that NLRP3 inflammasome is a potential mechanism of synovitis in KOA, but it needs to be further studied.…”

Platelet-Derived Mitochondria Attenuate 5-FU-Induced Injury to Bone-Associated Mesenchymal Stem Cells

“…The chemotherapy-caused injury of MSCs affects immune reconstitution and hematopoietic function recovery of donor HSCs in the host hematopoietic microenvironment after HSC transplantation [ 20 ]. Bone-associated mesenchymal stem cells (BA-MSCs), which are derived from the endosteum, are an essential component for the formation and maintenance of the hematopoietic microenvironment and play an important role in the regulation and support of hematopoietic activity [ 21 , 22 ]. Therefore, an in-depth study of the mechanism of BA-MSC injury caused by chemotherapy is crucial to improve the success rate of clinical HSC transplantation, promote immune reconstitution, and reduce the risk of postoperative infection.…”