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

Abstract

After publication of our paper, we noticed that one image demonstrating the perivascular bone marrow niche in healthy Gli1CreER; tdTomato mice (Figure 1B) had previously been used by us in a different paper to also demonstrate the perivascular bone marrow niche in healthy mice. We have therefore replaced the image, in the corrected figure below, with a different picture showing a similar perivascular localization of Gli1 cells in bone marrow homeostasis. This correction does not change any conclusions from our manuscript as both images represent the perivascular localization of Gli1 + cells in healthy murine bone marrow. We apologize for this error.

Periosteal Mesenchymal Progenitor Dysfunction and Extraskeletally-Derived Fibrosis Contribute to Atrophic Fracture Nonunion

“…Recently, studies showed that residential Gli1 þ cells are the source of injury-induced fibrosis in multiple organs, including kidney, liver, lung, heart, and bone marrow. (20,21) Interestingly, we found that the Gli1-CreER-labeled interstitial cells in bone-neighboring muscle are morphologically similar to fibro/adipogenic progenitors (FAPs) cells, another type of residential MSCs responsible for muscle fibrosis (37) (data not shown). Considering the close proximity of muscle to cortical bone, we speculate that one possible source of fibrosis in fracture nonunion could be muscle Gli1 þ /FAP cells.…”

“…Recent studies identified Gli1 as a faithful marker for fibrosis-driving mesenchymal stem cells in solid organs and bone marrow. (20,21) Therefore, it is likely that the fibrous cells in fracture nonunions comes from non-skeleton-resident Gli1 þ mesenchymal cells. To test this, we removed a portion of the periosteum at either the proximal or distal side, or both sides of the fracture gap immediately prior to fracture.…”

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].…”

“…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.…”

“…Using genetic fate tracing experiments in two murine models of BM fibrosis, we demonstrated that Gli1 + MSCs are fibrosis-driving cells of the BM (Figure 2). 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.…”