J Pathol. 2018 Mar 23. doi: 10.1002/path.5078. [Epub ahead of print]

Understanding deregulated cellular and molecular dynamics in the hematopoietic stem cell niche to develop novel therapeutics in bone marrow fibrosis.

Gleitz HFE¹, Kramann R², Schneider RK^1,3.

Abstract

Bone marrow fibrosis is the continuous replacement of blood forming cells in the bone marrow by excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Myofibroblasts are fibrosis-driving cells and well characterized in solid organ fibrosis but their role and cellular origin in bone marrow fibrosis has remained obscure. Recent work has demonstrated that Gli1⁺ and Leptin Receptor⁺ mesenchymal stromal cells are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation or pharmacologic inhibition of Gli1⁺ mesenchymal stromal cells ameliorated fibrosis in mouse models of myelofibrosis. Conditional deletion of the platelet-derived growth factor receptor alpha gene (Pdgfra) and inhibition of PDGFR by imatinib in Leptin Receptor⁺ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Understanding the cellular and molecular mechanisms in the hematopoietic stem cell niche that govern the mesenchymal stromal cell-to-myofibroblast transition and myofibroblast expansion will be critical to understand the pathogenesis of bone marrow fibrosis in both malignant and non-malignant conditions and will guide the development of novel therapeutics. In this review, we summarize recent discoveries of mesenchymal stromal cells as part of the hematopoietic niche and as myofibroblast precursors and discuss potential therapeutic strategies in the specific targeting of fibrotic transformation in bone marrow fibrosis.