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.

Keywords: Bone marrow; Hematopoietic stem cell; Leukemia; Microenvironment.