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  • Some of the key aspects of the myofibroblasts biology

    2022-06-13

    Some of the key aspects of the myofibroblasts’ biology, including their signaling sensitivity and residual regenerative potential, are shaped by their origin. In this respect, lineage studies on myofibroblast precursors are critical for increasing our understanding of the natural history of fibrosis and its potential treatment avenues. In this issue of Cell Stem Cell, Schneider et al. (2017) report that mesenchymal stromal SB 204990 mg (MSCs) are the major contributors toward myofibroblasts in diseased bone marrow. These fibrotic progenitors can be faithfully traced and therapeutically targeted on the basis of their expression and activity of Gli1, a transcriptional activator of the Hedgehog signaling pathway. By coupling an established mouse model for bone marrow fibrosis with a Gli1-specific genetic tracing tool, the authors show that Gli1+ MSCs give rise to approximately half of all contractile myofibroblasts. Furthermore, selective depletion of genetically marked Gli1+ cells with diphtheria toxin largely halts the progression of bone marrow fibrosis and preserves its major functions, including near-normal hemoglobin output levels. Expression profiling suggests a heterogeneous composition of the Gli1+ pool of cells, with two-thirds of them localizing near the bone surface of the marrow and the remainder in the perivascular space, along the length of arteriolar and sinusoid vessels. What is the lineage identity of Gli1+ MSCs under physiological conditions? A diverse constellation of mesenchymal cell types falls under the umbrella of bone marrow MSCs. Principal MSCs reside on arteriolar and sinusoid vessels, and in both locations they express distinct sets of markers and are associated with quiescent and activated hematopoietic stem cells, respectively. Perivascular MSCs also give rise to osteoprogenitors that relocate toward the bone surface of the marrow and generate mature osteoblasts. Other MSC derivatives include CAR cells, adipogenic precursors, and their differentiated progenies. Curiously, ablation of Gli1+ cells in the normal bone marrow does not lead to noticeable alterations in hematopoiesis (Schneider et al., 2017). This is intriguing and contrasts with the results of perivascular Nestin+ MSC depletion, which leads to a notable reduction in the marrow’s hematopoietic stem cells (Méndez-Ferrer et al., 2010). Thus, on the basis of their marker profile, their distribution within the bone marrow, and their apparent dispensability for normal hematopoietic stem cells, scar-prone Gli1+ cells appear to encompass a spectrum of mesenchymal cell types. This spectrum ranges from some, but not all, perivascular MSCs to many bone-lining cells, including osteoprogenitors and possibly CAR cells, and even adipogenic precursors (Figure 1). Consistent with the latter possibility, adiponectin, an adipose-specific hormone, is one of the top differentially downregulated genes in Gli1+ bone marrow cells upon fibrosis. Is Gli1 more than just a convenient marker for pro-fibrotic bone marrow progenitors? Schneider et al. (2017) showed that Hedgehog pathway signaling is an attractive double-prong therapeutic target in myelofibrosis. Pharmacologically antagonizing Gli proteins using a small-molecule inhibitor significantly reduces the size of both the malignant hematopoietic clone (corroborating previous studies) and the myofibroblast population. Mechanistically, the Gli inhibitor appears to exert its anti-fibrotic activity by inducing apoptosis of Gli1+ progenitors (Figure 1). These findings add to the growing evidence for the therapeutic potential of Hedgehog pathway inhibition in treating tissue fibrosis, including such in the liver, kidney, and lung (reviewed in Hu et al., 2015). Since many mesenchymal cell types in different organs readily respond to Hedgehog signaling, its inhibition might represent a broadly applicable, emerging anti-scarring strategy. However, caution should be exercised given that cellular targets and downstream effects of Hedgehog pathway are versatile, and in some instances, such as in the heart attack model (Kusano et al., 2005), activation rather than suppression of Hedgehog signaling limits the extent of fibrosis by enhancing heart muscle cell survival at the sites of injury. In the future, cell-type-specific targeting of Hedgehog pathway components will help to minimize off-target effects.