Abstract
BackgroundConsiderable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear.MethodsWe established an oncogenic N-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry.ResultsThe MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in our N-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs.ConclusionsChemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.
Highlights
Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche
We demonstrated that a chemotherapy-induced niche shielding residual B-cell acute lymphoblastic leukemia (B-ALL) cells can be rebuilt by recruiting BM cells via cytokines secreted from B-ALL cells after chemotherapy [15]
(See figure on previous page.) Fig. 2 Chemotherapy-induced mesenchymal stem cells (MSCs) are prone to differentiate into adipocytes and chondrocytes. a Osteogenic differentiation of MSCs derived from Ctrl+A2D and B-ALL+A2D by Alizarin Red S staining. b Statistical summary of osteoblast number per field in (a). c The osteoblastic differentiation markers (Gpnmb, Ogn and Sp7) were evaluated by qRT-PCR. d Chondrogenic differentiation of MSCs derived from Ctrl+A2D and B-ALL+A2D by Toluidine Blue staining. e Statistical summary of chondrogenic cell number per field in (d). f The chondrogenic differentiation markers (Acan and Col11a2) were evaluated by qRT-PCR. g Adipogenic differentiation of MSCs derived from Ctrl+A2D and B-ALL+A2D by Oil Red staining. h Statistical summary of adipogenic cell number per field in (g). i The chondrogenic differentiation markers (Cfd) were evaluated by qRT-PCR
Summary
Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. We demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. The roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear. Hematopoiesis is a continuous process of orchestrated proliferation, self-renewal, and differentiation of hematopoietic stem cells (HSCs) in the bone marrow (BM) and followed by the egress of mature progeny into the circulating blood [1, 2]. The several genetic studies have provided mechanistic insights into the functions of BM niche cells, mainly MSCs, in the regulation of hematopoiesis during homeostasis [10, 11], the effects of BM niche after stress or injury (such as chemotherapy) on HSCs remains unclear. Patients that have received several rounds of chemotherapy frequently show irreversible chronic bone marrow damage that often leads to impaired hematopoietic reserve and function [6]
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