The Adaptive Remodeling of Stem Cell Niche in Stimulated Bone Marrow Counteracts the Leukemic Niche

Abstract

Accumulating studies have shown the cellular nature of hematopoietic stem cell (HSC) niche in bone marrow (BM) and their degenerative changes under leukemic conditions. However, the dynamic adaptation of niche cells to changes in physiological stimulatory signals remains largely uncharacterized. Here, we have established a niche stimulation model induced by 5-fluorouracil. This model reveals a rapid and reversible conversion of mesenchymal cells into niche-like stromal cells, which exhibit a platelet-derived growth factor receptor-alpha /leptin receptor (PL) phenotype. These cells selectively induce the niche signaling molecule, Jagged-1, but not CXCL12, to initiate a stimulation-induced regeneration of HSCs in a Jagged-1 dependent manner. Conversion of mesenchymal cells into niche-like cells occurred independently of mitotic activation. The conversion was accompanied by the acquisition of primitive mesenchymal cell characteristics, including the rapid induction of stage specific embryonic antigen-3 and the acquisition of clonogenic potential. The stimulation-induced remodeling of the BM niche resulted in a positive stimulatory effect on the regeneration of normal HSC, but exerted inhibitory effects on leukemic cells, leading to a competitive advantage for normal HSCs in the BM niche and prolonged survival of mice engrafted with leukemic cells. Thus, the reactive conversion of mesenchymal stroma into niche-like cells reveals the adaptive changes of the BM microenvironment to stimuli, and provides insight on the remodeling of niche toward pronormal/antileukemic microenvironment, which can counteract the progressive proleukemic changes driven by the leukemic niche. Our study raises the potential for antileukemic niche targeting therapy. Stem Cells 2018;36:1617-1629.

Adult bone marrow progenitors become decidual cells and contribute to embryo implantation and pregnancy

“…Following our observations that adult BMDCs give rise to stromal decidual cells in our BMT model, we wished to investigate whether GFP + BM MSCs, the putative source of BM-derived DSCs, are reconstituted in BM of the transplanted mice following our non-gonadotoxic 5-FU–based submyeloablation protocol. Irradiation has been shown to be associated with severe and permanent damage of BM stromal cells, limiting engraftment of transplanted hematopoietic stem cells (HSCs) and MSCs [36], while 5-FU preconditioning results in a transient damage to the BM stromal cell niche, followed by extensive remodeling of MSCs in the BM supporting donor cell engraftment [37]. For this, we extracted BM from mice that underwent BMT from GFP donor according to our model.…”

CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners

“…Using this strategy, we demonstrated that the increased susceptibility of Cables1 −/− mice to 5-FU is mainly dependent on the BM microenvironment. Indeed, 5-FU not only acts on HSCs but also on niche cells that become stimulated, thus inducing a stimulating effect on HSCs (Jeong et al., 2018). Our hypothesis is supported by our results showing that niche cells, including MSCs, express high levels of CABLES1 mRNA and protein.…”

“…One potential mechanism could be stress- or age-associated decreases in the adhesion potential of Cables1 −/− MSCs (Rhee et al., 2007). The use of in vitro and in vivo models as described recently will help to more deeply understand how CABLES1 regulates the dynamic adaptation of niche cells to replicative stress and how this adaptation influences the regeneration of HSCs (Jeong et al., 2018).…”

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

“…In an in vivo study, mouse BM was transduced with constructs expressing p190 or p210 and injected into tail vein of irradiated, recipient mice. In one group donor BM was primed with 5-fluorouracil prior to harvest, which has been shown to stimulate HSCs and its niche [69]. Injection of primed BM caused development of CML-like disease in both p190 and p210 injected mice, but introduction of non-primed cells caused significantly different diseases.…”