Gli1 + Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target

Abstract

Bone marrow fibrosis (BMF) develops in various hematological and non-hematological conditions and is a central pathological feature of myelofibrosis. Effective cell-targeted therapeutics are needed, but the cellular origin of BMF remains elusive. Here, we show using genetic fate tracing in two murine models of BMF that Gli1 mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1 cells abolished BMF and rescued bone marrow failure. Pharmacological targeting of Gli proteins with GANT61 inhibited Gli1 cell expansion and myofibroblast differentiation and attenuated fibrosis severity. The same pathway is also active in human BMF, and Gli1 expression in BMF significantly correlates with the severity of the disease. In addition, GANT61 treatment reduced the myofibroblastic phenotype of human MSCs isolated from patients with BMF, suggesting that targeting of Gli proteins could be a relevant therapeutic strategy.

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

“…The identification of cells that drive the development of a fibrotic BM niche with its detrimental consequences for the maintenance of HSCs is a prerequisite for the development of novel targeted therapeutics. Two recent studies using state‐of‐the‐art techniques including genetic fate tracing in vivo , including our own work, provided evidence that LepR + and Gli1 + cells are key players in the initiation and progression of BM fibrosis 28, 37. Decker et al demonstrated that BM LepR + mesenchymal stromal lineage cells expand extensively and are fibrogenic in PMF 28.…”

“…We have shown that Gli1 expression is significantly increased in stromal cells from MPN patients (Figure 3). Pharmacological targeting with the Gli inhibitor GANT61 inhibits Gli1 + cell expansion and myofibroblast differentiation, and attenuates fibrosis severity 37. These data thus provide a rationale for targeted therapy of Gli proteins in BM fibrosis, as monotherapy or combined therapy with other agents.…”

“…Periarteriolar Gli1 + cells in the BM have similarities to Nes‐MSCs, but do not express LepR. The majority of Gli1 + cells in the endosteal niche are not associated with glial fibrillary acidic protein + glia or sympathetic nerve fibres, and only partially express Nes 37. Thus, they might represent a distinct subpopulation of stromal cells in the BM.…”

“…They are recruited from their endosteal and perivascular niche in the presence of mutated haematopoietic cells to become α‐smooth muscle actin (α‐SMA) + fibrosis‐driving myofibroblasts 37. Importantly, the genetic ablation of Gli1 + cells completely abolishes BM fibrosis and rescues BM failure, providing functional proof that these cells are drivers of the fibrotic transformation.…”

“…Importantly, the genetic ablation of Gli1 + cells completely abolishes BM fibrosis and rescues BM failure, providing functional proof that these cells are drivers of the fibrotic transformation. Upon myelofibrotic transformation, Gli1 + cells significantly expand in the BM, in both murine models and patient samples, whereas Nes + cells decrease in number, suggesting that neuropathic changes lead to dysregulation of the niche accompanied by enhanced expansion and myofibroblast differentiation of Gli1 + MSCs 37.…”